(2) Patent Application Publication (10) Pub. No.: US 2009/0226500 A1 Avelar Et Al

US 20090226500A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2009/0226500 A1 Avelar et al. (43) Pub. Date: Sep. 10, 2009

(54) SUTURES AND ANTI-SCARRINGAGENTS Related U.S. Application Data (75) Inventors: Rui Avelar, Vancouver (CA); (60) Provisional application No. 60/763,945, filed on Jan. Arpita Maiti, Vancouver (CA); 31, 2006. Philip M. Toleikis, Vancouver (CA); Johanne Diane Cashman, Publication Classification Vancouver (CA); David M. (51) Int. Cl. Gravett, Mountain View, CA (US) A6.1 F 2/04 (2006.01) Correspondence Address: A61 K. 3 1/135 (2006.01) SEED INTELLECTUAL PROPERTY LAW A61R 31/553 (2006.01) GROUP PLLC A61 K 31/496 (2006.01) 701 FIFTHAVENUE, SUITE 5400 A61 K 31/4164 (2006.01) SEATTLE, WA 98104-7092 (US) A61R 31/395 (2006.01) A61 K 37/426 (2006.01) (73) Assignee: Angiotech Pharmaceuticals, Inc, (52) U.S. Cl...... 424/423: 514/649; 514/211.08; Vancouver (CA) 514/254.07: 514/399; 514/183; 514/370 (21) Appl. No.: 12/162,572 (57) ABSTRACT (22) PCT Filed: Jan. 31, 2007 Sutures are used in combination with anti-scarring agents to (86) PCT No.: PCT/US07/02714 inhibit fibrosis between the sutures and the host tissues into which the sutures are inserted. Compositions and methods are § 371 (c)(1), described for use in reducing excessive scarring, surgical (2), (4) Date: May 6, 2009 adhesion, and other disorders. Patent Application Publication Sep. 10, 2009 Sheet 1 of 29 US 2009/0226500 A1

Patent Application Publication Sep. 10, 2009 Sheet 2 of 29 US 2009/0226500 A1

ºs||eoL-AHLKquoqonpoudp-JNLWu018=ºolZ802-14Ke8 Patent Application Publication Sep. 10, 2009 Sheet 3 of 29 US 2009/0226500 A1

IIDI}}{ITUTIII ºr Patent Application Publication Sep. 10, 2009 Sheet 4 of 29 US 2009/0226500 A1

à tºg $3 #4 : >4 3 s Patent Application Publication Sep. 10, 2009 Sheet 5 Of 29 US 2009/0226500 A1

s Patent Application Publication Sep. 10, 2009 Sheet 6 of 29 US 2009/0226500 A1

s I | Patent Application Publication Sep. 10, 2009 Sheet 7 of 29 US 2009/0226500 A1

E. s

3. E. 5 Patent Application Publication Sep. 10, 2009 Sheet 8 of 29 US 2009/0226500 A1

s Patent Application Publication Sep. 10, 2009 Sheet 9 of 29 US 2009/0226500 A1

Patent Application Publication Sep. 10, 2009 Sheet 10 of 29 US 2009/0226500 A1

Patent Application Publication Sep. 10, 2009 Sheet 11 of 29 US 2009/0226500 A1

| | i I. :5 C X — — — = <3 * *

AP– 1

FIG 10B Patent Application Publication Sep. 10, 2009 Sheet 12 of 29 US 2009/0226500 A1

(;-01 x udo) 4Ahoy Iyo Patent Application Publication Sep. 10, 2009 Sheet 13 of 29 US 2009/0226500 A1

SIROMELYSIN

GAPDH

FIG 10D Patent Application Publication Sep. 10, 2009 Sheet 14 of 29 US 2009/0226500 A1

Ly 290181

IL-1 (ng/ml) .0 20 20, 20 20 20 Drug (M) 0 0 10-, 10-4 10-5 10-4

FIG. 1 1A Patent Application Publication Sep. 10, 2009 Sheet 15 of 29 US 2009/0226500 A1

2-Methyl-2,4-Pentanediol (Hexylene Glycol)

cologenase

GAPDH

IL-1 (ng/ml) 0 20 20, 20. 20 Drug (M) 0 0 10-7 10-4 10° 10-4

FIG, 11B Patent Application Publication Sep. 10, 2009 Sheet 16 of 29 US 2009/0226500 A1

Deuterium Oxide 99.90?om?D

Collagenase . * : , ; ; ... .

Patent Application Publication Sep. 10, 2009 Sheet 17 of 29 US 2009/0226500 A1

Glycine Ethyl Ester

Collagenase- - . . . i... -º- *#* • ?: ... iºr.• . . . . - .a?º . . .”"...p. - . ;-- ...... • * ,

wn ºrd ºº L-1 (ng/ml) o 20 20 20 20, 20 Drug (M) 0 0 10-7 10-5 10-5 to

FIG. 1 1D Patent Application Publication Sep. 10, 2009 Sheet 18 of 29 US 2009/0226500 A1

(succinimidylsuccinate)Efhylene Glycol Bis–

Collagenase - : * * * - dºs

?º *** ". . * * * *** * * *ese :

GAPDH tº O s s i. º 1-1 (ºg/ml), D 20 20 20, 20. 20 Drug (M) 0 0 10-7 10-s 10-5 10-4

FIG 11E/ Patent Application Publication Sep. 10, 2009 Sheet 19 of 29 US 2009/0226500 A1

Tubercidin

Il-1 (ng/ml), 9, 20 20, 20, 20 20 Drug (M) 0, 0 (0-1 10-s 10-5 10

FIG 11 F Patent Application Publication Sep. 10, 2009 Sheet 20 of 29 US 2009/0226500 A1

Aluminum Fluoride

Patent Application Publication Sep. 10, 2009 Sheet 21 of 29 US 2009/0226500 A1

Epoihilone B.

. . cologenase º • *

GAPDH

IL-1 (ng/mL) 0 20 20 20 Drug (M) 0 0 10-9 10-7

FIG 11H Patent Application Publication Sep. 10, 2009 Sheet 22 of 29 US 2009/0226500A1

Patent Application Publication Sep. 10, 2009 Sheet 23 of 29 US 2009/0226500 A1

s Patent Application Publication Sep. 10, 2009 Sheet 24 of 29 US 2009/0226500 A1

s Patent Application Publication Sep. 10, 2009 Sheet 25 of 29 US 2009/0226500 A1

3 -- s Patent Application Publication Sep. 10, 2009 Sheet 26 of 29 US 2009/0226500 A1

Patent Application Publication Sep. 10, 2009 Sheet 27 of 29 US 2009/0226500 A1

UIC II/IIIllu º : Patent Application Publication Sep. 10, 2009 Sheet 28 of 29 US 2009/0226500 A1

: i : s i

Jaqun N. Ha3 Patent Application Publication Sep. 10, 2009 Sheet 29 of 29 US 2009/0226500 A1

TGF-B Level in Rat Tissues

7000

6O O O 5000 . 4000 Emplant 3000 . s Sham 2000

1000 .

Shoulder Hip Abdomen Site

FIG. 19 US 2009/0226500 A1 Sep. 10, 2009

SUTURES AND ANTI-SCARRING AGENTS related complications include chronic back or pelvic pain, intestinal obstruction, urethral obstruction and voiding dys BACKGROUND OF THE INVENTION function. Relieving the post-surgical complications caused by adhesions generally requires another surgery. However, [0001] 1. Field of the Invention the subsequent surgery is further complicated by adhesions [0002] The present invention relates generally to pharma formed as a result of the previous surgery. In addition, the ceutical agents and compositions for administration in asso second surgery is likely to result in further adhesions and a ciation with sutures. More specifically, the present invention continuing cycle of additional surgical complications relates to compositions and methods for preparing sutures [0007] Adhesions generally begin to form within the first that inhibits a fibrotic response between the sutures and the several days after surgery Generally, adhesion formation is an tissue in contact with the suture material. inflammatory reaction in which factors are released, increas [0003] 2. Description of the Related Art ing vascular permeability and resulting in fibrinogen influx [0004] Surgical adhesions are abnormal, fibrous bands of and fibrin deposition. This deposition forms a matrix that scar tissue that can form inside the body as a result of the bridges the abutting tissues. Fibroblasts accumulate, attach to healing process that follows any open or minimally invasive the matrix, deposit collagen and induce angiogenesis. If this surgical procedure including abdominal, gynecologic, car cascade of events can be prevented within 4 to 5 days follow diothoracic, spinal, plastic, vascular, ENT, opthalmologic, ing surgery, then adhesion formation may be inhibited. urologic, neuro, or orthopedic surgery. Surgical adhesions are [0008] Various modes of adhesion prevention have been typically connective tissue structures that form between adja examined, including (1) prevention of fibrin deposition, (2) cent injured areas within the body. Briefly, localized areas of reduction of local tissue inflammation and (3) removal of injury trigger an inflammatory and healing response that cul fibrin deposits. Fibrin deposition is prevented through the use minates in healing and scar tissue formation. If scarring of physical barriers that are either mechanical or comprised of results in the formation offibrous tissue bands or adherence of viscous solutions. Barriers have the added advantage of adjacent anatomical structures (that should be separate), sur physically preventing adjacent tissues from contacting each gical adhesion formation is said to have occurred. Adhesions can range from flimsy, easily separable structures to dense, other and thereby reducing the probability that they will scar tenacious fibrous structures that can only be separated by together. Although many investigators and commercial prod surgical dissection. While many adhesions are benign, some ucts utilize adhesion prevention barriers, a number of techni can cause significant clinical problems and are a leading cal difficulties exist and significant failure rates have been cause of repeat surgical intervention. Surgery to breakdown reported. Inflammation is reduced by the administration of adhesions (adhesiolysis) often results in failure and recur drugs such as corticosteroids and non-steroidal anti-inflam rence because the surgical trauma involved in breaking down matory drugs. However, the results from the use of these the adhesion triggers the entire process to repeat itself. Sur drugs in animal models have not been encouraging due to the gical breakdown of adhesions is a significant clinical problem extent of the inflammatory response and dose restriction due and it is estimated that there were 473,000 adhesiolysis pro to systemic side effects. Finally, the removal offibrin deposits cedures in the US in 2002 According to the Diagnosis-Re has been investigated using proteolytic and fibrinolytic lated Groups (DRGs), the total hospital charges for these enzymes. A potential complication to the clinical use of these procedures is likely to be at least US $10 billion annually. enzymes is the possibility for post-surgical excessive bleed [0005] Since all interventions involve a certain degree of ing (surgical hemostasis is critical for procedural success). trauma to the operative tissues, virtually any procedure (no [0009] Accordingly, there is need for developing new pre matter how well executed) has the potential to result in the vention or treatment methods for surgical adhesion. The formation of clinically significant adhesion formation. Adhe present invention fulfils this need and also provides additional sions can be triggered by surgical trauma such as cutting, related advantages. manipulation, retraction or suturing, as well as from inflam mation, infection (e.g., fungal or mycobacterium), bleeding SUMMARY OF THE INVENTION or the presence of a foreign body. Surgical trauma may also [0010] Briefly stated, the present invention provides result from tissue drying, ischemia, or thermal injury. Due to sutures (including plain and self-retaining sutures) that com the diverse etiology of surgical adhesions, the potential for prise an anti-scarring agent, as well as methods for making formation exists regardless of whether the surgery is done in and using such sutures In addition, the present invention also a so-called minimally invasive fashion (e.g., catheter-based provides compositions that comprise anti-scarring agents and therapies, laparoscopy) or in a standard open technique methods for using such compositions in combination with involving one or more relatively large incisions. Although a sutures (including plain and self-retaining sutures) in various potential complication of any surgical intervention, surgical applications (e.g., reducing excessive scarring or surgical adhesions are particularly problematic in GI surgery (causing adhesion). bowel obstruction), gynecological surgery (causing pain and/ [0011] In one aspect, the present invention provides an or infertility), tendon repairs (causing shortening and flexion anti-scarring suture comprising a suture and an anti-scarring deformities), joint capsule procedures (causing capsular con agent. In certain embodiments, the suture is a self-retaining tractures), and nerve and muscle repair procedures (causing suture. In certain embodiments, the anti-scarring suture fur diminished or lost function). ther comprises a polymer, including a polymeric carrier for [0006] Surgical adhesions may cause various, often serious the anti-scarring agent. and unpredictable clinical complications; some of which [0012] In a related aspect, the present invention provides an manifest themselves only years after completion of the origi anti-scarring suture connector comprising a suture connector nal procedure. Complications from surgical adhesions are a and an anti-scarring agent. In another related aspect, the major cause of failed surgical therapy and are the leading present invention provides an anti-scarring suture anchor that cause of bowel obstruction and infertility. Other adhesion comprises a suture and an anti-scarring agent. US 2009/0226500 A1 Sep. 10, 2009

[0013] In another aspect, the present invention provides a [0026] FIG. 8 is a picture that shows an injured carotid method for making an anti-scarring suture comprising: com artery from a rat balloon injury model. bining a suture with an anti-scarring agent or a composition [0027] FIG. 9 is a picture that shows a paclitaxel/mesh comprising an anti-scarring agent. treated carotid artery in a rat balloon injury model (345 pig [0014] In another aspect, the present invention provides a paclitaxel in a 50:50 PLG coating on a 10:90 PLG mesh). method for reducing, or reducing the risk of, excessive scar [0028] FIG. 10A schematically depicts the transcriptional ring, comprising: infiltrating a tissue at which a suture (e.g., a regulation of matrix metalloproteinases. plain suture or a self-retaining suture) has been, is being, or to [0029] FIG. 10B is a blot that demonstrates that IL-1 stimu be implanted with an effective amount of an anti-scarring lates AP-1 transcriptional activity. agent or a composition comprising an anti-scarring agent. [0030] FIG. 10C is a graph that shows that IL-1 induced [0015] In another aspect, the present invention provides a binding activity decreased in lysates from chondrocytes that method for reducing, or reducing the risk of, excessive scar were pretreated with paclitaxel. ring, comprising: implanting an anti-scarring suture provided [0031] FIG. 10D is a blot which shows that IL-1 induction herein into a tissue. increases collagenase and stromelysin in RNA levels in chon [0016] In certain embodiments of the methods for reduc drocytes, and that this induction can be inhibited by pretreat ing, or reducing the risk of, excessive scarring, the excessive ment with paclitaxel. scarring may be at a wound closure site a site of attachment of [0032] FIGS. 11A-H are blots that show the effect of vari a foreign element to a tissue or a site of a tissue repositioning ous anti-microtubule agents in inhibiting collagenase expres surgery In certain embodiments, the excessive scarring S1011. results in a keloid or hypertrophic scarorin surgical adhesion [0033] FIG. 12 is a graph showing the results of a screening [0017] The anti-scarring agent useful in combination with a assay for assessing the effect of paclitaxel on smooth muscle suture according to the present invention may be any anti cell migration (paclitaxel ICso-0.76 nM) scarring agent disclosed herein. In certain embodiments, the [0034] FIG. 13 is a graph showing the results of a screening anti-scarring agent is cerivastatin, terbinafine, radicicol, tri assay for assessing the effect of geldanamycin on IL-13 pro chostatin A, mithramycin A, 5-fluorouracil, doxorubicin, duction by macrophages (ICso-20 nM for IL-13 production mitoxantrone, etoposide, paclitaxel, rapamycin, halofugi by THP-1 cells) none hydrobromide, pitavastatin, or pirarubicin. In certain [0035] FIG. 14 is a graph showing the results of a screening embodiments, the anti-scarring agent inhibits inflammation; assay for assessing the effect of geldanamycin on IL-8 pro collagen production in, or release from, cells; or is an anti duction by macrophages (ICso-27 nM for IL-8 production by infective or antifungal agent. In certain embodiments, the THP-1 cells). anti-scarring agent is an mTOR inhibitor, HMGCoA reduc [0036] FIG. 15 is a graph showing the results of a screening tase inhibitor, DNA intercalator or reversible DNA binder, assay for assessing the effect of geldanamycin on MCP-1 heat shock protein 90 (HSP90) inhibitor, or histone deacety production by macrophages (ICso-7 nM for MCP-1 produc lase (HDAC) inhibitor. In certain embodiments, the anti tion by THP-1 cells). scarring agent is hydrophobic. [0037] FIG. 16 is graph showing the results of a screening [0018] These and other aspects of the present invention will assay for assessing the effect of paclitaxel on proliferation of become evident upon reference to the following detailed smooth muscle cells. description and attached drawings. In addition, various refer [0038] FIG. 17 is graph showing the results of a screening ences are set forth herein which describe in more detail cer assay for assessing the effect of paclitaxel (ICso-134 nM) for tain procedures and/or compositions (e.g., polymers), and are proliferation of the murine RAW264.7 macrophage cell line. therefore incorporated by reference in the entirety. [0039| FIG. 18 is a graph showing the effect of PDGF-BB on smooth muscle cell migration. BRIEF DESCRIPTION OF THE DRAWINGS [0040] FIG. 19 is a graph showing the results of the TGF-3 analysis in silicone disk implanted compared to sham treated [0019] FIG. 1 is a graph showing the results for the screen rats. ing assay for assessing the effect of mitoxantrone on nitric oxide production by macrophages. DETAILED DESCRIPTION OF THE INVENTION [0020) FIG. 2 is a graph showing the results for the screen ing assay for assessing the effect of various therapeutic agents [0041] The present invention provides sutures and self on TNF-alpha production by macrophages. retaining sutures that comprise an anti-scarring agent, as well [0021] FIG. 3 is a graph showing the results for the screen as methods for making and using such sutures. In addition, the ing assay for assessing the effect of rapamycin concentration present invention also provides compositions that comprise for TNFoº production by THP1 cells. anti-scarring agents and methods for using such compositions [0022] FIG. 4 is graph showing the results of a screening in combination with sutures in various applications (e.g., assay for assessing the effect of mitoxantrone (mitoxantrone surgical adhesion). ICso-20 nM) on proliferation of human fibroblasts [0023] FIG. 5 is graph showing the results of a screening DEFINITIONS assay for assessing the effect of rapamycin on cell prolifera [0042] Prior to setting forth the invention, it may be helpful tion of human fibroblasts. to an understanding thereof to first set forth definitions of [0024] FIG. 6 is graph showing the results of a screening certain terms that is used hereinafter. assay for assessing the effect of paclitaxel on cell prolifera [0043]. “Fibrosis,” or “scarring,” or “fibrotic response” tion of human fibroblasts. refers to the formation of fibrous (scar) tissue in response to [0025] FIG. 7 is a picture that shows an uninjured carotid injury or medical intervention. Therapeutic agents which artery from a rat balloon injury model. inhibit fibrosis or scarring are referred to herein as “fibrosis US 2009/0226500 A1 Sep. 10, 2009 inhibiting agents,” “fibrosis-inhibitors,” “anti-scarring repositioning tissue) with superior attachment or without the agents,” “anti-fibrotic agents,” “anti-fibrosis agents,” and the need for tying knots. Retainers may be configured to have like, where these agents inhibit fibrosis through one or more tissue insertion points (such as barbs), tissue insertion edges mechanisms including: inhibiting inflammation or the acute (such as conical or frusto-conical structures), and so forth. inflammatory response, inhibiting migration or proliferation [0054] “One-directional self-retaining suture” (also of connective tissue cells (such as fibroblasts, smooth muscle referred to as “one-directional suture,” “one-way self-retain cells, vascular smooth muscle cells), inhibiting angiogenesis, ing suture,” “one-way suture,” “uni-directional self-retaining reducing extracellular matrix (ECM) production or promot suture,” or “uni-directional suture”) refers to a suture having ing ECM breakdown, and/or inhibiting tissue remodeling. retainers on its exterior surface and facing towards one end of [0044) “Host”, “person”, “subject”, “patient” and the like the suture. Such arrangement of retainers on the suture allows are used synonymously to refer to the living being into which the suture to be drawn in only only one direction through a suture of the present invention is implanted. tissue, but not in the opposite direction. [0045] “Inhibit fibrosis”, “reduce fibrosis”, “inhibits scar [0055] “Two-way self-retaining suture” (also referred to ring” and the like are used synonymously to refer to the action “two-way suture,” “two-directional self-retaining suture.” of agents or compositions which result in a statistically sig “two-directional suture,” “bi-directional self-retaining nificant decrease in the formation offibrous tissue that can be suture,” or “bi-directional suture”) refers to a suture that has expected to occur in the absence of the agent or composition. retainers facing toward one end of the suture for about half the [0046) “Inhibitor” refers to an agent that prevents a biologi suture length and retainers facing the opposite direction cal process from occurring or slows the rate or degree of toward the other end of the suture for the other half of the occurrence of a biological process. The process may be a suture length. This arrangement allows the retainers to move general one such as scarring or refer to a specific biological in the same direction as each respective suture end is inserted action such as, for example, a molecular process resulting in into host tissue. release of a cytokine. [0056] “Localized delivery” refers to administration of a [0047] “Antagonist” refers to an agent that prevents a bio therapeutic agent from a suture or composition into or near a logical process from occurring or slows the rate or degree of tissue in need of the therapeutic agent and provides a high occurrence of a biological process. While the process may be local (regional) concentration of the therapeutic agent at or a general one, typically this refers to a drug mechanism where near the site of suture implantation. In certain aspects, the the drug competes with a molecule for an active molecular anti-scarring agent or composition that comprises the anti site or prevents a molecule from interacting with the molecu scarring agent is released from a suture locally into or in the lar site. In these situations, the effect is that the molecular vicinity of the site where the suture is implanted. In other process is inhibited. aspects, “localized delivery” is achieved by direct contact [0048] “Agonist” refers to an agent that stimulates a bio between the surface of a suture and the surface of the tissue in logical process or rate or degree of occurrence of a biological contact with the suture. process. The process may be a general one such as scarring or [0057]. “Release of an agent from a suture” refers to any refer to a specific biological action such as, for example, a statistically significant dissociation of an agent, or a subcom molecular process resulting in release of a cytokine. ponent thereoffrom a suture. [0049) “Anti-microtubule agents” should be understood to [0058] “Biodegradable” (used interchangeably with include any protein, peptide, chemical, or other molecule that “degradable” or “absorbable”) refers to materials for which impairs the function of microtubules, for example, through the degradation process is at least partially mediated by, or the prevention or stabilization of polymerization. Com performed in, a biological system. “Degradation” refers to a pounds that stabilize polymerization of microtubules are chain scission process by which a polymer chain is cleaved referred to herein as “microtubule stabilizing agents.” A wide into oligomers and monomers. Chain scission may occur variety of methods may be utilized to determine the anti through various mechanisms, including, for example, by microtubule activity of a particular compound, including for chemical reaction (e.g., hydrolysis, oxidation/reduction, example, assays described by Smith et al. (Cancer Lett 7902): enzymatic mechanisms or a combination or these) or by a 213–219, 1994) and Mooberry etal., (Cancer Lett. 96(2):261 thermal or photolytic process. Polymer degradation may be 266, 1995). characterized, for example, using gel permeation chromatog [0050] “Release of an agent” from a suture refers to a sta raphy (GPC), which monitors the polymer molecular mass tistically significant presence of an agent, or a subcomponent changes during erosion and drug release. “Biodegradable” thereof, which has dissociated from a suture that comprises also refers to materials may be degraded by an erosion pro the agent. cess at least partially mediated by, or performed in, a biologi [0051] “Suture” refers to the fine thread or other material cal system. “Erosion” refers to a process in which material is used to join two surfaces or edges together (e.g., closing a lost from the bulk. In the case of a polymeric system, the wound, joining tissues, or performing repositioning proce material may be a monomer, an oligomer, a part of a polymer dures). Sutures include both plain sutures and self-retaining backbone, and/or a part of the polymer bulk. Erosion includes sutures, and may comprise bioabsorbable or nonabsorbable (i) surface erosion, in which erosion affects only the surface material. and not the inner parts of a matrix; and (ii) bulk erosion, in [0052] “Plain suture” refers to a suture without any barbs or which the entire system is rapidly hydrated and polymer other retainers located along the body of the suture. chains are cleaved throughout the matrix. Depending on the [0053]. “Self-retaining suture” refers to a suture with one or type of polymer, erosion generally occurs by one of three more retainers are located along the suture. The retainers are basic mechanisms (see, e.g., Heller, J., CRC Critical Review of sufficient size and appropriate geometry for fastening to, or in Therapeutic Drug Carrier Systems (1984), 1(1), 39-90); gripping, the tissue through which the self-retaining suture is Siepmann, J. et al., Adv. Drug Del Rev. (2001), 48, 229-247): inserted and achieving closure of an incision or wound (or (1) water-soluble polymers that have been insolubilized by US 2009/0226500 A1 Sep. 10, 2009

covalent cross-links and that solubilize as the cross-links or [0064] “Hydrocarbyl” refers to univalent hydrocarbyl radi the backbone undergo a hydrolytic cleavage, enzymatic cals containing 1 to about 30 carbon atoms, preferably 1 to cleavage or a combination of these; (2) polymers that are about 24 carbon atoms, most preferably 1 to about 12 carbon initially water insoluble are solubilized by hydrolysis, enzy atoms, including branched or unbranched, saturated or unsat matic cleavage, ionization, or pronation of a pendant group or urated species, such as alkyl groups, alkenyl groups, aryl a combination of these mechanisms; and (3) hydrophobic groups, and the like. The term “lower hydrocarbyl” intends a polymers are converted to small water-soluble molecules by hydrocarbyl group of one to six carbonatoms, preferably one backbone cleavage. Techniques for characterizing erosion to four carbon atoms. The term “hydrocarbylene” intends a include thermal analysis (e.g., DSC), X-ray diffraction, scan divalent hydrocarbyl moiety containing 1 to about 30 carbon ning electron microscopy (SEM), electron paramagnetic atoms, preferably 1 to about 24 carbon atoms, most prefer resonance (EPR) spectroscopy, NMR imaging, and recording ably 1 to about 12 carbon atoms, including branched or mass loss during an erosion experiment. For microspheres, unbranched, saturated or unsaturated species, or the like. The photon correlation spectroscopy (PCS) and other particles term “lower hydrocarbylene” intends a hydrocarbylene group size measurement techniques may be applied to monitor the of one to six carbon atoms, preferably one to four carbon size evolution of erodible devices versus time. atoms. “Substituted hydrocarbyl” refers to hydrocarbyl sub [0059] Any concentration ranges, percentage range, or stituted with one or more substituent groups, and the terms ratio range recited herein are to be understood to include “heteroatom-containing hydrocarbyl” and “heterohydrocar concentrations, percentages or ratios of any integer within byl” refer to hydrocarbyl in which at least one carbon atom is that range and fractions thereof, such as one tenth and one replaced with a heteroatom. Similarly, “substituted hydrocar hundredth of an integer, unless otherwise indicated Also, any bylene” refers to hydrocarbylene substituted with one or number range recited herein relating to any physical feature, more substituent groups, and the terms “heteroatom-contain such as polymer subunits, size or thickness are to be under ing hydrocarbylene” and “heterohydrocarbylene” refer to stood to include any integer within the recited range, unless hydrocarbylene in which at least one carbon atom is replaced otherwise indicated. It should be understood that the terms with a heteroatom. If not otherwise indicated, “hydrocarbyl” “a” and “an” as used above and elsewhere herein refer to “one indicates both unsubstituted and substituted hydrocarbyls, or more” of the enumerated components. As used herein, the “heteroatom-containing hydrocarbyl” indicates both unsub term “about” means-E15% stituted and substituted heteroatom-containing hydrocarbyls [0060] With regard to nomenclature pertinent to molecular and so forth. structures, the following definitions apply: [0065] By “substituted” as in “substituted hydrocarbyl,” [0061] The term “alkyl” as used herein refers to a branched “substituted alkyl,” and the like, as alluded to in some of the or unbranched saturated hydrocarbon group typically aforementioned definitions, is meant that in the hydrocarbyl, although not necessarily containing 1 to about 24 carbon alkyl, or other moiety, at least one hydrogen atom bound to a atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, carbonatomis replaced with one or more substituents that are isobutyl, t-butyl, octyl, decyl, and the like, as well as functional groups such as alkoxy, hydroxy, halo, nitro, and the cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Unless otherwise indicated, it is to be understood that like. Generally, although again not necessarily, alkyl groups specified molecular segments can be substituted with one or herein contain 1 to about 12 carbon atoms. The term “lower more substituents that do not compromise a compound's util alkyl” intends an alkyl group of one to six carbon atoms, ity. For example, “succinimidyl” is intended to include preferably one to four carbon atoms. “Substituted alkyl” unsubstituted succinimidyl as well as sulfosuccinimidyl and refers to alkyl substituted with one or more substituent other succinimidyl groups substituted on a ring carbon atom, groups. “Alkylene,” “lower alkylene” and “substituted alky e.g., with alkoxy substituents, polyether substituents, or the lene” refer to divalent alkyl, lower alkyl, and substituted alkyl like. groups, respectively. A. Anti-Scarring Agents [0062] The term “aryl” as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single [0066] Numerous anti-scarring agents have been identified aromatic ring (monocyclic) or multiple aromatic rings that that can be used in combination with a suture according to the are fused together, linked covalently, or linked to a common present invention. The agents may be furtherformulated with group such as a methylene or ethylene moiety. The common one or more other materials, such as anothertherapeutic agent linking group may also be a carbonyl as in benzophenone, an (e.g., an anti-infective agent or an anti-inflammatory agent) oxygen atom as in diphenylether, or a nitrogen atom as in and/or a polymeric carrier, which formulations are discussed diphenylamine. Preferred aryl groups contain one aromatic below. ring or two fused or linked aromatic rings, e.g., phenyl, naph [0067] Many suitable anti-scarring agents are specifically thyl, biphenyl, diphenylether, diphenylamine, benzophe identified herein (including those used in the Examples sec none, and the like. “Substituted aryl” refers to an aryl moiety tion), and others, depending on their mechanisms of action, substituted with one or more substituent groups, and the terms may be readily determined based upon one or more in vitro “heteroatom-containing aryl” and “heteroaryl” refer to aryl in and in vivo (animal) models including those provided in the which at least one carbon atom is replaced with a heteroatom. examples and those otherwise known in the art. For example, The terms “arylene” and “substituted arylene” refer to diva anti-scarring agents useful in the present invention include lent aryl and substituted aryl groups as lust defined. those having an ICso value tested according to Example 32 [0063] The term “heteroatom-containing” as in a “heteroa between 0.1 nM and 10 nM, between 10 nM and 100 nM, tom-containing hydrocarbyl group” refers to a molecule or between 100 nM and 600 nM, or between 600 nM and 1200 molecular fragment in which one or more carbon atoms is nM. replaced with an atom other than carbon, e.g., nitrogen, oxy [0068] Anti-scarring agents useful in the present invention gen, sulfur, phosphorus or silicon may inhibit one or more aspect of the fibrosis process. For US 2009/0226500 A1 Sep. 10, 2009 example, in certain embodiments, the anti-scarring agent Oglu?anide disodium (Cytran), BW-114 (Phaminox), Calreti inhibits inflammation; collagen production in, or release culin (NIH), WX-678 (Wilex), SD-7784 (Pfizer), WX-UK1 from, cells; and/or is an anti-infective or antifungal agent. (Wilex), SH-268 (Schering AG), 2-Me-PGA (Celgene), [0069| Exemplary therapeutic compounds that may be use S-137 (Pfizer), ZD-6126 (Angiogene Pharmaceuticals), ful in the invention include, but are not limited to: SG-292 (SignalGen), Benefin (Lane Labs), A6, A36 (Ang [0070) 1. Angiogenesis Inhibitors strom), SB-2723005 (GlaxoSmithKline), SC-7 (Cell Thera [0071] In one embodiment, the pharmacologically active peutics), ZEN-014 (AEterna Zentaris), 2-methoxyestradiol compound is an angiogenesis inhibitor (e.g., 2-ME (NSC (EntreMed), NK-1301.19 (Nippon Kayaku), CC-10004 (Cel 659853), PI-88 (D-mannose, O-6-O-phosphono-alpha-D gene), AVE-8062A (Ajinomoto), Tacedinaline (Pfizer), Acti mannopyranosyl-(1-3)-O-alpha-D-mannopyranosyl-(1-3) nonin (Tokyo Metropolitan Institute of Medical Science), O-alpha-D-mannopyranosyl-(1-3)-O-alpha-D Lenalidomide (Celgene), VGA-1155, BTO-956 (SRI Inter mannopyranosyl-(1-2)-hydrogen sulphate), thalidomide national), ER-68203-00 (Eisai), CT-6685 (UCB), JKC-362 (1H-isoindole-1,3(2H)-dione, 2-(2,6-dioxo-3-piperidinyl)-), (Phoenix Pharmaceuticals), DMI-3798 (DMI Biosciences, CDC-394, CC-5079, ENMD-0995 (S-3-amino-phthalido Angiomate (Ipsen), ZD-6474 (AstraZeneca), CEP-5214 glutarimide), AVE-8062A, vatalanib, SH-268, halofuginone (Cephalon), Canstatin (Genzyme), NM-3 (Mercian), Ori hydrobromide, atiprimod dimaleate (2-azaspivo[4.5|decane digm (MediQuest Therapeutics), Exherin (Adherex), BLS 2-propanamine, N,N-diethyl-8,8-dipropyl, dimaleate), ATN 0597 (Boston Life Sciences), PTC-299 (PTC Therapeutics), 224, CHIR-258, combretastatin A-4 (phenol, 2-methoxy-5 NPI-2358 (Nereus Pharmaceuticals), CGP-79787 (Novartis), [2-(3,4,5-trimethoxyphenyl)ethenyl]-, (Z)-), GCS-100LE, or AEE-788 (Novartis), CKD-732 (Chong Kun Dang), an analogue or derivative thereof). CP-564959 (OSI Pharmaceuticals), CM-101 (CarboMed), [0072] Additional angiogenesis inhibitor include, but are CT-2584, CT3501 (Cell Therapeutics), combretastatin and not limited to, AG-12,958 (Pfizer), ATN-161 (Attenuon analogues and derivatives thereof (such as combretastatin LLC), neovastat, an angiogenesis inhibitor from Jerina AG A-1, A-2, A-3, A-4, A-5, A-6, B-1, B-2, B-3, B-4, D-1, D-2, (Germany), NM-3 (Mercian), VGA-1155 (Taisho), and combretastatin A-4 phosphate (Oxigene)), Rebimastat FCE-26644 (Pfizer), FCE-26950 (Pfizer), FPMA (Meiji (Bristol-Meyers Squibb), Dextrin 2-sulfate (ML Laborato Daries), FR-111142 (Fujisawa), GGTI-298, GM-1306 ries), Cilengitide (Merk KGaA), NSC-706704 (Phaminox) (Ligand), GPA-1734 (Novartis), NNC-47-0011 (Novo Nord KRN-951 (Kirin Brewery), Ukrain, NSC-631570 (Nowicky isk), herbamycin (Nippon Kayaku), lenalidomide (Cele Pharma), Tecogalan sodium (Daiichi Pharmaceutical), Tz-93 gene), IP-10 (NIH), ABT-828 (Abbott), KIN-841 (Tsumura), TBC-1635 (Encysive Pharmaceuticals), (Tokushima University, Japan), SF-1126 (Semafore Pharma TAN-1120 (Takeda), Semaxanib (Pfizer), BDI-7800 (Biop ceuticals), laminin technology (NIH), CHIR-258 (Chiron), harmacopae), SD-186, SD-983 (Bristol-Meyers Squibb), NVP-AEW541 (Novartis), NVP-AEW541 (Novartis), SB-223245 (GlaxoSmithKline), SC-236 (Pfizer), Vt16907 (Alchemia), OXI-8007 (Oxigene), EG-3306 (Ark RWJ-590973 (Johnson and Johnson), ILX-1850 (Genzyme), Therapeutics), Maspin (Arriva), ABT-567 (Abbott), SC-68488, S-836 (Pfizer), CG-55069-11 (CuraGen), PPI-2458 (Praecis Pharmaceuticals), CC-5079, CC-4089 Ki-23057 (Kirin Brewery), CCX-700 (Chemoentryx), (Celgene), HIF-1 alpha inhibitors (Xenova), S-247 (Pfizer), Pegaptanib octasodium (Giled Sciences), or an analogue or AP-23573 (Ariad), AZD-9935 (Astra Zeneca), mebendazole derivative thereof). In other embodiments, the angiogenesis (Introgen Therapeutics), MetAP-2 inhibitors (GlaxoSmith inhibitor may be a recombinant anti-angiogenic compound Kline), AG-615 (Angiogene Pharmaceuticals), Tie-2 antago such as ANGIOCOL (available from Biostratum Inc., nists (Hybrigenics), NC-381, CYC-381, NC-169, NC-219, Durham, N.C.). NC-383, NC-384, NC-407 (Lorus Therapeutics), ATN-224 [0073] 2.5-Lipoxygenase Inhibitors and Antagonists (Attenuon), ON-01370 (Onconova), Vitronectin antagonists [0074] In another embodiment, the pharmacologically (Amgen), SDX-103 (Salmedix), Vitronectin antagonists active compound is a 5-lipoxygenase inhibitor or antagonist (Shire), CHP (Riemser), TEK (Amgen), Anecortave acetate (e.g., Wy-50295 (2-naphthaleneacetic acid, alpha-methyl-6 (Alcon), T46.2 (Matrix Therapeutics), HG-2 (Heptagen). (2-quinolinylmethoxy)-, (S)—), ONO-LP-269 (2,11,14 TEM antagonists (Genzyme), Oxi-4500 (Oxigene), ATN-161 eicosatrienamide, N-(4-hydroxy-2-(1H-tetrazol-5-yl)-8 (Attenuon), WX-293 (Wilex), M-2025 (Metris Therapeu quinolinyl)-, (E,Z,Z)-), licofelone (1H-pyrrolizine-5-acetic tics), Alphastatin (BioActa), YH-16 (Yantai Rongchang), acid, 6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phe BIBF-1120 (Boehringer Ingelheim), BAY-57-9352 (Bayer), nyl-), CMI-568 (urea, N-butyl-N-hydroxy-N'-(4-(3-(methyl AS-1404 (Cancer Research Technology), SC-77964 (Pfizer), sulfonyl)-2-propoxy-5-(tetrahydro-5-(3,4,5-trimethoxyphe glycomimetics (BioTie Therapies), TIE-2 Inhibitors (Onto nyl)-2-furanyl)phenoxy)butyl)-trans-), IP-751 ((3R,4R) gen), DIMI, Octamer (Octamer), ABR-215050 (Active Bio (delta 6)-THC-DMH-11-oic acid), PF-5901 tech), ABT-518 (Abbott), KDR inhibitors (Abbott), BSF (benzenemethanol, alpha-pentyl-3-(2-quinolinylmethoxy)-), 466895 (Abbott), SCH-221153 (Schering-Plough), DAC: LY-293111 (benzoic acid, 2-(3-(3-((5-ethyl-4'-fluoro-2-hy antiangiogenic (Conjuchem), TFPI (EntreMed), AZD-2171 droxy(1,1'-biphenyl)-4-yl)oxy)propoxy)-2-propylphe (Astra-Zenaca), CDC-394 (Celgene), LY290293 (Eli Lilly), noxy)-), RG-5901-A (benzenemethanol, alpha-pentyl-3-(2 IDN-5390 (Indena), Kdr Kinase Inhibitors (Merck), quinolinylmethoxy)-, hydrochloride), rilopirox (201H) CT-113020, CT-116433, CT-116563, CT-31890, CT-32228) pyridinone, 6-((4-(4-chlorophenoxy)phenoxy)methyl)-1 (Cell Therapeutics), A-299620 (Abbott), TWEAK Inhibitor hydroxy-4-methyl-), L-674636 (acetic acid, ((4-(4 (Amgen), VEGF modulators (Johnson and Johnson), Tum chlorophenyl)-1-(4-(2-quinolinylmethoxy)phenyl)butyl) N53, tumstatin (Genzyme), Thios-1, Thios-2 (Thios Pharma thio)-AS)), 7-((3-(4-methoxy-tetrahydro-2H-pyran-4-yl) ceuticals), MV-6401 (Miravant Medical Technologies), phenyl)methoxy)-4-phenylnaphtho(2,3-c)furan-1(3H)-one, Spisulosine (PharmaMar), CEP-7055 (Cephalon), AUV-201 MK-886 (1H-indole-2-propanoic acid, 1-((4-chlorophenyl) (Auvation), LM-609 (Eli Lilly), SKF-106615 (AnorMED), methyl)-3-((1,1-dimethylethyl)thio)-alpha,alpha-dimethyl US 2009/0226500 A1 Sep. 10, 2009

5-(1-methylethyl)-), quiflapon (1H-indole-2-propanoic acid, ers for cancer therapy. U.S. Pat. No. 5,641,764, Jun. 24, 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-al 1997), 1,2,4 benzotriazine oxides (W. W. Lee et al. 1,2,4 pha,alpha-dimethyl-5-(2-quinolinylmethoxy)-), quiflapon benzotriazine oxides as radiosensitizers and selective cyto (1H-Indole-2-propanoic acid, 1-((4-chlorophenyl)methyl) toxic agents. U.S. Pat. No. 5,616,584, Apr. 1, 1997; U.S. Pat. 3-((1,1-dimethylethyl)thio)-alpha,alpha-dimethyl-5-(2 No. 5,624,925, Apr. 29, 1997. Process for Preparing 1,2,4 quinolinylmethoxy)-), docebenone (2,5-cyclohexadiene-1,4 Benzotriazine oxides U.S. Pat. No. 5,175,287. Dec. 29, dione, 2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-), 1992), nitric oxide (J. B. Mitchell et al. Use of Nitric oxide zileuton (urea, N-(1-benzo(b)thien-2-ylethyl)-N-hydroxy-), releasing compounds as hypoxic cell radiation sensitizers or an analogue or derivative thereof). U.S. Pat. No. 5,650,442, Jul. 22, 1997), 2-nitroimidazole [0075] 3. Chemokine Receptor Antagonists CCR (1, 3, and derivatives (M. J. Suto et al. 2-Nitroimidazole derivatives 5) useful as radiosensitizers for hypoxic tumor cells. U.S. Pat. [0076] In another embodiment, the pharmacologically No. 4,797.397, Jan. 10, 1989: T. Suzuki. 2-Nitroimidazole active compound is a chemokine receptor antagonist which derivative, production thereof, and radiosensitizer containing inhibits one or more subtypes of CCR (1, 3, and 5) (e.g., the same as active ingredient U.S. Pat. No. 5,270,330, Dec. ONO-4128 (1,4,9-triazaspiro(5.5)undecane-2,5-dione, 1-bu 14, 1993; T Suzuki et al. 2-Nitroimidazole derivative, pro tyl-3-(cyclohexylmethyl)-9-((2,3-dihydro-1,4-benzodioxin duction thereof, and radiosensitizer containing the same as 6-yl)methyl-), L-381, CT-112 (L-arginine, L-threonyl-L active ingredient. U.S. Pat. No. 5,270,330, Dec. 14, 1993; T. threonyl-L-seryl-L-glutaminyl-L-valyl-L-arginyl-L Suzuki. 2-Nitroimidazole derivative, production thereof and prolyl-), AS-900004, SCH-C, ZK-811752, PD-172084, radiosensitizer containing the same as active ingredient; UK-427857, SB-380732, vMIP II, SB-265610, DPC-168, Patent EP 0513.351 B1, Jan. 24, 1991), fluorine-containing TAK-779 (N,N-dimethyl-N-(4-(2-(4-methylphenyl)-6,7-di nitroazole derivatives (T. Kagiya. Fluorine-containing nitroa hydro-5H-benzocycloheptem-8-ylcarboxamido)benzyl)tet zole derivatives and radiosensitizer comprising the same. U.S. Pat. No. 4,927,941, May 22, 1990), copper (M. J. rahydro-2H-pyran-4-aminium chloride), TAK-220, KRH Abrams. Copper Radiosensitizers. U.S. Pat. No. 5,100,885, 1120), GSK766994, SSR-150106, or an analogue or Mar. 31, 1992), combination modality cancer therapy (D. H. derivative thereof). Other examples of chemokine receptor Picker et al. Combination modality cancer therapy. U.S. Pat. antagonists include a-Immunokine-NNS03, BX-471, CCX No. 4,681,091, Jul. 21, 1987). 5-CldC or (d)Hau or 5-halo 282, Sch-350634; Sch-351125; Sch-417690: SCH-C, and 2'-halo-2'-deoxy-cytidine or -uridine derivatives (S. B. Greer. analogues and derivatives thereof. Method and Materials for sensitizing neoplastic tissue to [0077| 4. Cell Cycle Inhibitors radiation. U.S. Pat. No. 4,894,364 Jan. 16, 1990), platinum [0078] In another embodiment, the pharmacologically complexes (K. A. Skov. Platinum Complexes with one radi active compound is a cell cycle inhibitor. Representative osensitizing ligand. U.S. Pat. No. 4,921,963. May 1, 1990; K. examples of such agents include taxanes (eg. paclitaxel (dis A. Skov. Platinum Complexes with one radiosensitizing cussed in more detail below) and docetaxel) (Schiff et al. ligand. Patent EP 0 287 317 A3), fluorine-containing nitroa Nature 277 665-667, 1979, Long and Fairchild. Cancer zole (T. Kagiya, et al. Fluorine-containing nitroazole deriva Research 54.4355-4361, 1994, Ringel and Horwitz, J Nat’l tives and radiosensitizer comprising the same. U.S. Pat. No. Cancer Inst83(4):288-291, 1991, Pazduret al., Cancer Treat. 4,927,941. May 22, 1990), benzamide (W.W. Lee. Substi Rev. 19(40) 351-386, 1993), etanidazole, nimorazole (B.A. tuted Benzamide Radiosensitizers. U.S. Pat. No. 5,032,617, Chabner and D. L. Longo. Cancer Chemotherapy and Bio Jul. 16, 1991), autobiotics (L. G. Egyud. Autobiotics and the therapy—Principles and Practice. Lippincott-Raven Publish use in eliminating nonself cells in vivo. U.S. Pat. No. 5,147, ers, New York, 1996, p. 554), perfluorochemicals with hyper 652. Sep. 15, 1992), benzamide and nicotinamide (W. W. Lee baric oxygen, transfusion, erythropoietin, BW12C, et al. Benzamide and Nictoinamide Radiosensitizers. U.S. nicotinamide, hydralazine, BSO, WR-2721, ludR, DUdR, Pat. No. 5,215,738, Jun. 1, 1993), acridine-intercalator (M etanidazole, WR-2721, BSO, mono-substituted keto-alde Papadopoulou-Rosenzweig Acridine Intercalator based hyde compounds (L. G. Egyud. Keto-aldehyde-amine addi hypoxia selective cytotoxins. U.S. Pat. No. 5,294,715, Mar. tion products and method of making same. U.S. Pat. No. 15, 1994), fluorine-containing nitroimidazole (T. Kagiya et 4,066,650, Jan. 3, 1978), nitroimidazole (K. C. Agrawal and al. Fluorine containing nitroimidazole compounds. U.S. Pat. M. Sakaguchi. Nitroimidazole radiosensitizers for Hypoxic No. 5,304,654, Apr. 19, 1994), hydroxylated texaphyrins (J. tumor cells and compositions thereof. U.S. Pat. No. 4,462, L. Sessleretal. Hydroxylated texaphrins. U.S. Pat. No. 5,457, 992, Jul. 31, 1984), 5-substituted-4-nitroimidazoles (Adams 183. Oct. 10, 1995), hydroxylated compound derivative (T. et al., Int. J. Radiat. Biol. Relat. Stud. Phys., Chem. Med. Suzuki et al. Heterocyclic compound derivative, production 40(2):153-61, 1981), SR-2508 (Brown et al., Int. J. Radiat. thereof and radiosensitizer and antiviral agent containing said Oncol., Biol. Phys. 7(6):695-703, 1981), 2H-isoindolediones derivative as active ingredient. Publication Number (J. A. Myers, 2H-Isoindolediones, the synthesis and use as 011106775A (Japan), Oct. 22, 1987; T. Suzuki et al. Hetero radiosensitizers. U.S. Pat. No. 4,494,547, Jan. 22, 1985), cyclic compound derivative, production thereof and radiosen chiral (((2-bromoethyl)-amino)methyl)-nitro-1H-imidazole sitizer, antiviral agent and anti cancer agent containing said 1-ethanol (V. G. Beylin, et al., Process for preparing chiral derivative as active ingredient. Publication Number (((2-bromoethyl)-amino)methyl)-nitro-1H-imidazole-1 01139596 A (Japan), Nov. 25, 1987; S. Sakaguchi et al. Het ethanol and related compounds. U.S. Pat. No. 5,543,527, erocyclic compound derivative, its production and radiosen Aug. 6, 1996; U.S. Pat. No. 4,797.397; Jan. 10, 1989; U.S. sitizer containing said derivative as active ingredient; Publi Pat. No. 5,342,959, Aug. 30, 1994), nitroaniline derivatives cation Number 63170375 A (Japan), Jan. 7, 1987), fluorine (W. A. Denny, et al. Nitroaniline derivatives and the use as containing 3-nitro-1,2,4-triazole (T. Kagitani et al. Novel anti-tumor agents. U.S. Pat. No. 5,571,845, Nov. 5, 1996), fluorine-containing 3-nitro-1,2,4-triazole and radiosensitizer DNA-affinic hypoxia selective cytotoxins (M.V. Papadopou containing same compound. Publication Number 02076861 lou-Rosenzweig. DNA-affinic hypoxia selective cytotoxins. A (Japan), Mar. 31, 1988), 5-thiotretrazole derivative or its U.S. Pat. No. 5,602,142, Feb. 11, 1997), halogenated DNA salt (E. Kano et al. Radiosensitizer for Hypoxic cell. Publi ligand (R. F. Martin. Halogenated DNA ligand radiosensitiz cation Number 61010511 A (Japan), Jun. 26, 1984), US 2009/0226500 A1 Sep. 10, 2009

Nitrothiazole (T. Kagitani et al. Radiation-sensitizing agent. mine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Publication Number 61167616 A (Japan) Jan. 22, 1985), Biochem., 26(4):257-67, 1986; Fanetal., Cancer Res.48(11): imidazole derivatives (S. Inayma et al. Imidazole derivative. 3135-9, 1988; Heiger-Bernays et al., Biochemistry 29(36): Publication Number 6203767 A (Japan) Aug. 1, 1985; Pub 8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res. lication Number 62030768A (Japan) Aug. 1, 1985; Publica tion Number 62030777A (Japan) Aug. 1, 1985), 4-nitro-1,2, 12(4):233-40, 1993; Murray et al., Biochemistry 3-triazole (T. Kagitani et al. Radiosensitizer. Publication 31(47): 11812-17, 1992; Takahashi et al., Cancer Chemother. Number 620395.25 A (Japan), Aug. 15, 1985), 3-nitro-1,2,4 Pharmacol. 33(1):31-5, 1993), cis-amine-cyclohexylamine triazole (T. Kagitani et al. Radiosensitizer. Publication Num dichloroplatinum(II) (Yoshida et al., Biochem. Pharmacol. ber 62138427A (Japan), Dec. 12, 1985), Carcinostatic action 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues regulator (H. Amagase. Carcinostatic action regulator. Publi (FR 2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyphe cation Number 63099017 A (Japan), Nov. 21, 1986), 4,5 nyl)ethylenediamine) dichloroplatinum(II) (Bednarski et al., dinitroimidazole derivative (S. Inayama. 4,5-Dinitroimida J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues zole derivative. Publication Number 63310873A (Japan) Jun. containing a tethered dansyl group (Hartwig et al., J. Am. 9, 1987), nitrotriazole Compound (T Kagitanil Nitrotriazole Chem. Soc. 114(21):8292-3, 1992), platinum(II) polyamines Compound Publication Number 07149737A (Japan) Jun. 22, (Siegmann et al., Inorg. Met.-Containing Polym. Mater., 1993), cisplatin, doxorubin, misonidazole, mitomycin, tiri pazamine, nitrosourea, mercaptopurine, methotrexate, fluo (Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990), cis-(3H) rouracil, bleomycin, vincristine, carboplatin, epirubicin, dichloro(ethylenediamine)platinum(II) (Eastman, Anal. Bio doxorubicin, cyclophosphamide, vindesine, etoposide (I. F. chem. 197(2):311-15, 1991), trans-diamminedichloroplati Tannock. Review Article: Treatment of Cancer with Radia num(II) and cis-(Pt(NH3)2(N3-cytosine)C1) (Bellon & tion and Drugs. Journal of Clinical Oncology 14(12):3156 Lippard, Biophys. Chem. 35(2-3):179-88, 1990), 3H-cis-1,2 3174, 1996), camptothecin (Ewend M. G. et al., Local deliv diaminocyclohexanedichloroplatinum(II) and 3H-cis-1,2-di ery of chemotherapy and concurrent external beam aminocyclohexanemalonatoplatinum (II) (Oswald et al., Res. radiotherapy prolongs survival in metastatic brain tumor Commun. Chem. Pathol. Pharmacol. 64(1):41-58, 1989), models. Cancer Research 56(22):5217-5223, 1996) and diaminocarboxylatoplatinum (EPA 296321), trans-(D,1)-1, paclitaxel (Tishler R. B. et al. Taxol: a novel radiation sensi 2-diaminocyclohexane carrier ligand-bearing platinum ana tizer. International Journal of Radiation Oncology and Bio logues (Wyrick & Chaney, J Labelled Compa Radiopharm. logical Physics 22(3):613-617, 1992). 25(4) 349-57, 1988), aminoalkylaminoanthraquinone-de [0079) A number of the above-mentioned cell cycle inhibi rived cisplatin analogues (Kitov et al. Eur J. Med. Chem. tors also have a wide variety of analogues and derivatives, 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and including, but not limited to, cisplatin, cyclophosphamide, JM40 platinum analogues (Schroyen et al., Eur, J. Cancer misonidazole, tiripazamine, nitrosourea, mercaptopurine, Clin. Oncol. 24(8): 1309-12, 1988), bidentate tertiary methotrexate, fluorouracil, epirubicin, doxorubicin, vin diamine-containing cisplatinum derivatives (Orbell et al., desine and etoposide. Analogues and derivatives include Inorg. Chim. Acta 152(2):125-34, 1988), platinum(II), plati (CPA),Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin num(IV) (Liu & Wang, Shandong Yike DaxueXuebao 24(1): (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), 35-41, 1986), cis-diammine(1,1-cyclobutanedicarboxylato-) Cis-(PtCl2(4,7-H-5-methyl-7-oxo) 1,2,4(triazolo(1,5-a)pyri platinum(II) (carboplatin, JM8) and ethylenediammine midine),) (Navarro et al., J. Med. Chem. 41(3):332-338, malonatoplatinum(II) (JM40) (Begg et al., Radiother. Oncol. 1998), (Pt(cis-1,4-DACH)(trans-Cl2)(CBDCA)).9%MeoH 9(2):157-65, 1987), JM8 and JM9 cisplatin analogues (Har cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969 strick et al., Int. J. Androl. 10(1): 139-45, 1987), (NPr4)2 5971, 1997), 4-pyridoxate diammine hydroxy platinum ((PtCL4).cis-(PtCl2-(NH2Me)2) (Brammer et alt, J. Chem. (Tokunaga et al., Pharm. Sci. 3(7):353–356, 1997), Pt(II) . . . Soc., Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic Pt(II) (Pt.2(NHCHN(C(CH2)(CH3)))a) (Navarro et al., Inorg. acid platinum complexes (EPA 185225), cis-dichloro(amino Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue acid) (tert-butylamine)platinum(II) complexes (Pasini & Ber (Koga et al., Neurol. Res. 18(3):244-247, 1996), o-phenylene sanetti, Inorg. Chim. Acta 107(4):259-67, 1985), 4-hydrop diamine ligand bearing cisplatin analogues (Koeckerbauer & eroxycylcophosphamide (Ballard et al., Cancer Chemother Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, Pharmacol. 26(6):397-402, 1990), acyclouridine cyclophos cis-(Pt(OAc), I,(en)) (Kratochwil et al., J. Med. Chem. phamide derivatives (Zakerinia et al., Helv. Chim. Acta 73(4): 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenedi 912-15, 1990), 1,3,2-dioxa- and -oxazaphosphorinane cyclo amine ligand (with sulfur-containing amino acids and glu phosphamide analogues (Yang et al., Tetrahedron 44(20): tathione) bearing cisplatin analogues (Bednarski, J. Inorg. 6305-14, 1988), C5-substituted cyclophosphamide Biochem. 62(1) 75, 1996), cis-1,4-diaminocyclohexane cis analogues (Spada, University of Rhode Island Dissertation, platin analogues (Shamsuddin et al., J. Inorg. Biochem. 61(4) 1987), tetrahydrooxazine cyclophosphamide analogues 29.1-301, 1996), 5' orientational isomer of cis-(Pt(NH3)(4 (Valente, University of Rochester Dissertation, 1988), phenyl aminoTEMP-O){d(GpG)}) (Dunham & Lippard, J. Am. ketone cyclophosphamide analogues (Hales et al., Teratology Chem. Soc 117(43): 10702-12, 1995), chelating diamine 39(1):31-7, 1989), phenylketophosphamide cyclophospha bearing cisplatin analogues (Koeckerbauer & Bednarski, J. mide analogues (Ludeman et al., J. Med. Chem. 29(5):716 Pharm. Sci. 84(7):819-23, 1995), 1,2-diarylethyleneamine 27, 1986), ASTA Z-7557 cyclophosphamide analogues ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. (Evans et al., Int. J. Cancer 34(6):883-90, 1984), 3-(1-oxy-2, Clin. Oncol. 121(1):31-8, 1995), (ethylenediamine)platinum 2,6,6-tetramethyl-4-piperidinyl)cyclophosphamide (Tsui et (II) complexes (Pasini et al., J. Chem. Soc., Dalton Trans. al., J. Med. Chem. 25(9): 1106-10, 1982), 2-oxobis(2-3-chlo 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al., Int. J. roethylamino)-4-,6-dimethyl-1,3,2-oxazaphosphoriname Oncol. 5(3):597–602, 1994), cis-diamminedichloroplatinum cyclophosphamide (Carpenter et al., Phosphorus Sulfur (II) and its analogues cis-1,1-cyclobutanedicarbosylato(2R) 12(3):287-93, 1982), 5-fluoro- and 5-chlorocyclophospha 2-methyl-1,4-butanediam-mineplatinum(II) and cis-diam mide (Foster et al., J. Med. Chem. 24(12) 1399-403, 1981), US 2009/0226500 A1 Sep. 10, 2009 cis- and trans-4-phenylcyclophosphamide (Boyd et al., J Chemother 16:285-70–285-77, 1983), 3'-deamino-3'-hy Med. Chem. 23(4):372-5, 1980). 5-bromocyclophosphamide, droxydoxorubicin (Horton et al., J. Antibiot. 37(8):853-8, 3,5-dehydrocyclophosphamide (Ludeman et al., J. Med. 1984), 4-demethyoxy doxorubicin analogues (Barbieri et al., Chem. 22(2):151-8, 1979), 4-ethoxycarbonyl cyclophospha Drugs Exp. Clin. Res. 10(2):85-90, 1984), N-L-leucyl doxo mide analogues (Foster. J. Pharm. Sci. 67(5):709-10, 1978), rubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. arylaminotetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide Symp. Tumor Pharmacother.), 179-81, 1983), 3'-deamino-3' cyclophosphamide analogues (Hamacher, Arch. Pharm. (4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. Pat. (Weinheim, Ger)310(5).J.428-34, 1977), NSC-26271 cyclo No. 4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin phosphamide analogues (Montgomery & Struck, Cancer derivatives (U.S. Pat. No. 4,301,277), 4'-deoxydoxorubicin Treat. Rep. 60(4); J381-93, 1976), benzo annulated cyclo and 4'-O-methyldoxorubicin (Giuliani et al., Int. J. Cancer phosphamide analogues (Ludeman & Zon, J. Med. Chem. 27(1):5-13, 1981), aglycone doxorubicinderivatives (Chan & 18(12):J1251-3, 1975), 6-trifluoromethylcyclophosphamide Watson, J. Pharm. Sci. 67(12):1748-52, 1978), SM 5887 (Farmer & Cox, J. Med. Chem. 18(11):J 1106-10, 1975), (Pharma Japan 1468:20, 1995), MX-2 (Pharma Japan 1420. 4-methycyclophosphamide and 6-methycyclophosphamide 19, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP analogues (Cox et al., Biochem. Pharmacol. 24(5):J599–606, 275966), morpholinyl doxorubicin derivatives (EPA 1975); FCE 23762 doxorubicin derivative (Quaglia et al., J. 434960), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxoru Liq. Chromatogr. 17(18):3911-3923, 1994), annamycin (Zou bicin derivatives (U.S. Pat. No. 4,314,054), doxorubicin-14 et al., J. Pharm. Sci. 82(11):1151-1154, 1993), ruboxyl valerate, morpholinodoxorubicin (U.S. Pat. No. 5,004,606), (Rapoport et al., J. Controlled Release 58(2):153-162, 1999), 3'-deamino-3'-(3" cyano-4"-morpholinyl doxorubicin; anthracycline disaccharide doxorubicin analogue (Pratesi et 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-dihydroxoru al., Clin. Cancer Res.4(11):2833–2839, 1998), N-(trifluoro bicin, (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubi acetyl)doxorubicin and 4'-O-acetyl-N-(trifluoroacetyl)cioxo cin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihy rubicin (Berube & Lepage, Synth. Commun. 28(6):1109– drodaunorubicin, and 3'-deamino-3'-(4"-morpholinyl-5 1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat’l iminodoxorubicin and derivatives (U.S. Pat. No. 4,585,859), Acad. Sci. U.S.A. 95(4):1794-1799, 1998), disaccharide 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin doxorubicin analogues (Arcamone et al., J. Nat 'l Cancer Inst. derivatives (U.S. Pat. No. 4,314,054) and 3-deamino-3-(4 89(16):1217-1223, 1997), 4-demethoxy-7-O-(2,6-dideoxy morpholinyl) doxorubicin derivatives (U.S. Pat. No. 4,301, 4-O-(2,3,6-trideoxy-3-amino-O-L-lyxo-hexopyranosyl)-O 277); 4,5-dimethylmisonidazole (Bornet al., Biochem. Phar L-lyxo-hexopyranosyl)adriamicinone doxorubicin disaccha macol. 43(6):1337-44, 1992), azo and azoxy misonidazole ride analogue (Monteagudo et al., Carbohydr. Res. 30001): derivatives (Gattavecchia & Tonelli, Int. J. Radiat. Biol. 11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Relat. Stud. Phys., Chem. Med. 45(5):469-77, 1984); Nat’l Acad. Sci. U.S.A. 94(2):652-656, 1997), morpholinyl RB90740 (Wardman et al., Br. J. Cancer, 74 Suppl. (27):S70 doxorubicin analogues (Duran et al., Cancer Chemother. S74, 1996), 6-bromo and 6-chloro-2,3-dihydro-1,4-ben Pharmacol. 38(3):210-216, 1996), enaminomalonyl-[3-ala zothiazines nitrosourea derivatives (Rai et al., Heterocycl. nine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. Commun. 2(6):587-592, 1996), diamino acid nitrosourea 36(9): 1413-16, 1995), cephalosporin doxorubicinderivatives derivatives (Dulude et al., Biocrg. Med. Chem. Lett. 4(22): (Vrudhula et al., J. Med. Chem. 38(3):1380-5, 1995), 2697-700, 1994, Dulude et al., Biocrg. Med. Chem. 3(2):151 hydroxyrubicin (Solary et al., Int. J. Cancer 58(1):85-94, 60, 1995), amino acid nitrosourea derivatives (Zheleva et al., 1994), methoxymorpholino doxorubicin derivative (Kuhl et Pharmazie 50(11):25-6, 1995), 3',4'-didemethoxy-3',4'-di al. Cancer Chemother Pharmacol. 33(1):10-16, 1993), oxo-4-deoxypodophyllotoxin nitrosourea derivatives (Miya (6-maleimidocaproyl)hydrazone doxorubicin derivative hara et al., Heterocycles 39(1):361-9, 1994), ACNU (Matsu (Willner et al., Bioconjugate Chem 4(6):521-7, 1993), N-(5, naga et al., Immunopharmacology 23(3):199-204, 1992), 5-diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J. tertiary phosphine oxide nitrosourea derivatives (Guguva et Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxy al., Pharmazie 46(8):603, 1991), sulfamerizine and sulfame morpholinyl doxorubicin derivative (Ripamonti et al., Br. J. thizole nitrosourea derivatives (Chiang et al., Zhonghua Yao Cancer 65(5):703-7, 1992), N-hydroxysuccinimide ester zue Zazhi 43(5):401-6, 1991), thymidine nitrosourea ana doxorubicin derivatives (Demant et al., Biochim. Biophys. logues (Zhang et al., Cancer Commun. 3(4): 119–26, 1991), Acta 1118(1):83-90, 1991), polydeoxynucleotide doxorubi 1,3-bis(2-chloroethyl)-1-nitrosourea (August et al., Cancer cin derivatives (Ruggiero et al., Biochim. Biophys. Acta 1129 Res. 51(6):1586-90, 1991), 2,2,6,6-tetramethyl-1-oxopip (3):294-302, 1991), morpholinyl doxorubicin derivatives eridiunium nitrosourea derivatives (U.S.S.R. 1261253), 2 (EPA 434960), mitoxantrone doxorubicin analogue and 4-deoxy sugar nitrosourea derivatives (U.S. Pat. No. (Krapcho et al., J. Med. Chem. 34(8):2373-80, 1991), AD198 4,902,791), nitroxyl nitrosourea derivatives (U.S.S.R. doxorubicin analogue (Traganos et al., Cancer Res. 51 (14): 1336489), fotemustine (Boutin et al., Eur, J. Cancer Clin. 3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyldoxorubi Oncol. 25(9): 1311-16, 1989), pyrimidine (II) nitrosourea cin (Horton et al., Drug Des. Delivery 6(2):123-9, 1990), derivatives (Wei et al., Chung-hua Yao Hsuch Tsa Chih 41(1): 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. 19–26, 1989), CGP 6809 (Schieweck et al., Cancer Pharm. 40(2):159-65, 1988; Weenen et al., Eur, J. Cancer Chemother. Pharmacol 23(6) 341-7, 1989), B-3839 (Prajda Clin. Oncol. 2007):919–26, 1984), alkylating cyanomor et al., In Vivo 2(2) 151-4, 1988), 5-halogenocytosine pholino doxorubicin derivative (Scudder et al., J. Nat'l Can nitrosourea derivatives (Chiang & Tseng, T’ai-wan Yao cer Inst. 80016): 1294–8, 1988), deoxydihydroiodooxorubicin Hsuch Tsa Chih 38(1): 37-43, 1986), 1-(2-chloroethyl)-3 (EPA 275966), adriblastin (Kalishevskaya et al., Vestn. Mosk. isobutyl-3-(5-maltosyl)-1-nitrosourea (Fujimoto & Ogawa, Univ., 16(Biol. 1):21-7, 1988), 4'-deoxydoxorubicin (Schoei J. Pharmacobio-Dyn, 10(7):341-5, 1987), sulfur-containing zel et al., Leuk. Res. 10(12):1455-9, 1986), 4-demethyoxy-4' nitrosoureas (Tang et al., Yaoxue Xuebao 21(7):502-9, 1986), o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. sucrose, 6-((((2-chloroethyl)nitrosoamino-)carbonyl) US 2009/0226500 A1 Sep. 10, 2009

amino)-6-deoxysucrose (NS-1C) and 6'-((((2-chloroethyl)mi (Matsuoka et al., Chem. Pharm. Bull. 45(7):1146-1150, trosoamino)carbonyl)amino)-6'-deoxysucrose (NS-1D) 1997), alkyl-substituted benzene ring C bearing methotrexate nitrosourea derivatives (Tanoh et al., Chemotherapy (Tokyo) derivatives (Matsuoka et al., Chem. Pharm. Bull. 44(12): 33(11):969-77, 1985), CNCC, RFCNU and chlorozotocin 2287–2293, 1996), benzoxazine or benzothiazine moiety (Mena et al., Chemotherapy (Basel) 32(2): 131–7, 1986), bearing methotrexate derivatives (Matsuoka et al., J. Med. CNUA (Edanami et al., Chemotherapy (Tokyo).33(5):455-61, Chem. 40(1):105-111, 1997), 10-deazaminopterin analogues 1985), 1-(2-chloroethyl)-3-isobutyl-3-(D-maltosyl)-1-ni (DeGraw et al., J. Med. Chem, 40(3) 370-376, 1997), 5-dea trosourea (Fujimoto & Ogawa, Jpn. J. Cancer Res. (Gann) zaminopterin and 5,10-dideazaminopterin methotrexate ana 76(7):651-6, 1985), choline-like nitrosoalkylureas (Belyaev logues (Piperetal, JMed Chem, 40(3):377-384, 1997), indo et al., Izv. Akad NAUK SSSR, Ser Khim. 3:553-7, 1985), line moiety-bearing methotrexate derivatives (Matsuoka et sucrose nitrosourea derivatives (JP 842.19300), sulfa drug al., Chem. Pharm Bull 44(7):1332-1337, 1996), lipophilic nitrosourea analogues (Chiang et al., Proc. Nat'l Sci. Counc., amide methotrexate derivatives (Pignatello et al., World Repub. China, Part A 8(1):18-22, 1984), DONU (Asanuma et Meet. Pharm., Biopharm. Pharm. Technol., 563-4, 1995), al., J. Jpn. Soc. Cancer Ther. 17(8):2035-43, 1982), N,N'-bis L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoro (N-(2-chloroethyl)-N-nitrosocarbamoyl)cystamine (CNCC) glutamic acid-containing methotrexate analogues (Hartet al., (Blazsek et al., Toxicol. Appl. Pharmacol. 74(2):250-7, J. Med. Chem. 39(1):56-65, 1996), methotrexate tetrahydro 1984), dimethylnitrosourea (Krutova et al., Izv. Akad. NAUK quinazoline analogue (Gangjee, et al., J. Heterocycl. Chem. SSSR, Ser. Biol. 3:439-45, 1984), GANU (Sava & Giraldi, 32(1):243-8, 1995), N-(o-aminoacyl) methotrexate deriva Cancer Chemother Pharmacol. 10(3):167-9, 1983), CCNU tives (Cheung et al., Pteridines 3(1-2), 101-2, 1992), biotin (Capelli et al., Med., Biol, Environ. 11(1): 111-16, 1983), methotrexate derivatives (Fan et al., Pteridines 3(1-2): 131-2, 5-aminomethyl-2'-deoxyuridine nitrosourea analogues 1992), D-glutamic acid or D-erythrou, threo-4-fluoro (Shiau, Shih Ta Hsuch Pao (Taipei) 27:681-9, 1982), TA-077 glutamic acid methotrexate analogues (McGuire et al., Bio (Fujimoto & Ogawa, Cancer Chemother. Pharmacol. 9(3): chem. Pharmacol. 42(12):2400-3, 1991), 5,7-methano meth 134-9, 1982), gentianose nitrosourea derivatives (JP 82 otrexate analogues (Rosowsky et al., Pteridines 2(3):133-9, 80396), CNCC, RFCNU, RPCNU AND chlorozotocin 1991), 10-deazaminopterin (10-EDAM) analogue (Braa (CZT) (Marzin et al., INSERM Symp., 19(Nitrosoureas Can khuis et al., Chem. Biol. Pteridines, Proc. Int. Symp. Pte cer Treat.):165-74, 1981), thiocolchicine nitrosourea ana ridines Folic Acid Deriv., 1027-30, 1989), Y-tetrazole meth logues (George, Shih Ta Hsuch Pao (Taipei) 25:355-62, otrexate analogue (Kalman et al., Chem. Biol. Pteridines, 1980), 2-chloroethyl-nitrosourea (Zeller & Eisenbrand, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1154-7, 1989), Oncology 38(1):39–42, 1981), ACNU, (1-(4-amino-2-me N-(L-O-aminoacyl) methotrexate derivatives (Cheung et al., thyl-5-pyrimidinyl)methyl-3 (2-chloroethyl)-3-nitrosourea Heterocycles 28(2):751-8, 1989), meta and ortho isomers of hydrochloride) (Shibuya et al., Gan To Kagaku Ryoho 7(8): aminopterin (Rosowsky et al., J. Med. Chem. 32(12):2582, 1393-401, 1980), N-deacetylmethyl thiocolchicine 1989), hydroxymethylmethotrexate (DE 267495), Y-fluo nitrosourea analogues (Linet al., J. Med. Chem. 23(12): 1440 romethotrexate (McGuire et al., Cancer Res.49(16):45.17–25, 2, 1980), pyridine and piperidine nitrosourea derivatives 1989), polyglutamyl methotrexate derivatives (Kumar et al., (Crider et al., J. Med. Chem. 23(8):848-51, 1980), methyl Cancer Res. 46(10):5020-3, 1986), gem-diphosphonate CCNU (Zimber & Perk, Refu. Wet 35(1):28, 1978), phensuz methotrexate analogues (WO 88/06158), Cº- and Y-substituted imide nitrosourea derivatives (Crider et al., J. Med. Chem. methotrexate analogues (Tsushima et al., Tetrahedron 23(3):324-6, 1980), ergoline nitrosourea derivatives (Crider 44(17):5375-87, 1988), 5-methyl-5-deaza methotrexate ana et al., J. Med. Chem. 22(1):32–5, 1979), glucopyranose logues (U.S. Pat. No. 4,725,687), Nô-acyl-No-(4-amino-4 nitrosourea derivatives (JP 78 95917), 1-(2-chloroethyl)-3 deoxypteroyl)-L-ornithine derivatives (Rosowsky et al., J. cyclohexyl-1-nitrosourea (Farmeret al., J. Med. Chem. 21(6): Med. Chem. 31(7): 1332-7, 1988), 8-deaza methotrexate ana 514-20, 1978), 4-(3-(2-chloroethyl)-3-nitrosoureid-o)-cis logues (Kuehl et al., Cancer Res.48(6):1481-8, 1988), acivi cyclohexanecarboxylic acid (Drewinko et al., Cancer Treat. cin methotrexate analogue (Rosowsky et al., J. Med. Chem. Rep. 61(8):J1513-18, 1977), RPCNU (ICIG 1163) (Larnicol 30(8) 1463-9, 1987), polymeric platinol methotrexate deriva et al., Biomedicine 26(3).J176-81, 1977), IOB-252 (Sorodoc tive (Carraher et al., Polym Sci Technol. (Plenum), 35(Adv. et al., Rev. Roum. Med., Virol. 28(1):J 55-61, 1977), 1,3-bis Biomed. Polym) 311-24, 1987), methotrexate-Y-dimyris (2-chloroethyl)-1-nitrosourea (BCNU) (Siebert & Eisen toylphophatidylethanolamine (Kinsky et al. Biochim. Bio brand, Mutat. Res. 42(11):J45-50, 1977), 1-tetrahydroxycy phys. Acta 917(2):211-18, 1987), methotrexate poly clopentyl-3-nitroso-3-(2-chloroethyl)-urea (U.S. Pat. No. glutamate analogues (Rosowsky et al., Chem. Biol. 4,039,578), d-1-1-(5-chloroethyl)-3-(2-oxo-3-hexahy Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. droazepinyl)-1-nitrosourea (U.S. Pat. No. 3,859,277) and Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: gentianose nitrosourea derivatives (JP 57080396); 6-S-ami 985-8, 1986), poly-Y-glutamyl methotrexate derivatives (Kis noacyloxymethyl mercaptopurine derivatives (Harada et al., liuk et al., Chem. Biol. Pteridines, Pteridines Folid Acid Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., (6-MP) (Kashida et al., Biol. Pharm. Bull, 18(11):1492-7, Biol Clin. Aspects: 989-92, 1986), deoxyuridylate methotr 1995), 7,8-polymethyleneimidazo-1,3,2-diazaphosphorines exate derivatives (Webber et al., Chem. Biol. Pteridines, Pte (Nilov et al., Mendeleev Commun. 2:67, 1995), azathioprine ridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid (Chifotides et al., J. Inorg. Biochem. 56(4):249-64, 1994), Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986), methyl-D-glucopyranoside mercaptopurine derivatives (Da iodoacetyl lysine methotrexate analogue (Delcamp et al., Silva et al., Eur, J. Med. Chem. 29(2):149-52, 1994) and Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Farm. Zh. 15(8):65-7, 1981); indoline ring and a modified Aspects: 807-9, 1986), 2,.omega.-diaminoalkanoid acid-con ornithine or glutamic acid-bearing methotrexate derivatives taining methotrexate analogues (McGuire et al., Biochem. US 2009/0226500 A1 Sep. 10, 2009

Pharmacol. 35(15):2607-13, 1986), polyglutamate methotr N'-(2-furanidyl)-5-fluorouracil (JP 53149985) and 1-(2-tet exate derivatives (Kamen & Winick, Methods Enzymol. 122 rahydrofuryl)-5-fluorouracil (JP 52089680); 4'-epidoxorubi (Vitam. Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza cin (Lanius, Adv. Chemother. Gastrointest. Cancer, (Int. analogues (Piper et al., J. Med. Chem. 29(6):1080–7, 1986), Symp.), 159-67, 1984); N-substituted deacetylvinblastine quinazoline methotrexate analogue (Mastropaolo et al., J. amide (vindesine) sulfates (Conrad et al., J. Med. Chem. Med. Chem. 29(1): 155-8, 1986), pyrazine methotrexate ana 22(4):391-400, 1979); and Cu(II)-VP-16 (etoposide) com logue (Lever & Vestal, J. Heterocycl. Chem. 22(1):5-6, 1985), plex (Tawaetal., Biocrg. Med. Chem. 6(7):1003-1008, 1998), cysteic acid and homocysteic acid methotrexate analogues pyrrolecarboxamidino-bearing etoposide analogues (Jiet al., (U.S. Pat. No. 4,490,529), Y-tert-butyl methotrexate esters Biocrg. Med. Chem. Lett. 7(5):607-612, 1997), 43-amino (Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985), fluori etoposide analogues (Hu, University of North Carolina Dis nated methotrexate analogues (Tsushima et al., Heterocycles sertation, 1992), Y-lactone ring-modified arylamino etopo 23(1):45-9, 1985), folate methotrexate analogue (Trombe, J. side analogues (Zhou et al., J. Med. Chem. 37(2):287-92, Bacteriol. 160(3):849-53, 1984), phosphonoglutamic acid 1994), N-glucosyl etoposide analogue (Allevi et al., Tetrahe analogues (Sturtz & Guillamot, Eur, J. Med. Chem.–Chim. dron Lett. 34(45):7313-16, 1993), etoposide A-ring ana Ther. 19(3):267-73, 1984), poly(L-lysine) methotrexate con logues (Kadow et al., Bioorg. Med. Chem. Lett. 2(1):17-22, jugates (Rosowsky et al., J. Med. Chem. 27(7):888-93, 1984), 1992), 4'-deshydroxy-4'-methyl etoposide (Saulnier et al., dilysine and trilysine methotrexate derivates’ (Forsch & Biodrq. Med. Chem. Lett. 2(10): 1213-18, 1992), pendulum Rosowsky, J. Org. Chem, 49(7):1305-9, 1984), 7-hy ring etoposide analogues (Sinha et al., Eur, J. Cancer 26(5): droxymethotrexate (Fabre et al., Cancer Res. 43(10):4648 590–3, 1990) and E-ring desoxy etoposide analogues 52, 1983), poly-Y-glutamyl methotrexate analogues (Piper & (Saulnier et al., J. Med. Chem, 32(7):1418-20, 1989). Montgomery, Adv Exp Med Biol, 163(Folyl Antifolyl Poly [0080] Within one preferred embodiment of the invention, glutamates):95-100, 1983), 3',5'-dichloromethotrexate the cell cycle inhibitor is paclitaxel, a compound that disrupts (Rosowsky & Yu, J. Med. Chem. 26(10): 1448-52, 1983), mitosis (M-phase) by binding to tubulin to form abnormal diazoketone and chloromethylketone methotrexate ana mitotic spindles or an analogue or derivative thereof. Briefly, logues (Gangjee et al., J. Pharm. Sci. 71(6):717-19, 1982), paclitaxel is a highly derivatized diterpenoid (Wani et al., J. 10-propargylaminopterin and alkyl methotrexate homologs Am. Chem. Soc. 93:2325, 1971) that has been obtained from (Piperetal.J.Med. Chem. 25(7):877-80, 1982), lectin deriva the harvested and dried bark of Taxus brevifolia (Pacific Yew) tives of methotrexate (Lin et al., JNCI (3):523-8, 1981), poly and Taxomyces Andreanae and Endophytic Fungus of the glutamate methotrexate derivatives (Galivan, Mol. Pharma Pacific Yew (Stierle et al., Science 60:214-216, 1993). “Pacli col. 17(1): 105-10, 1980), halogentated methotrexate taxel” (which should be understood herein to include formu derivatives (Fox, JNCI 58(4):J955-8, 1977), 8-alkyl-7,8-di lations, prodrugs, analogues and derivatives such as, for hydro analogues (Chaykovsky et al., J. Med. Chem. 20010): example, TAXOL (Bristol Myers Squibb, New York, N.Y., J1323-7, 1977), 7-methyl methotrexate derivatives and TAXOTERE (Aventis Pharmaceuticals, France), docetaxel, dichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 10-desacetyl analogues of paclitaxel and 3'N-desbenzoyl 17(12):J1308-11, 1974), lipophilic methotrexate derivatives 3'N-t-butoxy carbonyl analogues of paclitaxel) may be and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. readily prepared utilizing techniques known to those skilled 16(10):J1190–3, 1973), deaza amethopterin analogues in the art (see, eg., Schiff et al., Nature 277:665-667, 1979; (Montgomery et al., Ann. N.Y. Acad. Sci. 186:J227–34, 1971), Long and Fairchild, Cancer Research 54:4355-4361, 1994; MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and Ringel and Horwitz, J. Nat'l Cancer Inst. 83(4):288-291, homocysteic acid methotrexate analogues (EPA 0142220); 1991, Pazdur et al., Cancer Treat. Rev. 19(4):351-386, 1993, N3-alkylated analogues of 5-fluorouracil (Kozai et al., J. WO 94/07882, WO 94/07881; WO94/07880, WO 94/07876: Chem. Soc., Perkin Trans. 1(19):3145-3146, 1998), 5-fluo WO 93/23555, WO 93/10076; WO94/00156; WO 93/24476: rouracil derivatives with 1,4-oxaheteroepane moieties (Go EP590267; WO 94/20089; U.S. Pat. Nos. 5,294,637; 5,283, mez et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluo 253: 5,279,949; 5,274,137; 5,202,448; 5,200,534, 5,229,529; rouracil and nucleoside analogues (Li, Anticancer Res. 5,254,580; 5,412,092; 5,395,850: 5,380,751; 5,350,866; 17(1A):21-27, 1997), cis- and trans-5-fluoro-5,6-dihydro-6 4,857,653: 5,272,171; 5,411,984; 5,248,796; 5,248,796; alkoxyuracil (Van der Wilt et al., Br. J. Cancer 68(4):702-7, 5,422.364; 5,300,638; 5,294,637; 5,362.831; 5,440,056; 1993), cyclopentane 5-fluorouracil analogues (Hronowski & 4,814,470; 5,278.324; 5,352,805; 5,411,984; 5,059,699; Szarek, Can. J. Chem. 70(4):1162-9, 1992), A-OT-fluorou 4.942,184; Tetrahedron Letters 35(52):9709-9712, 1994; J. racil (Zhang et al., Zongguo Yiyao Gongye Zazhi 20011):513 Med. Chem. 35:4230-4237, 1992; J. Med. Chem. 34:992–998, 15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine 1991; J. Natural Prod. 57(10):1404-1410, 1994; J. Natural and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Prod. 57(11):1580–1583, 1994; J. Am. Chem. Soc. 110:6558 Bull, 38(4):998-1003, 1990), 1-hexylcarbamoyl-5-fluorou 6560, 1988), or obtained from a variety of commercial racil (Hoshi et al., J. Pharmacobio-Dun. 3(9):478-81, 1980; sources, including for example, Sigma Chemical Co., St. Maehara et al., Chemotherapy (Basel) 34(6):484-9, 1988), Louis, Mo. (T7402—from Taxus brevifolia). B-3839 (Prajda et al., In Vivo 2(2):151-4, 1988), uracil-1-(2 [0081] Representative examples of paclitaxel derivatives or tetrahydrofuryl)-5-fluorouracil (Anai et al., Oncology 45(3): analogues include 7-deoxy-docetaxol. 7,8-cyclopropatax 144-7, 1988), 1-(2?-deoxy-2'-fluoro-5-D-arabinofuranosyl) anes, N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7 5-fluorouracil (Suzuko et al. Mol Pharmacol 31(3):301-6, modified paclitaxeis, 10-desacetoxytaxol, 10-deacetyltaxol 1987), doxifluridine (Matuura et al., Oyo Yakun 29(5)803-31, (from 10-deacetylbaccatin III), phosphonooxy and carbonate 1985), 5'-deoxy-5-fluorouridine (Bollag & Hartmann. Eur, J. derivatives of taxol, taxol. 2',7-di(sodium 1,2-benzenedicar Cancer 16(4):427–32, 1980), 1-acetyl-3-O-toluyl-5-fluorou boxylate, 10-desacetoxy-11,12-dihydrotaxol-10,12(18)-di racil (Okada, Hiroshima J. Med. Sci. 28(1):49-66, 1979), ene derivatives, 10-desacetoxytaxol, Protaxol (2'- and/or 5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173), 7-O-ester derivatives), (2'-and/or 7-O-carbonate derivatives), US 2009/0226500 A1 Sep. 10, 2009 asymmetric synthesis of taxol side chain, fluoro taxols, paclitaxel analogues, Girard taxane derivatives, nitrophenyl 9-deoxotaxane, (13-acetyl-9-deoxobaccatine III, 9-deoxo paclitaxel, 10-deacetylated substituted paclitaxel derivatives, taxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9 14-beta-hydroxy-10 deacetylbaccatin III taxane derivatives, deoxotaxol, Derivatives containing hydrogen or acetyl group C7 taxane derivatives, C10 taxane derivatives, 2-debenzoyl 2-acyl taxane derivatives, 2-debenzoyl and -2-acyl paclitaxel and a hydroxy and tert-butoxycarbonylamino, sulfonated derivatives, taxane and baccatin III analogues bearing new C2 2'-acryloyltaxol and sulfonated 2'-O-acyl acid taxol deriva and C4 functional groups, n-acyl paclitaxel analogues, tives, succinyltaxol. 2'-Y-aminobutyryltaxol formate, 10-deacetylbaccatin III and 7-protected-10-deacetylbaccatin 2'-acetyl taxol, 7-acetyl taxol, 7-glycine carbamate taxol, III derivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, 2'-OH-7-PEG(5000) carbamate taxol. 2'-benzoyl and 2',7 and 10-deacetyl taxol, benzoate derivatives of taxol, 2-aroyl dibenzoyl taxol derivatives, other prodrugs (2'-acetyltaxol, 4-acyl paclitaxel analogues, orthro-ester paclitaxel ana 2',7-diacetyltaxol; 2'succinyltaxol. 2'-(beta-alanyl)-taxol), logues, 2-aroyl-4-acyl paclitaxel analogues and 1-deoxy 2'gamma-aminobutyryltaxol formate, ethylene glycol deriva paclitaxel and 1-deoxy paclitaxel analogues. tives of 2'-succinyltaxol. 2'-glutaryltaxol; 2'-(N,N-dimeth [0082] In one aspect, the cell cycle inhibitor is a taxane ylglycyl) taxol; 2'-(2-(N,N-dimethylamino)propionyl)taxol; having the formula (C1):

(C1)

2'orthocarboxybenzoyl taxol; 2'aliphatic carboxylic acid where the gray-highlighted portions may be substituted and derivatives of taxol, Prodrugs {2'(N,N-diethylaminopropio the non-highlighted portion is the taxane core A side-chain nyl)taxol. 2'(N,N-dimethylglycyl)taxol, 7(N,N-dimethylgly (labeled “A” in the diagram) is desirably present in order for cyl)taxol, 2',7-di-(N,N-dimethylglycyl)taxol, 7(N,N-diethy the compound to have good activity as a cell cycle inhibitor. laminopropionyl)taxol. 2',7-di(N,N-diethylaminopropionyl) Examples of compounds having this structure include pacli taxol. 2'-(L-glycyl)taxol, 7-(L-glycyl)taxol. 2',7-di(L-glycyl) taxel (Merck Index entry 7117), docetaxol (TAXOTERE, taxol. 2'-(L-alanyl)taxol, 7-(L-alanyl)taxol. 2',7-di(L-alanyl) Merck Index entry 3458), and 3'-desphenyl-3'-(4-ntirophe taxol. 2'-(L-leucyl)taxol, 7-(L-leucyl)taxol. 2',7-di(L-leucyl) nyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10-deacetyltaxol. taxol. 2'-(L-isoleucyl)taxol, 7-(L-isoleucyl)taxol. 2', 7-di(L [0083] In one aspect, suitable taxanes such as paclitaxel and isoleucyl)taxol. 2'-(L-valyl)taxol, 7-(L-valyl)taxol. 2',7-di(L its analogues and derivatives are disclosed in U.S. Pat. No. valyl)taxol. 2'-(L-phenylalanyl)taxol, 7-(L-phenylalanyl) 5,440,056 as having the structure (C2): taxol. 2',7-di(L-phenylalanyl)taxol. 2'-(L-prolyl)taxol, 7-(L prolyl)taxol, 2', 7-di(L-prolyl)taxol. 2'-(L-lysyl)taxol, 7-(L lysyl)taxol. 2',7-di(L-lysyl)taxol, 2’-(L-glutamyl)taxol, 7-(L (C2) glutamyl)taxol. 2",7-di(L-glutamyl)taxol. 2'-(L-arginyl) taxol, 7-(L-arginyl)taxol. 2',7-di(L-arginyl)taxol, taxol analogues with modified phenylisoserine side chains, TAXO TERE, (N-debenzoyl-N-tert-(butoxycaronyl)-10-deacetyl taxol, and taxanes (e.g., baccatin III, cephalomannine, 10-deacety(baccatin III, brevifoliol, yunantaxusin and tax usin); and other taxane analogues and derivatives, including 14-beta-hydroxy-10 deacetybaccatin III, debenzoyl-2-acyl (?) indicates text missing or illegible when filed paclitaxel derivatives, benzoate paclitaxel derivatives, phosphonooxy and carbonate paclitaxel derivatives, sul fonated 2'-acryloyltaxol; sulfonated 2'-O-acyl acid paclitaxel wherein X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives, 18-site-substituted paclitaxel derivatives, chlori derivatives), thioacyl, or dihydroxyl precursors; R is selected nated paclitaxel analogues, C4 methoxy ether paclitaxel from paclitaxel or TAXOTERE side chains or alkanoyl of the derivatives, sulfonamide taxane derivatives, brominated formula (C3) US 2009/0226500 A1 Sep. 10, 2009 12

[0085] WO 93/10076 discloses that the taxane nucleus may (C3) be substituted at any position with the exception of the exist ing methyl groups. The substitutions may include, for example, hydrogen, alkanoyloxy, alkenoyloxy, aryloyloxy. In addition, oxo groups may be attached to carbons labeled 2, 4, 9, and/or 10. As well, an oxetane ring may be attached at carbons 4 and 5. As well, an oxirane ring may be attached to the carbon labeled 4. wherein R2 is selected from hydrogen, alkyl, phenyl, alkoxy, [0086) In one aspect, the taxane-based cell cycle inhibitor amino, phenoxy (substituted or unsubstituted); Rs is selected useful in the present invention is disclosed in U.S. Pat. No. from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ami 5,440,056, which discloses 9-deoxo taxanes. These are com noalkyl, phenyl (substituted or unsubstituted), alpha or beta pounds lacking an oxo group at the carbon labeled 9 in the naphthyl; and R9 is selected from hydrogen, alkanoyl, substi taxane structure shown above (formula C4). The taxane ring tuted alkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl, halogen, thio may be substituted at the carbons labeled 1, 7 and 10 (inde alkoxyl, N,N-dimethylamino, alkylamino, dialkylamino, pendently) with H, OH, O—R, or O—CO—R where R is an nitro, and –OSOs??, and/or may refer to groups containing alkyl or an aminoalkyl. As well, it may be substituted at such substitutions; R2 is selected from hydrogen or oxygen carbons labeled 2 and 4 (independently) with aryol, alkanoyl, containing groups, such as hydrogen, hydroxyl, alkoyl, aminoalkanoyl or alkyl groups. The side chain of formula alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy; Rs is selected from hydrogen or oxygen-containing groups, (C3) may be substituted at R, and Rs (independently) with such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoal phenyl rings, substituted phenyl rings, linear alkanes/alkenes, kanoyloxy, and peptidyalkanoyloxy, and may further be a and groups containing H, O or N. Ro may be substituted with silyl containing group or a sulphur containing group; Ra is H, or a substituted or unsubstituted alkanoyl group. selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidy [0087] Taxanes in general, and paclitaxel is particular, is lalkanoyl and aroyl; Rs is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; Ra is selected considered to function as a cell cycle inhibitor by acting as an from hydrogen or oxygen-containing groups, such as hydro anti-microtubule agent, and more specifically as a stabilizer gen, hydroxyl alkoyl, alkanoyloxy, aminoalkanoyloxy, and These compounds have been shown useful in the treatment of peptidyalkanoyloxy. proliferative disorders, including: non-small cell (NSC) lung, [0084] In one aspect, the paclitaxel analogues and deriva small cell lung, breast, prostate, cervical, endometrial, head tives useful as cell cycle inhibitors are disclosed in PCT and neck cancers International Patent Application No. WO 93/10076 As dis closed in this publication, the analogue or derivative should [0088) In another aspect, the anti-microtuble agent (micro have a side chain attached to the taxane nucleus at C1s, as tubule inhibitor) is albendazole (carbamic acid, [5-(propy shown in the structure below (formula C4), in order to confer lthio)-1H-benzimidazol-2-yl]-, methyl ester), LY-355703 antitumor activity to the taxane. (1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12 10 9 (C4) tetrone, 10-[(3-chloro-4-methoxyphenyl)methyl]-6,6-dim ethyl-3-(2-methylpropyl)-16-[(1S)-1-[(2S,3R)-3-phenylox iranyl]ethyl]-, (3S,10R,13E,16S)—), vindesine 13 (vincaleukoblastine, 3-(aminocarbonyl)-O4-deacetyl-3-de (methoxycarbonyl)-), or WAY-174286 [0089] In another aspect, the cell cycle inhibitor is a vinca alkaloid. Vinca alkaloids have the following general struc ture. They are indole-dihydroindole dimers.

H US 2009/0226500 A1 Sep. 10, 2009 13

[0090] As disclosed in U.S. Pat. Nos. 4,841,045 and 5,030, [0093] In another aspect, the cell cycle inhibitor is a camp 620, RI can be a formyl or methyl group or alternately H. R. tothecin, or an analog or derivative thereof. Camptothecins can also be an alkyl group or an aldehyde-substituted alkyl have the following general structure (e.g., CH2CHO). R, is typically a CH3 or NH2 group. How everit can be alternately substituted with a lower alkyl esteror the ester linking to the dihydroindole core may be substituted with C(O)—R where R is NH2, an amino acid ester or a peptide ester. Rs is typically C(O)CHA, CH3 or H. Alternately, a protein fragment may be linked by a bifunctional group, such as maleoylamino acid. Rs can also be substituted to form an alkyl ester which may be further substituted Ra may be —CH2—or a single bond Rs and Ra may be H, OH or a lower alkyl, typically —CH2CHs Alternatively Ra and R7 may together form an oxetane ring. R7 may alternately be H. Fur ther substitutions include molecules wherein methyl groups are substituted with other alkyl groups, and whereby unsat [0094] In this structure, X is typically 0, but can be other urated rings may be derivatized by the addition of a side group groups, e.g., NH in the case of 21-lactam derivatives. R1 is such as an alkane, alkene, alkyne, halogen, ester, amide or typically H or OH, but may be other groups, e.g., a terminally amino group. hydroxylated C1-s alkane. R2 is typically H or an amino con [0091) Exemplary vinca alkaloids are vinblastine, vincris taining group such as (CH3)2NHCH2, but may be other time, vincristine sulfate, vindesine, and vinorelbine, having groups e.g., NO2, NH2, halogen (as disclosed in, e.g., U.S. the structures: Pat. No. 5,552,156) or a short alkane containing these groups.

R1 R2 R3 R4 Rs

Vinblastine: CH3 CH3 C(O)CH3 OH CH2 Vincristine: CH2O CH3 C(O)CH3 OH CH2 Vindesine: CHs NH, H OH CH, Vinorelbine: CH3 CH2 CH3 H single bond

[0092] Analogues typically require the side group (shaded Rs is typically Hora short alkyl such as C2Hs. Ra is typically area) in order to have activity. These compounds are thought H but may be other groups, e.g., a methylenedioxy group with to act as cell cycle inhibitors by functioning as anti-microtu R bule agents, and more specifically to inhibit polymerization. [0095) Exemplary camptothecin compounds include topo These compounds have been shown useful in treating prolif tecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lac erative disorders, including NSClung; small cell lung; breast; tam-20(S)-camptothecin, 10, 11-methylenedioxycamptoth prostate; brain; head and neck; retinoblastoma; bladder; and ecin, SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. penile cancers; and soft tissue sarcoma. Exemplary compounds have the structures: US 2009/0226500 A1 Sep. 10, 2009 14

[0099] Another example of a DNA topoisomerase inhibitor is lurtotecan dihydrochloride (11H-1,4-dioxino|2,3-g] pyrano?3',4':6,7|indolizino|1,2-b]quinoline-9,12(8H,14H) dione, 8-ethyl-2,3-dihydro-8-hydroxy-15-[(4-methyl-1-pip erazinyl)methyl]-, dihydrochloride, (S)—). [0100] In another aspect, the cell cycle inhibitor is an anthracycline. Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:

R1 R2 R3

Camptothecin: H H H Topotecan: OH (CH3)2NHCH, H SN-38: OH H C2H5

X: O for most analogs, NH for 21-lactam analogs [0096] Camptothecins have the five rings shown here. The [0101] According to U.S. Pat. No. 5,594,158, suitable R ring labeled E must be intact (the lactone rather than carboxy groups are R1 is CH3 or CH2OH, R2 is daunosamine or H. Rs late form) for maximum activity and minimum toxicity. and Ra are independently one of OH, NO2, NH2, F, Cl, Br, I, These compounds are useful to as cell cycle inhibitors, where CN, H or groups derived from these, Rs 7 are all H or Rs and they can function as topoisomerase I inhibitors and/or DNA Ra are H and R7 and Rs are alkyl or halogen, or vice versa R2 cleavage agents They have been shown useful in the treatment and Rs are H and Rs and Ra are alkyl or halogen. of proliferative disorders, including, for example, NSC lung: [0102] According to U.S. Pat. No. 5,843,903, R., may be a small cell lung; and cervical cancers. conjugated peptide. According to U.S. Pat. Nos. 4,215,062 [0097] In another aspect, the cell cycle inhibitor is a podo and 4,296,105, Rs may be OH or an ether linked alkyl group. phyllotoxin, or a derivative or an analogue thereof. Exem R? may also be linked to the anthracycline ring by a group plary compounds of this type are etoposide or teniposide, other than C(O), such as an alkyl or branched alkyl group which have the following structures: having the C(O) linking moiety at its end, such as —CH2CH (CH2—X)C(O)—R1, wherein X is H or an alkyl group (see, e.g., U.S. Pat. No. 4,215,062). R, may alternately be a group linked by the functional group =N–NHC(O)—Y, where Y O O is a group such as a phenyl or substituted phenyl ring. Alter HO O nately Rs may have the following structure: OH O K O

# O

H3CO OCH3 OH in which Rø is OH either in or out of the plane of the ring, or R is a second sugar moiety such as Rs. Rio may be H or form a Etopside CH3 secondary amine with a group such as an aromatic group, Teniposide saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Pat. No. 5,843, 903). Alternately, Rio may be derived from an amino acid, having the structure –C(O)CH(NHR11)(R12), in which R1 | is H, or forms a Cs a membered alkylene with R12, R12 may be [0098] These compounds are thought to function as cell H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, ben cycle inhibitors by being topoisomerase II inhibitors and/or zyl or methylthio (see U.S. Pat. No. 4,296,105). by DNA cleaving agents. They have been shown useful as [0103] Exemplary anthracyclines are doxorubicin, dauno antiproliferative agents in, e.g., small cell lung, prostate, and rubicin, idarubicin, epirubicin, pirarubicin, Zorubicin, and brain cancers, and in retinoblastoma. carubicin. Suitable compounds have the structures: US 2009/0226500 A1 Sep. 10, 2009

-continued

OH O HN OH SJTS NH

OH O HN OH Svºs NH

Mitoxantrone H3C O NH2 OR, CH3 O R3 OR2 CH3 HO O O R2 R2 R3 O S.

Doxorubicin OCH3 CH2OH OH out of ring plane OCH3 OH Epirubicin OCH3 CH2OH OH in ring plane (4 epimer of doxorubicin) Daunorubicin OCH3 CH3 OH out of ring plane Idarubicin H CHs OH out of ring plane Pirarubicin OCH, OH A. Zorubicin OCHA =N–NHC(O)C.H., B Carubicin OH CH3 B H3C A. RIO O yº HO

B Olivomycin A COCH(CH3), CHs COCH, H CH3 Chromomycin As COCH3 CH3 COCH3 CH3 O / Plicamycin H H H CHs CH3 O

OH CH3 NH2

[0104] Other suitable anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin As, and plicamycin having the Structures:

OH OH R1 R2 R3 H3C N Menogaril H OCHs H Nogalamycin O-sugar H COOCH3

N NH 2 2. 2 Sugar: CH3 O H3C ~O O º Anthramycin H3CO ÖH, OCH3 US 2009/0226500 A1 Sep. 10, 2009 16

-continued

H3C O N(CH3)2 O

H3C O OH O [0108] Exemplary platinum compounds are cisplatin, car boplatin, oxaliplatin, and miboplatin having the structures: H3C O

O NH3 NH Aclacinomycin A | 3 O “s Cl—Pt—NH3 | `NH, | O [0105] These compounds are thought to function as cell Cl Cisplatin cycle inhibitors by being topoisomerase inhibitors and/or by O DNA cleaving agents They have been shown useful in the Carboplatin treatment of proliferative disorders, including small cell lung; O O breast; endometrial; head and neck; retinoblastoma; liver; O. NH2 O. NH2 bile duct; islet cell; and bladder cancers; and soft tissue sar \ / \s COIll&l of/* NHS' * * * O/* HN2. H [0106] In another aspect, the cell cycle inhibitor is a plati O O num compound. In general, suitable platinum complexes may Oxaliplatin be of Pt(II) or Pt(IV) and have this basic structure: Miboplatin

[0109] These compounds are thought to function as cell cycle inhibitors by binding to DNA, i.e., acting as alkylating agents of DNA. These compounds have been shown useful in the treatment of cell proliferative disorders, including, e.g., NSC lung; small cell lung; breast; cervical; brain; head and neck; esophageal, retinoblastom, liver, bile duct, bladder; penile; and vulvar cancers, and soft tissue sarcoma wherein X and Y are anionic leaving groups such as sulfate, [0110] In another aspect, the cell cycle inhibitor is a phosphate, carboxylate, and halogen; R1 and R2 are alkyl, nitrosourea Nitrosourease have the following general struc amine, amino alkyl any may be further substituted, and are ture (C5), where typical R groups are shown below. basically inert or bridging groups. For Pt(II) complexes Z! and Z., are non-existent. For Pt(IV) Z, and Z, may be anionic (C5) groups such as halogen, hydroxy, carboxylate, ester, sulfate O or phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4,250, R’ Js R. 189. > NH [0107] Suitable platinum complexes may contain multiple N Pt atoms. See, e.g., U.S. Pat. Nos. 5,409,915 and 5,380,897. So For example bisplatinum and triplatinum complexes of the R Group type: US 2009/0226500 A1 Sep. 10, 2009 17

2'-(N–(N-(2-chloroethyl)-N-nitroso-carbamoyl)-glycyl) -continued amino-2'-deoxy-O-D-glucopyranoside). As disclosed in U.S. H2C Pat. No. 4,150,146, R of formula (C5) may be an alkyl group O CH3 of 2 to 6 carbons and may be substituted with an ester, sulfo Cl OH nyl, or hydroxyl group. It may also be substituted with a H3 cºs,” carboxylic acid or CONH2 group. C - OH O—CH3 [0113] Exemplary nitrosoureas are BCNU (carmustine), ãrillustine OH Lomustine methyl-CCNU (semustine), CCNU (lomustine), ranimus time, nimustine, chlorozotocin, fotemustine, and streptozocin, Ranimustine having the structures:

O CH3 CH3 OH p-N 2's / CH3 Cl H on H3C &P Soºen, ne’N,” O Carmustine Js Fotemustine H2C H3C O ` NH OH N S. O So OH O—CH, Lomustine Streptozocin OH OH Ranimustine

NH2 OH NH2 O OH H3C S O H3C S OH OH OH 22 N CH3 H3C §2. CH3 OH OH Nimustine Chlorozotocin Nimustine H3C Chlorozotocin

[0111] Other suitable R groups include cyclic alkanes, alkanes, halogen substituted groups, sugars, aryl and het eroaryl groups, phosphonyl and sulfonyl groups. As disclosed in U.S. Pat. No. 4,367,239, R may suitably be CH2—C(X) (Y)(Z), wherein X and Y may be the same or different mem bers of the following groups: phenyl, cyclyhexyl, or a phenyl or cyclohexyl group substituted with groups such as halogen, lower alkyl (C1-4), trifluore methyl, cyano, phenyl, cyclo hexyl, lower alkyloxy (Cla). Z has the following structure: OH -alkylene-N-R, R2, where R1 and R2 may be the same or different members of the following group: lower alkyl (Cla) and benzyl, or together R, and R2 may form a saturated 5 or 6 membered heterocyclic such as pyrrolidine, piperidine, mor foline, thiomorfoline, N-lower alkyl piperazine, where the heterocyclic may be optionally substituted with lower alkyl groups. [0112] As disclosed in U.S. Pat. No. 6,096,923, R and R' of formula (C5) may be the same or different, where each may [0114] These nitrosourea compounds are thought to func be a substituted or unsubstituted hydrocarbon having 1-10 tion as cell cycle inhibitors by binding to DNA, that is, by carbons. Substitutions may include hydrocarbyl, halo, ester, functioning as DNA alkylating agents. These cell cycle amide, carboxylic acid, ether, thioether and alcohol groups. inhibitors have been shown useful intreating cell proliferative As disclosed in U.S. Pat. No. 4,472,379, R of formula (C5) disorders such as, for example, islet cell; small cell lung; may be an amide bond and a pyranose structure (e.g., methyl melanoma; and brain cancers. US 2009/0226500 A1 Sep. 10, 2009 18

[0115] In another aspect, the cell cycle inhibitor is a nitroimidazole, where exemplary nitroimidazoles are met ronidazole, benznidazole, etanidazole, and misonidazole, R11 “'s `s R9 having the structures: R5 R4 2 2N R3 Ré R3 R3' R10

R} º, R8 [0118] The identity of the R group may be selected from organic groups, particularly those groups set forthin U.S. Pat. ~~\ N Nos. 5,166,149 and 5,382,582. For example, R, may be N, R, may be N or C(CH3), Rs and Rs' may H or alkyl, eg. CHA, Ra may beasingle bond or NR, where Ris Horalkyl group Rs.gs R1 R2 R3 may be H, OCHs, or alternately they can behalogens or hydro groups. R4 is a side chain of the general structure: Metronidazole OH CH3 NO, Benznidazole C(O)NHCH,-benzyl NO, H Etamidazole CONHCH,CH,OH NO, H O NH CH3 HO [0116] Suitable nitroimidazole compounds are disclosed O in, e.g., U.S. Pat. Nos. 4,371,540 and 4,462,992. O OH #

[0117] In another aspect, the cell cycle inhibitor is a folic wherein n=1 for methotrexate, n=3 for pteropterin. The car acid antagonist, such as methotrexate or derivatives or ana boxyl groups in the side chain may be esterified or form a salt such as a Znº salt. R, and Rio can be NH2 or may be alkyl logues thereof, including edatrexate, trimetrexate, raltitrexed, substituted. piritrexim, denopterin, tomudex, and pteropterin. Methotrex [0119) Exemplary folic acid antagonist compounds have ate analogues have the following general structure: the structures:

R1 N NH2 S Sr. R4 22 2N R6 R3 R3 Ro R; R8

Ro R1 R2 R3 R4 Rs Re R7 Rs

Methotrexate NH, N N H N(CH3) H H A (n = 1) H Edatrexate NH, N N H N(CH2CH3) H H A (n = 1) H Trimetrexate NH, N C(CH3) H NH H OCHs OCHs OCHs Pteropterin NH, N N H N(CH3) H H A (n = 3) H Denopterin OH N N CHs N(CH3) H H A (n = 1) H Piritrexin NH, N C(CH3)H single OCH3 H H OCHs H bond

A: O

NH CH3 HO

O O OH # US 2009/0226500 A1 Sep. 10, 2009 19

-continued R1 N NH2 R5 S sº R4 2 2N R6 R3 R3 Ro R; R8 Ro R1 R2 R3 Ra Rs Ré R7 Rs N CH HoocºS O º | sº 3 HoocºSNii: \ S / N NH

Tomudex

[0120) These compounds are thought to function as cell cycle inhibitors by serving as antimetabolites of folic acid. -continued They have been shown useful in the treatment of cell prolif NH erative disorders including, for example, soft tissue sarcoma,

small cell lung, breast, brain, head and neck, bladder, and penile cancers. [0121] In another aspect, the cell cycle inhibitor is a cyti dine analogue, such as cytarabine or derivatives or analogues thereof, including enocitabine, FMdC ((E(-2'-deoxy-2'-(fluo romethylene)cytidine), gemcitabine, 5-azacitidine, ancitab ine, and 6-azauridine. Exemplary compounds have the struc tures: Ancitabine

2° R HN O

HO O2's N~ N O

OH OH 6-Azauridine R1 R2 R3 R4

Cytarabine H OH H CH Enocitabine C(O)(CH2)2OCH3 OH H CH Gemcitabine H F F CH [0122] These compounds are thought to function as cell Azacitidine H H OH N cycle inhibitors as acting as antimetabolites of pyrimidine. FMdC H CH,F H CH These compounds have been shown useful in the treatment of cell proliferative disorders including, for example, pancre atic, breast, cervical, NSC lung, and bile duct cancers. US 2009/0226500 A1 Sep. 10, 2009 20

[0123] In another aspect, the cell cycle inhibitor is a pyri midine analogue. In one aspect, the pyrimidine analogues have the general structure: O

R2 F ºSN | R1

R1 R2

5 Fluorouracil H H Carmofur C(O)NH(CH2)5OHs H Doxifluridine A1 H wherein positions 2',3' and 5' on the sugarring (R2, Rs and R4, Floxuridine A2 H respectively) can be H, hydroxyl, phosphoryl (see, e.g., U.S. Emitefur CH2OCH2CH3 B Pat. No. 4,086,417) or ester (see, e.g., U.S. Pat. No. 3,894, Tegafur C H 000). Esters can be of alkyl, cycloalkyl, aryl or heterocyclo/ aryl types. The 2' carbon can be hydroxylated at either R, or HO CH3 R2', the other group is H. Alternately, the 2' carbon can be O substituted with halogens e.g., fluoro or difluoro cytidines such as Gemcytabine. Alternately, the sugar can be substi tuted for another heterocyclic group such as a furyl group or OH OH for an alkane, an alkyl ether oran amide linked alkane such as C(O)NH(CH2)3CHs. The 2° amine can be substituted with an A1 HO aliphatic acyl (R1) linked with an amide (see, e.g., U.S. Pat. CH3 No. 3,991,045) or urethane (see, e.g., U.S. Pat. No. 3,894, O 000) bond. It can also be further substituted to form a quater nary ammonium salt. Rs in the pyrimidine ring may be N or CR, where R is H, halogen containing groups, or alkyl (see, OH e.g., U.S. Pat. No. 4,086,417). Re and R, can together can A2 form an oxo group or Re-NH-R, and R7–H. Rs is H or R7 and Rs together can form a double bond or Rs can be X, where X is: CN O 2. O O

CN S. O 2. O O S. cº N O CH3 O N O CH3 B CH3

[012.4] Specific pyrimidine analogues are disclosed in U.S. O Pat. No. 3,894,000 (see, e.g., 2'-O-palmityl-ara-cytidine, 3'-O-benzoyl-ara-cytidine, and more than 10 other C examples); U.S. Pat. No. 3,991,045 (see, e.g., N4-acyl-1-3 D-arabinofuranosylcytosine, and numerous acyl groups derivatives as listed therein, such as palmitoyl. [0126] Other suitable fluoropyrimidine analogues include [0125] In another aspect, the cell cycle inhibitor is a fluo 5-FudR (5-fluoro-deoxyuridine), or an analogue orderivative ropyrimidine analogue, such as 5-fluorouracil, oran analogue thereof, including 5-iododeoxyuridine (5-IudR),5-bromode or derivative thereof, including carmofur, doxifluridene, oxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), emitefur, tegafur, and floxuridine Exemplary compounds and fluorodeoxyuridine monophosphate (5-dPUMP). Exem have the structures: plary compounds have the structures: US 2009/0226500 A1 Sep. 10, 2009 21

wherein N signifies nitrogen and V, W, X, Z can be either carbon or nitrogen with the following provisos. Ring A may O have 0 to 3 nitrogenatoms in its structure. If two nitrogens are R present in ring A, one must be in the W position. If only one | NH is present, it must not be in the Q position. V and Q must not be simultaneously nitrogen. Z and Q must not be simulta HO * neously nitrogen. If Z is nitrogen, Rs is not present. Further O more, R1s are independently one of H, halogen, C1-2 alkyl, C1-2 alkenyl, hydroxyl, mercapto, C1-2 alkylthio, C1-2 alkoxy, C2.7 alkenyloxy, aryloxy, nitro, primary, secondary or tertiary amine containing group. Rs.s are H or up to two of the posi OH tions may contain independently one of OH, halogen, cyano, 5-Fluoro-2'-deoxyuridine: R = F azido, substituted amino, Rs and R2 can together form a 5-Bromo-2'-deoxyuridine: R = Br double bond. Y is H, a C-7 alkylcarbonyl, or a mono- di or tri 5-lodoo-2'-deoxyuridine: R = I phosphate. [0131] Exemplary suitable purine analogues include [0127] These compounds are thought to function as cell 6-mercaptopurine, thiguanosine, thiamiprine, cladribine, flu cycle inhibitors by serving as antimetabolites of pyrimidine. daribine, tubercidin, puromycin, pentoxyfilline; where these These compounds have been shown useful in the treatment of compounds may optionally be phosphorylated. Exemplary cell proliferative disorders such as breast, cervical, non-mela compounds have the structures: noma skin, head and neck, esophageal, bile duct, pancreatic, islet cell, penile, and vulvar cancers. [0128] In another aspect, the cell cycle inhibitor is a purine analogue. Purine analogues have the following general struc R2 ture. Nº | N} | Ri2's N i X R3 2sOC) R1 R2 R3 Ri N i 6-Mercaptopurine H SH H R3 Thioguanosine NH, SH B1 Thiamiprine NH, A. H Cladribine C| NH, B2 Fludarabine F NH, B3 wherein X is typically carbon; R1 is H, halogen, amine or a Puromycin H N(CH3)2 B4 substituted phenyl; R2 is H, a primary, secondary or tertiary Tubercidin H NH, B1 amine, a sulfur containing group, typically –SH, an alkane, a cyclic alkane, a heterocyclic or a sugar; Rs is H, a sugar (typically a furanose or pyranose structure), a substituted sugar or a cyclic or heterocyclic alkane or aryl group. See, A: ºr N e.g., U.S. Pat. No. 5,602,140 for compounds of this type. O \ [0129] In the case of pentostatin, X-R2 is —CH2CH | CH3 (OH)—. In this case a second carbon atom is inserted in the B1: HO ring between X and the adjacent nitrogen atom. The X—N O double bond becomes a single bond. H [0130] U.S. Pat. No. 5,446,139 describes suitable purine analogues of the type shown in the formula. OH OH B2: HO O H

OH B3: HO O OH

OH US 2009/0226500 A1 Sep. 10, 2009 22

or —CH3 or other alkane, or chloronated alkane, typically -continued CH2CH(CH2)C1, or a polycyclic group such as B, or a sub stituted phenyl such as C or a heterocyclic group such as D. R2

N - - N2 | } (ii) R;2s N i R3

R1 R2 R3

B4 HO O (iii)iii H NH2 NH OH (iv) O CH3

O N

H3C N sº iCH3 [0136] Examples of suitable nitrogen mustards are dis Pentoxyfilline- closed in U.S. Pat. No. 3,808.297, wherein A is:

[0132] These compounds are thought to function as cell Os, 2CH3 cycle inhibitors by serving as antimetabolites of purine. |so [0133] In another aspect, the cell cycle inhibitor is a nitro- Ns gen mustard. Many suitable nitrogen mustards are known and R2 are suitably used as a cell cycle inhibitor in the present inven- R3 tion. Suitable nitrogen mustards are also known as cyclophos phamides. [0137) R-2 are H or CH2CH2C1Rs is Hor oxygen-contain [0134] A preferred nitrogen mustard has the general struc ing groups such as hydroperoxy; and R4 can be alkyl, aryl, ture: heterocyclic [0138] The cyclic moiety need not be intact See, e.g., U.S. (i) Pat. Nos. 5,472,956, 4,908,356, 4,841,085 that describe the | following type of structure.

O N Where A is R6 ` S-TNo. [0135) R4, 2NS

wherein R, is H or CH2CH2C1, and R2 g are various substitu O ent groups. `R, [0139| Exemplary nitrogen mustards include methylchlo roethamine, and analogues or derivatives thereof, including methylchloroethamine oxide hydrochloride, novembichin, and mannomustine (a halogenated sugar). Exemplary com pounds have the structures: US 2009/0226500 A1 Sep. 10, 2009 23

-continued º N Sºo

R Mechlorethanime CH3 Novembichin CH3CH(CH3)Cl Prednimustine

[0142] The nitrogen mustard may be chlorambucil, or an Mechlorethanime Oxide HCI analogue orderivative thereof, including melphalan and chlo rmaphazine. Thus, suitable nitrogen mustard type cell cycle inhibitors of the present invention have the structures: [0140] The nitrogen mustard may be cyclophosphamide, ifosfamide, perfosfamide, or torofosfamide, where these compounds have the structures:

R1 o, A. Spø "S-2^c R1 R2 R3 So Chlorambucil CH2COOH H H N • Melphalan COOH NH, H R2 Chlornaphazine H together forms a benzene ring R3

R R2 R3 [0143] The nitrogen mustard may be uracil mustard, which has the structure: Cyclophosphamide H CH2CH2Cl H Ifosfamide CH2CH2Cl H H Perfosfamide CH,CH,Cl H OOH Torofosfamide CH,CH,Cl CH,CH,Cl H

[0141] The nitrogen mustard may be estramustine or an analogue or derivative thereof, including phenesterine, pred nimustine, and estramustine PO4. Thus, suitable nitrogen mustard type cell cycle inhibitors of the present invention [0144] The nitrogen mustards are thought to function as have the structures. cell cycle inhibitors by serving as alkylating agents for DNA. Nitrogen mustards have been shown useful in the treatment of cell proliferative disorders including, for example, small cell lung, breast, cervical, head and neck, prostate, retinoblas toma, and soft tissue sarcoma. [0145] The cell cycle inhibitor of the present invention may be a hydroxyurea. Hydroxyureas have the following general Structure:

R3s N Js N 20–x Estramustine R^ NR, Phenesterine C(CH3)(CH3)3CH(CH3)2 US 2009/0226500 A1 Sep. 10, 2009 24

[0146] Suitable hydroxyureas are disclosed in, for [0153] These compounds are thought to function as cell example, U.S. Pat. No. 6,080,874, wherein R, is: cycle inhibitors by serving as DNA alkylating agents. Mito mycins have been shown useful in the treatment of cell pro liferative disorders such as, for example, esophageal, liver, bladder, and breast cancers. [0154) In another aspect, the cell cycle inhibitor is an alkyl sulfonate, such as busulfan, or an analogue or derivative thereof, such as treosulfan, improsulfan, piposultan, and and R2 is an alkyl group having 14 carbons and Rs is one of H, pipobroman Exemplary compounds have the structures acyl, methyl, ethyl, and mixtures thereof, such as a methyl ether. [0147| Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No. 5,665,768, wherein R, is a cycloalkenyl group, | | for example N-(3-(5-(4-fluorophenylthio)-furyl)-2-cyclo H3C–S—O O—S—CH3 penten-1-yl)N-hydroxyurea; R2 is Horan alkyl group having 1 to 4 carbons and Rs is H; X is H or a cation. O O [0148] Other suitable hydroxyureas are disclosed in, e.g., R U.S. Pat. No. 4,299,778, wherein R, is a phenyl group sub Busulfan single bond stituted with on or more fluorine atoms; R2 is a cyclopropyl Improsultan —CH2—NH–CH2— group; and Rs and X is H. Piposulfan [0149] Other suitable hydroxyureas are disclosed in, eg. U.S. Pat. No. 5,066,658, wherein R, and Rs together with the adjacent nitrogen form: CH3

Pipobroman wherein m is 1 or 2, n is 0–2 and Y is an alkyl group. [0150] In one aspect, the hydroxy urea has the structure: [0155] These compounds are thought to function as cell O cycle inhibitors by serving as DNA alkylating agents. Js _OH [0156] In another aspect, the cell cycle inhibitor is a ben H2N NH zamide. In yet another aspect, the cell cycle inhibitor is a Hydroxyurea nicotinamide. These compounds have the basic structure: [0151] Hydroxyureas are thought to function as cell cycle inhibitors by serving to inhibit DNA synthesis. [0152] In another aspect, the cell cycle inhibitor is a myto micin, such as mitomycin C, or an analogue or derivative thereof, such as porphyromycin. Exemplary compounds have the structures:

wherein X is either O or S: A is commonly NH2 or it can be OH or an alkoxy group; B is N or C–Ra, where Ra is Horan ether-linked hydroxylated alkane such as OCH2CH2OH, the alkane may be linear or branched and may contain one or more hydroxyl groups. Alternately, B may be N–Rs in which case the double bond in the ring involving B is a single bond. R Rs may be H, and alkyl or an aryl group (see, e.g., U.S. Pat. Mitomycin C H No. 4,258,052); R, is H, OR2, SR, or NHRA, where Re is an Porphyromycin CH3 (N-methyl Mitomycin C) alkyl group; and Rs is H, a lower alkyl, an ether linked lower alkyl such as —O-Me or —O-ethyl (see, e.g., U.S. Pat. No. 5,215,738). US 2009/0226500 A1 Sep. 10, 2009

[0157| Suitable benzamide compounds have the structures CH2Br CH2Br CH3NH2"CH2CH2Cl H OH HO H HO H

S NH2 HO H HO H HO H

HO H H OH H OH

H OH H OH H OH Benzamides X = O or S Y = H, OR, CH3 or acetoxy CH2Br CH2Br CH3NH2"CH2CH2Cl Z = H, OR, SR, or NHR R = alkyl group Mitolactol Mitobronitol Mannomustine where additional compounds are disclosed in U.S. Pat. No. [0161] In another aspect, the cell cycle inhibitor is a diazo 5,215,738, (listing some 32 compounds). compound, such as azaserine, or an analogue or derivative [0158] Suitable nicotinamide compounds have the struc thereof, including 6-diazo-5-oxo-L-norleucine and 5-diazou tures: racil (also a pyrimidine analog). Exemplary compounds have the structures:

Z O S NH2 "N-N' – RI R2 22 N ~~ Sº OH O NH2 Nicotinamides X = O or S Z = H, OR, SR, or NHR R1 R2 R = alkyl group Azaserine O single bond 6-diazo-5-oxo- single bond CH2 [0159] where additional compounds are disclosed in U.S. L-norleucine Pat. No. 5,215,738, [0162] Other compounds that may serve as cell cycle inhibitors according to the present invention are pazelliptine; wortmannin; metoclopramide; RSU; buthionine sulfoxime; R O tumeric; curcumin; AG337, a thymidylate synthase inhibitor; R2 AsN—P–NH i Jº o’ Sº, levamisole; lentinan, a polysaccharide; razoxane, an EDTA R2 | analogue; indomethacin; chlorpromazine; O. and f interferon; N MnBOPP; gadolinium texaphyrin, 4-amino-1,8-naphthalim R2 ide; staurosporine derivative of CGP; and SR-2508. R3 R2 [0163] Thus, in one aspect, the cell cycle inhibitoris a DNA R2 R2 alylating agent. In another aspect, the cell cycle inhibitoris an anti-microtubule agent. In another aspect, the cell cycle R1 R2 inhibitor is a topoisomerase inhibitor. In another aspect, the Benzodepa phenyl H cell cycle inhibitor is a DNA cleaving agent. In another Meturedepa CHs CHs aspect, the cell cycle inhibitor is an antimetabolite. In another Uredepa CH3 H aspect, the cell cycle inhibitor functions by inhibiting adenos ine deaminase (e.g., as a purine analogue). In another aspect, O the cell cycle inhibitor functions by inhibiting purine ring H3C {\ synthesis and/or as a nucleotide interconversion inhibitor (eg. O as a purine analogue such as mercaptopurine) In another aspect, the cell cycle inhibitor functions by inhibiting dihy drofolate reduction and/or as a thymidine monophosphate N *. block (e.g., methotrexate). In another aspect, the cell cycle O O inhibitor functions by causing DNA damage (e.g. bleomy NoH, cin). In another aspect, the cell cycle inhibitor functions as a Carboquone DNA intercalation agent and/or RNA synthesis inhibition (e.g., doxorubicin, aclarubicin, or detorubicin (acetic acid, diethoxy-, 2-[4-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hex [0160] In another aspect, the cell cycle inhibitor is a halo opyranosyl)oxy]-1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy genated sugar, such as mitolactol, oran analogue orderivative 7-methoxy-6,11-dioxo-2-naphthacenyl]-2-oxoethyl ester, thereof, including mitobronitol and mannomustine. Exem (2S-cis)-)). In another aspect, the cell cycle inhibitor func plary compounds have the structures: tions by inhibiting pyrimidine synthesis (e.g., N-phospho US 2009/0226500 A1 Sep. 10, 2009 26 noacetyl-L-aspartate). In another aspect, the cell cycle inhibi glucopyranosyl)oxy)-, (5R-(5alpha,5a?,8aAlpha,93(R*)))-), tor functions by inhibiting ribonucleotides (e.g., eptaplatin (platinum, ((4R,5R)-2-(1-methylethyl)-1,3-diox hydroxyurea). In another aspect, the cell cycle inhibitor func olane-4,5-dimethanamine-kappa N4,kappa N5)(propanedio tions by inhibiting thymidine monophosphate (e.g., 5-fluo ato(2-)-kappa O1, kappa O3)-, (SP-4-2)-), amrubicin hydro rouracil). In another aspect, the cell cycle inhibitor functions chloride (5,12-naphthacenedione, 9-acetyl-9-amino-7-((2 by inhibiting DNA synthesis (e.g., cytarabine). In another deoxy-6D-erythro-pentopyranosyl)oxy)-7,8,9,10 aspect, the cell cycle inhibitor functions by causing DNA tetrahydro-6,11-dihydroxy-, hydrochloride, (7S-cis)-), adduct formation (e.g., platinum compounds). In another ifosfamide (2H-1,3,2-oxazaphosphorin-2-amine, N,3-bis(2 aspect, the cell cycle inhibitor functions by inhibiting protein synthesis (e.g., L-asparginase). In another aspect, the cell chloroethyl)tetrahydro-,2-oxide), cladribine (adenosine, cycle inhibitor functions by inhibiting microtubule function 2-chloro-2'-deoxy-), mitobronitol (D-mannitol, 1,6-di (e.g., taxanes). In another aspect, the cell cycle inhibitor acts bromo-1,6-dideoxy-), fludaribine phosphate (9H-purin-6 at one or more of the steps in the biological pathway shown in amine, 2-fluoro-9-(5-O-phosphono-fl-D-arabinofurano syl)-), enocitabine (docosanamide, N-(1-fl-D FIG. 1. arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-), [0164] Additional cell cycle inhibitors useful in the present invention, as well as a discussion of the mechanisms of action, vindesine (vincaleukoblastine, 3-(aminocarbonyl)-O4 may be found in Hardman J. G., Limbird L. E. Molinoff R. B., deacetyl-3-de(methoxycarbonyl)-), idarubicin (5,12-naph Ruddon R W., Gilman A. G. editors, Chemotherapy of Neo thacenedione, 9-acetyl-7-((3-amino-2,3,6-trideoxy-alpha-L plastic Diseases in Goodman and Gilman’s The Pharmaco lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,9,11 logical Basis of Therapeutics Ninth Edition, McGraw-Hill trihydroxy-, (7S-cis)-), zinostatin (neocarzinostatin), Health Professions Division, New York, 1996, pages 1225 Vincristine (vincaleukoblastine, 22-oxo-), tegafur (2,4(1H, 1287. See also U.S. Pat. Nos. 3,387,001: 3,808.297; 3,894, 3H)-pyrimidinedione, 5-fluoro-1-(tetrahydro-2-furanyl)-), 000; 3,991,045; 4,012,390; 4,057,548; 4,086,417; 4,144,237; Taz0Xaine (2,6-piperazinedione, 4,4'-(1-methyl-1,2 4,150,146; 4,210,584; 4,215,062; 4,250,189; 4,258,052: ethanediyl)bis-), methotrexate (L-glutamic acid, N-(4-(((2,4 4,259,242; 4,296,105; 4,299,778; 4,367,239; 4,374,414: diamino-6-pteridinyl)methyl)methylamino)benzoyl)-), ralti 4,375,432; 4,472.379; 4,588,831; 4,639,456; 4,767,855: trexed (L-glutamic acid, N-((5-(((1,4-dihydro-2-methyl-4 4,828,831; 4.841,045; 4.841,085; 4,908.356; 4,923,876: oxo-6-quinazolinyl)methyl)methylamino)-2-thienyl) 5,030,620; 5,034,320, 5,047,528: 5,066.658; 5,166,149: carbonyl)-), oxaliplatin (platinum, (1,2 5,190,929: 5,215.738: 5,292.731; 5,380.897; 5,382,582: cyclohexanediamine-N,N')(ethanedioato(2-)-O,O')-, (SP-4 5,409,915; 5,440,056; 5,446,139; 5,472,956; 5,527,905; 2-(1R-trans))-), doxifluridine (uridine, 5'-deoxy-5-fluoro-), 5,552,156; 5,594,158; 5,602,140, 5,665,768; 5,843,903; mitolactol (galactitol, 1,6-dibromo-1,6-dideoxy-), piraubicin 6,080,874; 6,096,923; and RE030561. (5,12-naphthacenedione, 10-((3-amino-2,3,6-trideoxy-4-O [0165] In another embodiment, the cell-cycle inhibitor is (tetrahydro-2H-pyran-2-yl)-alpha-L-lyxo-hexopyranosyl) camptothecin, mitoxantrone, etoposide, 5-fluorouracil, doxo oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxy rubicin, methotrexate, peloruside A, mitomycin C, or a acetyl)-1-methoxy-, (8S-(8 alpha, 10 alpha(S*)))-), docetaxel CDK-2 inhibitor or an analogue or derivative of any member ((2R,3S)—N-carboxy-3-phenylisoserine, N-tert-butyl ester, of the class of listed compounds. 13-ester with 53,20-epoxy-1,2 alpha,4,73,103,13 alpha [0166] In another embodiment, the cell-cycle inhibitor is hexahydroxytax-11-en-9-one 4-acetate 2-benzoate-), HTI-286, plicamycin; or mithramycin, or an analogue or capecitabine (cytidine, 5-deoxy-5-fluoro-N-((pentyloxy)car derivative thereof. bonyl)-), cytarabine (2(1H)-pyrimidone, 4-amino-1-fl-D-ara [0167] Other examples of cell cycle inhibitors also include, bino furanosyl-), valrubicin (pentanoic acid, 2-(1,2,3,4,6,11 e.g., 7-hexanoyltaxol (QP-2), cytochalasin A, lantrunculin D, hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-((2, actinomycin-D, Ro-31-7453 (3-(6-nitro-1-methyl-3-in 3,6-trideoxy-3-((trifluoroacetyl)amino)-alpha-L-lyxo dolyl)-4-(1-methyl-3-indolyl)pyrrole-2,5-dione), PNU hexopyranosyl)oxy)-2-naphthacenyl)-2-oxoethyl ester (2S 151807, brostallicin, C2-ceramide, cytarabine ocfosfate cis)-), trofosfamide (3-2-(chloroethyl)-2-(bis(2-chloroethyl) (201H)-pyrimidinone, 4-amino-1-(5-O-(hydroxy(octadecy amino)tetrahydro-2H-1,3,2-oxazaphosphorin 2-oxide), loxy)phosphinyl)-fl-D-arabinofuranosyl)-, monosodium prednimustine (pregna-1,4-diene-3,20-dione, 21-(4-(4-(bis salt), paclitaxel (53.20-epoxy-1,2 alpha,4,73,103,13 alpha (2-chloroethyl)amino)phenyl)-1-oxobutoxy)-1,1,17-dihy hexahydroxytax-11-en-9-one-4,10-diacetate-2-benzoate-13 droxy-, (113)-), lomustine (Urea, N-(2-chloroethyl)-N'-cy (alpha-phenylhippurate)), doxorubicin (5,12-naphthacenedi clohexyl-N-nitroso-), epirubicin (5,12-naphthacenedione, One, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo 10-((3-amino-2,3,6-trideoxy-alpha-L-arabino-hexopyrano hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy syl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxy 8-(hydroxyacetyl)-1-methoxy-, (8S)-cis-), daunorubicin (5,12-naphthacenedione, 8-acetyl-10-((3-amino-2,3,6 acetyl)-1-methoxy-, (8S-cis)-), or an analogue or derivative trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tet thereof). rahydro-6,8,11-trihydroxy-1-methoxy-, (8S-cis)-), gemcit [0168] In certain embodiments, the fibrosis-inhibiting abine hydrochloride (cytidine, 2’-deoxy-2,2'-difluoro-, compound is a cell cycle inhibitor (e.g., SNS-595 (Sunesis) or monohydrochloride), nitacrine (1,3-propanediamine, N,N an analogue or derivative thereof). dimethyl-N'-(1-nitro-9-acridinyl)-), carboplatin (platinum, [0169] In certain embodiments, the cell cycle inhibitor is an diammine(1,1-cyclobutanedicarboxylato(2-))-, (SP-4-2)-), anti-microtubule agent (e.g., synthadotin, or an analogue or altretamine (1,3,5-triazine-2,4,6-triamine, N,N,N',N',N',N' derivative thereof). hexamethyl-), teniposide (furo(3',4':6,7)naphtho(2,3-d)-1,3 [0170] In certain embodiments, cell cycle inhibitor is a dioxol-6(5ah)-one, 5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5 microtubule stimulant (e.g., KRX-0403, or an analogue or dimethoxyphenyl)-9-((4,6-O-(2-thienylmethylene)-fl-D derivative thereof).

US 2009/0226500 A1 Sep. 10, 2009 30

[0202] The structures of sirolimus, everolimus, and tacroli examples of sirolimus analogues and derivatives include mus are provided below: ABT-578 and others may be found in PCT Publication Nos. WO 97/10502. WO 96/41807, WO 96/35423, WO 96/03430, WO 9600282, WO 95/16691, WO 95/5328, WO 95/07468, WO95/04738, WO95/04060, WO 94/25022, WO 94/21644, Name Code Name Company Structure WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, Everolimus SAR–943 Novartis See below WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, Sirolimus AY-22989 Wyeth See below WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, RAPAMUNE NSC-226080 Rapamycin WO 93/04680, WO 92/14737, and WO 92/05179. Represen Tacrolimus FK506 Fujusawa See below tative U.S. patents include U.S. Pat. Nos. 6,342,507; 5,985, 890; 5,604,234, 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189, 5,534,632; 5,527,907; 5,484,799; 5,457,194, 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901: 5,258,389: 5,252,732: 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241, 5,200,411; 5,198.421; 5,147,877; 5,140,018; 5,116,756; 5,109,112, 5,093,338; and 5,091,389. [0204] In one aspect, the fibrosis-inhibiting agent may be, e.g., rapamycin (sirolimus), everolimus, biolimus, tresperi mus, auranofin, 27-O-demethylrapamycin, tacrolimus, gus perimus, pimecrolimus, or ABT-578. [0205] 19. Inosine Monophosphate Dehydrogenase Inhibi torS [0206] In another embodiment, the pharmacologically active compound is an inosine monophosphate dehydroge nase (IMPDH) inhibitor (e.g., mycophenolic acid, mycophe molate mofetil (4-hexenoic acid, 6-(1,3-dihydro-4-hydroxy 6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-, Everolimus 2-(4-morpholinyl)ethyl ester, (E)-), ribavirin (1H-1,2,4-tria zole-3-carboxamide, 1-3-D-ribofuranosyl-), tiazofurin (4-thiazolecarboxamide, 2-6-D-ribofuranosyl-), viramidine, aminothiadiazole, thiophenfurin, tiazofurin) or an analogue or derivative thereof. Additional representative examples are included in U.S. Pat. Nos. 5,536,747, 5,807,876, 5,932,600, 6,054,472, 6,128,582, 6,344,465, 6,395,763, 6,399,773, 6,420,403, 6,479,628, 6,498,178, 6,514,979, 6,518,291, 6,541,496, 6,596,747, 6,617,323, 6,624,184, Patent Applica tion Publication Nos. 2002/0040022A1, 2002/0052513A1. 2002/0055483A1, 2002/0068346A1, 2002/011 1378A1, 2002/0111495A1, 2002/0123520A1, 2002/0143176A1, 2002/0147160A1, 2002/0161038A1, 2002/0173491A1, 2002/0183315A1, 2002/0193612A1, 2003/0027845A1, 2003/0068302A1, 2003/0105073A1, 2003/0130254A1, 2003/0143197A1, 2003/0144300A1, 2003/0166201A1, 2003/0181497A1, 2003/0186974A1, 2003/0186989A1, 2003/0195202A1, and PCT Publication Nos. WO 0024725A1, WO 00/25780A1, WO 00/2619741, WO 00/51615A1, WO 00/56331A1, WO 00/73288A1, WO 01/00622A1, WO 01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO 02/16382A1, WO 02/18369A2, WO 2051814A1, WO 2057287A2, WO2057425A2, WO 2060875A1, WO 2060896A1, WO 2060898A1, WO 2068058A2, WO 3020298A1, WO 3037349A1, WO 303.9548A1, WO 3045901A2, WO 3047512A2, WO 3053958A1, WO 3055447A2, WO 3059269A2, WO 3063573A2, WO 3087071A1, WO 90/01545A1, WO 97/40028A1, WO 97/41211A1, WO 98/40381A1, and WO 99/55663A1). Sirolimus [0207] Leukotriene Inhibitors [0208] In another embodiment, the pharmacologically [0203] Further sirolimus analogues and derivatives include active compound is a leukotreine inhibitor (e.g., ONO-4057 tacrolimus and derivatives thereof (e.g., EP0184162B1 and (benzenepropanoic acid, 2-(4-carboxybutoxy)-6-((6-(4 U.S. Pat. No. 6,258,823) everolimus and derivatives thereof methoxyphenyl)-5-hexenyl)oxy)-, (E)-), ONO-LB-448, (e.g., U.S. Pat. No. 5,665,772). Further representative pirodomast 1,8-naphthyridin-2(1H)-one, 4-hydroxy-1-phe

US 2009/0226500 A1 Sep. 10, 2009 dazol-1-yl)butyl)imino))-), roxithromycin (erythromycin, GW-597599, lanepitant ((1,4'-bipiperidine)-1'-acetamide, 9-(0-((2-methoxyethoxy)methyl)oxime)), rokitamycin (leu N-(2-(acetyl((2-methoxyphenyl)methyl)amino)-1-(1H-in comycin V, 4B-butanoate 3B-propanoate), RV-11 (erythro dol-3-ylmethyl)ethyl)-(R)—), molpitantium chloride (1-azo mycin monopropionate mercaptosuccinate), midecamycin niabicyclo[22.2]octane, 1-[2-[3-(3,4-dichlorophenyl)-1-[[3 acetate (leucomycin V, 3B,9-diacetate 3,4B-dipropanoate), (1-methylethoxy)phenyl]acetyl]-3-piperidinyl]ethyl]-4 midecamycin (leucomycin V, 3,4B-dipropanoate), josamycin phenyl-, chloride, (S)—), or saredutant (benzamide, N-[4-(4 (leucomycin V, 3-acetate 4B-(3-methylbutanoate), or an ana (acetylamino)-4-phenyl-1-piperidinyl]-2-(3,4 logue or derivative thereof). dichlorophenyl)butyl]-N-methyl-, (S)—), or vofopitant [0258] 44. GPIIb IIIa Receptor Antagonists (3-piperidinamine, N-IL2-methoxy-5-[5-(trifluoromethyl) [0259] In another embodiment, the pharmacologically 1H-tetrazol-1-yl)phenyl]methyl]-2-phenyl-, (2S,3S)—, oran active compound is a GPIIb IIIa receptor antagonist (e.g., analogue or derivative thereof). tirofiban hydrochloride (L-tyrosine, N-(butylsulfonyl)-O-(4 [0271] 50. Neurokinin 3 Antagonist (4-piperidinyl)butyl)-, monohydrochloride-), eptifibatide [0272] In another embodiment, the pharmacologically (L-cysteinamide, N6-(aminoiminomethyl)-N2-(3-mercapto active compound is a neurokinin 3 antagonist (e.g., talnetant 1-oxopropyl)-L-lysylglycyl-L-alpha-aspartyl-L-tryptophyl (4-quinolinecarboxamide, 3-hydroxy-2-phenyl-N-[(1S)-1 L-prolyl-, cyclic(1->6)-disulfide), xemilofiban hydrochlo phenylpropyl]-, or an analogue or derivative thereof). ride, or an analogue or derivative thereof). [0273) 51. Neurokinin Antagonist [0260] 45. Endothelin Receptor Antagonists [0274] In another embodiment, the pharmacologically [0261] In another embodiment, the pharmacologically active compound is a neurokinin antagonist (e.g., GSK active compound is an endothelin receptor antagonist (e.g., 679769, GSK-823296, SR-489686 (benzamide N-[4-(4 bosentan (benzenesulfonamide, 4-(1,1-dimethylethyl)-N-(6 (acetylamino)-4-phenyl-1-piperidinyl]-2-(3,4-dichlorophe (2-hydroxyethoxy)-5-(2-methoxyphenoxy)(2,2'-bipyrimi nyl)butyl]-N-methyl-, (S)—), SB-223412, SB-235375 din)-4-yl)-, or an analogue or derivative thereof). (4-quinolinecarboxamide, 3-hydroxy-2-phenyl-N-[(1S)-1 [0262] 46. Peroxisome Proliferator-Activated Receptor phenylpropyl]-), UK-226471, or an analogue or derivative Agonists thereof) [0263] In another embodiment, the pharmacologically [0275] 52. VLA-4Antagonist active compound is a peroxisome proliferator-activated [0276] In another embodiment, the pharmacologically receptor agonist (e.g., gemfibrozil (pentanoic acid, 5-(2,5 active compound is a VLA-4 antagonist (e.g., GSK683699, or dimethylphenoxy)-2,2-dimethyl-), fenofibrate (propanoic an analogue or derivative thereof). acid, 2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-, 1-methyl (0277] 53. Osteoclast Inhibitor ethyl ester), ciprofibrate (propanoic acid, 2-(4-(2,2-dichloro [0278] In another embodiment, the pharmacologically cyclopropyl)phenoxy)-2-methyl-), rosiglitazone maleate active compound is a osteoclast inhibitor (e.g., ibandronic (2,4-thiazolidinedione, 5-((4-(2-(methyl-2-pyridinylamino) acid (phosphonic acid, [1-hydroxy-3-(methylpentylamino) ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1)), pioglita propylidene|bis-), alendronate sodium, or an analogue or zone hydrochloride (2,4-thiazolidinedione, 5-((4-(2-(5 derivative thereof). ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, [0279 54. DNA topoisomerase ATP Hydrolysing Inhibitor monohydrochloride (+/-)-), etofylline clofibrate (propanoic [0280] In another embodiment, the pharmacologically acid, 2-(4-chlorophenoxy)-2-methyl-, 2-(1,2,3,6-tetrahydro active compound is a DNA topoisomerase ATP hydrolysing 1,3-dimethyl-2,6-dioxo-7H-purin-7-yl)ethyl ester), etofi inhibitor (e.g., enoxacin (1,8-naphthyridine-3-carboxylic brate (3-pyridinecarboxylic acid, 2-(2-(4-chlorophenoxy)-2 acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazi methyl-1-oxopropoxy)ethyl ester), clinofibrate (butanoic nyl)-), levofloxacin (7H-Pyrido[1,2,3-de]-1,4-benzoxazine acid, 2,2'-(cyclohexylidenebis(4,1-phenyleneoxy)bis(2-me 6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10-(4-me thyl-)), bezafibrate (propanoic acid, 2-(4-(2-((4-chloroben thyl-1-piperazinyl)-7-oxo-, (S)—), ofioxacin (7H-pyrido[1, zoyl)amino)ethyl)phenoxy)-2-methyl-), binifibrate (3-py 2,3-de]-1,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3 ridinecarboxylic acid, 2-(2-(4-chlorophenoxy)-2-methyl-1 dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-. oxopropoxy)-1,3-propanediyl ester), or an analogue or (+/-)-), pefloxacin (3-quinolinecarboxylic acid, 1-ethyl-6 derivative thereof). fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-), [0264] In one aspect, the pharmacologically active com pipemidic acid (pyrido[2,3-d]pyrimidine-6-carboxylic acid, pound is a peroxisome proliferator-activated receptor alpha 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-), pirarubicin agonist, such as GW-590735, GSK-677954, GSK501516, (5,12-naphthacenedione, 10-[[3-amino-2,3,6-trideoxy-4-O pioglitazone hydrochloride (2,4-thiazolidinedione, 5-[[4-[2 (tetrahydro-2H-pyran-2-yl)-alpha-L-lyxo-hexopyranosyl] (5-ethyl-2-pyridinyl)ethoxyphenyl]methyl]-, monohydro oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxy chloride (+/-)-, or an analogue or derivative thereof). acetyl)-1-methoxy-, [8S-[8 alpha,10 alpha(S*)]]-), [0265] 47. Estrogen Receptor Agents sparfloxacin (3-quinolinecarboxylic acid, 5-amino-1-cyclo [0266] In another embodiment, the pharmacologically propyl-7-(3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-di active compound is an estrogen receptor agent (eg. estradiol, hydro-4-oxo-, cis-), AVE-6971, cinoxacin ([1,3]dioxolo[4,5 17-fl-estradiol, or an analogue or derivative thereof). g]cinnoline-3-carboxylic acid, 1-ethyl-1,4-dihydro-4-oxo-), [0267] 48. Somatostatin Analogues or an analogue or derivative thereof) [0268] In another embodiment, the pharmacologically [0281] 55. Angiotensin I Converting Enzyme Inhibitor active compound is a somatostatin analogue (e.g., angiopep [0282] In another embodiment, the pharmacologically tin, or an analogue or derivative thereof). active compound is an angiotensin I converting enzyme [0269] 49. Neurokinin 1 Antagonists inhibitor (e.g., ramipril (cyclopental blpyrrole-2-carboxylic [0270] In another embodiment, the pharmacologically acid, 1-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl)amino]-1 active compound is a neurokinin 1 antagonist (e.g., oxopropyl]octahydro-, [2S-[1-[R*(R*)].2 alpha,3aff,6affl|-), US 2009/0226500 A1 Sep. 10, 2009 36 trandolapril (1H-indole-2-carboxylic acid, 1-[2-[(1-carboxy [0297] 63. Cytosolic Phospholipase A2-alpha Inhibitors 3-phenylpropyl)amino]-1-oxopropyl]octahydro-, [2S-[1|R* [0298] In another embodiment, the pharmacologically (R*)].2 alpha,3a alpha, 7aff]]-), fasidotril (L-alanine, active compound is a cytosolic phospholipase A2-alpha N-[(2S)-3-(acetylthio)-2-(1,3-benzodioxol-5-ylmethyl)-1 inhibitor such as efipladib (PLA-902) or analogue or deriva oxopropyl]-, phenylmethyl ester), cilazapril (6H-pyridazino tive thereof. [1,2-al? 1,2|diazepine-1-carboxylic acid, 9-[[1-(ethoxycarbo [0299| 64. PPAR Agonist nyl)-3-phenylpropyl)amino]octahydro-10-oxo-. [1S-[1 [0300] In another embodiment, the pharmacologically alpha, 9 alpha(R*)]]-), ramipril (cyclopental blpyrrole-2-car active compound is a PPAR Agonist (e.g., Metabolex ((-) boxylic acid, 1-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl] benzeneacetic acid, 4-chloro-alpha-3-(trifluoromethyl) amino]-1-oxopropyl]octahydro-, [2S-[1|R*(R*)], 2 alpha, phenoxy]-, 2-(acetylamino)ethyl ester), balaglitazone (5-(4 (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl-methoxy) 3aff,3af,6aß]]-, or an analogue or derivative thereof). benzyl)-thiazolidine-2,4-dione), ciglitazone (2,4 [0283] 56. Angiotensin II Antagonist thiazolidinedione, 5-[[4-[(1-methylcyclohexyl)methoxy] [0284] In another embodiment, the pharmacologically phenyl]methyl]-), DRF-10945, farglitazar, GS K-677954, active compound is an angiotensin II antagonist (e.g., GW-409544, GW-501516, GW-590735, GW-590735, HR-720 (1H-imidazole-5-carboxylic acid, 2-butyl-4-(meth K-111, KRP-101, LSN-862, LY-519818, LY-674, LY-929, ylthio)-1-[[2'-[[[(propylamino)carbonyl]amino]sulfonyl][1, muraglitazar, BMS-298585 (Glycine, N-[(4-methoxyphe 1'-biphenyl]-4-yl)methyl]-, dipotassium salt, or an analogue noxy)carbonyl]-N–[[4-[2-(5-methyl-2-phenyl-4-oxazolyl) or derivative thereof). ethoxyphenyl]methyl]-), netoglitazone; isaglitazone (2,4 [0285] 57. Enkephalinase Inhibitor thiazolidinedione, 5-[[6-[(2-fluorophenyl) methoxy]-2 naphthalenyl]methyl]-), Actos AD-4833; U-72107A (2,4 [0286] In another embodiment, the pharmacologically thiazolidinedione, 5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy] active compound is an enkephalinase inhibitor (e.g., Aventis phenyl]methyl]-, monohydrochloride (+/-)-), JTT-501; 100240 (pyrido[2,1-a??2]benzazepine-4-carboxylic acid, PNU-182716 (3,5-Isoxazolidinedione, 4-[[4-[2-(5-methyl 7-[2-(acetylthio)-1-oxo-3-phenylpropyl)amino]-1,2,3,4,6, 2-phenyl-4-oxazolyl)ethoxyphenyl]methyl]-), AVANDIA 7,8,12b-octahydro-6-oxo-[4S-[4 alpha, 7 alpha(R*), (from SB Pharmco Puerto Rico, Inc. (Puerto Rico), BRL 12bf{||-), AVE-7688, or an analogue or derivative thereof) 48482, BRL-49653, BRL-49653c, NYRACTA and Venvia [0287) 58. Peroxisome Proliferator-Activated Receptor (both from (SmithKline Beecham (United Kingdom)), tesa Gamma Agonist Insulin Sensitizer glitazar ((2S)-2-ethoxy-3-[4-(2-[4-(methylsulfonyl)oxy] phenyl]ethoxyphenyl] propanoic acid), troglitazone (2,4 [0288] In another embodiment, the pharmacologically Thiazolidinedione, 5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8 active compound is peroxisome proliferator-activated recep tetramethyl-2H-1-benzopyran-2-yl)methoxyphenyl] tor gamma agonist insulin sensitizer (e.g., rosiglitazone male methyl]-), and analogues and derivatives thereof). ate (2,4-thiazolidinedione, 5-((4-(2-(methyl-2-pyridiny [0301] 65. Immunosuppressants lamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1), [0302] In another embodiment, the pharmacologically farglitazar (GI-262570, GW-2570, GW-3995, GW-5393, active compound is an immunosuppressant (e.g., batebulast GW-9765), LY-929, LY-519818, LY-674, or LSN-862), or an (cyclohexanecarboxylic acid, 4-[[(aminoiminomethyl) analogue or derivative thereof). amino]methyl]-, 4-(1,1-dimethylethyl)phenyl ester, trans-), [0289] 59. Protein Kinase C Inhibitor cyclomunine, exalamide (benzamide, 2-(hexyloxy)-), LYN [0290] In another embodiment, the pharmacologically 001, CCI-779 (rapamycin 42-(3-hydroxy-2-(hydroxym active compound is a protein kinase C inhibitor, such as ethyl)-2-methylpropanoate)),1726; 1726-D; AVE-1726, or ruboxistaurin mesylate (9H,18H-5,21:12,17-dimethenod an analogue or derivative thereof). ibenzo(e.k)pyrrolo(3,4-h)(1,4,13)oxadiazacyclohexadecine [0303] 66. Erb Inhibitor 18,20019FI)-dione,9-((dimethylamino)methyl)-6,7,10,11 [0304] In another embodiment, the pharmacologically tetrahydro-, (S)—), safingol (1,3-octadecanediol, 2-amino-, active compound is an Erb inhibitor (e.g., camertinib dihydro |S–(R*,R*)]-), or enzastaurin hydrochloride (1H-pyrole-2, chloride (N-[4-(3-(chloro-4-fluoro-phenylamino)-7-(3-mor 5-dione, 3-(1-methyl-1H-indol-3-yl)-4-[1-[1-(2-pyridinylm pholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide dihydro ethyl)-4-piperidinyl]-1H-indol-3-yl]-, monohydrochloride), chloride), CP-724714, or an analogue or derivative thereof). or an analogue or derivative thereof. [0305] 67. Apoptosis Agonist [0291) 60. ROCK (rho-Associated Kinase) Inhibitors [0306] In another embodiment, the pharmacologically [0292] In another embodiment, the pharmacologically active compound is an apoptosis agonist (e.g., CEFLATO active compound is a ROCK (rho-associated kinase) inhibi NIN (CGX-635) (from Chemgenex Therapeutics, Inc., tor, such as Y-27632, HA-1077, H-1152 and 4-1-(ami Menlo Park, Calif.), CHML, LBH-589, metoclopramide noalkyl)-N-(4-pyridyl)cyclohexanecarboxamide or an ana (benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl] 2-methoxy-), patupilone (4,17-dioxabicyclo(14.1.0)heptade logue or derivative thereof. cane-5,9-dione, 7,11-dihydroxy-8,8,10,12,16-pentamethyl [0293] 61. CXCR3 Inhibitors 3-(1-methyl-2-(2-methyl-4-thiazolyl)ethenyl, (1R,3S,7S, [0294] In another embodiment, the pharmacologically 10R,11S, 12S,16R)), AN-9; pivanex (butanoic acid, (2,2 active compound is a CXCR3 inhibitor such as T487, dimethyl-1-oxopropoxy)methyl ester), SL-100, SL-102; T0906487 or analogue or derivative thereof SL-11093: SL-1 1098. SL-1 1099: SL-93; SL-98. SL-99, or an [0295) 62. Itk Inhibitors analogue or derivative thereof) [0296) In another embodiment, the pharmacologically [0307| 68. Lipocortin Agonist active compound is an Itkinhibitor such as BMS-509744 or [0308] In another embodiment, the pharmacologically an analogue or derivative thereof. active compound is an lipocortin agonist (e.g., CGP-13774 US 2009/0226500 A1 Sep. 10, 2009 37

(9Alpha-chloro-6Alpha-fluoro-113,17alpha-dihydroxy (UCB), Pharmaprojects No. 6603 (Wyeth), TBC-3342, TBC 16Alpha-methyl-3-oxo-1,4-androstadiene-17'-carboxylic 772, and TBC-3486 (Encysive Pharmaceuticals), TBC-4746 acid-methylester-17-propionate), or analogue or derivative (Schering-Plough), or a VLA4/VCAM inhibitor (Elan Phar thereof). maceuticals), ZD-7349 (AstraZeneca), or an analogue or [0309| 69. VCAM-1 Antagonist derivative thereof). [0310] In another embodiment, the pharmacologically [0329] 79. Alpha 7 Nicotinic Receptor Agonist active compound is a VCAM-1 antagonist (e.g., DW-908e, or [0330] In another embodiment, the fibrosis-inhibiting com an analogue or derivative thereof). pound is an alpha 7 nicotinic receptor agonist (e.g., AZD [0311] 70. Collagen Antagonist 0328 (AstraZeneca), galantamine (CAS No. 357-70-0) (Syn [0312] In another embodiment, the pharmacologically aptec), MEM-3454 or nicotinic alpha-7 agonist (Memory active compound is a collagen antagonist (e.g., E-5050 (Ben Pharmaceuticals and Critical Therapeutics), Pharmaprojects zenepropanamide, 4-(2,6-dimethylheptyl)-N-(2-hydroxy No. 4779 (AstraZeneca), PNU-282987 (Pfizer), SSR-180711 ethyl)-3-methyl-), lufironil (2,4-Pyridinedicarboxamide, (Sanofi-Aventis), TC-1698 or TC-5280 (Targacept), or an N,N'-bis(2-methoxyethyl)-), or an analogue or derivative analogue or derivative thereof). thereof). [0313| 71. Alpha 2 Integrin Antagonist [0331] 80. Angiogenesis Inhibitors [0314] In another embodiment, the pharmacologically [0332] In one embodiment, the fibrosis-inhibiting com active compound is an alpha 2 integrin antagonist (e.g., pound is an angiogenesis inhibitor (e.g., AG-12,958 (Pfizer), E-7820, or an analogue or derivative thereof). ATN-161 (Attenuon LLC), neovastat, an angiogenesis inhibi [0315|| 72. TNF Alpha Inhibitor tor from Jerina AG (Germany), NM-3 (Mercian), VGA-1155 [0316] In another embodiment, the pharmacologically (Taisho), FCE-26644 (Pfizer), FCE-26950 (Pfizer), FPMA active compound is a TNF alpha inhibitor (e.g., ethyl pyru (Meiji Daries), FR-111142 (Fujisawa), GGTI-298, GM-1306 vate, Genz-29155, lentinan (Ajinomoto Co., Inc. (Japan)), (Ligand), GPA-1734 (Novartis), NNC-47-0011 (Novo Nord linomide (3-quinolinecarboxamide, 1,2-dihydro-4-hydroxy isk), herbamycin (Nippon Kayaku), lenalidomide (Cele N,1-dimethyl-2-oxo-N-phenyl-), UR-1505, orananalogue or gene), IP-10 (NIH), ABT-828 (Abbott), KIN-841 (Tokushima University, Japan), SF-1126 (Semafore Pharma derivative thereof). ceuticals), laminin technology (NIH), CHIR-258 (Chiron), [0317| 73. Nitric Oxide Inhibitor NVP-AEW541 (Novartis), NVP-AEW541 (Novartis), [0318] In another embodiment, the pharmacologically Vt16907 (Alchemia), OXI-8007 (Oxigene), EG-3306 (Ark active compound is a nitric oxide inhibitor (e.g., guanidioet Therapeutics), Maspin (Arriva), ABT-567 (Abbott), hyldisulfide, or an analogue or derivative thereof). PPI-2458 (Praecis Pharmaceuticals), CC-5079, CC-4089 [0319| 74. Cathepsin Inhibitor (Celgene), HIF-1alpha inhibitors (Xenova), S-247 (Pfizer), [0320] In another embodiment, the pharmacologically AP-23573 (Ariad), AZD-9935 (Astra Zeneca), mebendazole active compound is a cathepsin inhibitor (e.g., SB-462795 or (Introgen Therapeutics), MetAP-2 inhibitors (GlaxoSmith an analogue or derivative thereof). Kline), AG-615 (Angiogene Pharmaceuticals), Tie-2 antago [0321] 75. Adensosine A2A Receptor Antagonist nists (Hybrigenics), NC-381, CYC-381, NC-169, NC-219, [0322] In another embodiment, the fibrosis-inhibiting.com NC-383, NC-384, NC-407 (Lorus Therapeutics), ATN-224 pound is an adensosineA2A receptor antagonist (e.g., Sch (Aftenuon), ON-01370 (Onconova), Vitronectin antagonists 63390 (Schering-Plough) or an A2A receptor antagonists (Amgen), SDX-103 (Salmedix), Vitronectin antagonists from Almirall-Prodesfarma, SCH-58261 (CAS No. 160098 (Shire), CHP (Riemser), TEK (Amgen), Anecortave acetate 96-4), or an analogue or derivative thereof). (Alcon), T46.2 (Matrix Therapeutics), HG-2 (Heptagen), [0323] 76. AKT Inhibitor TEM antagonists (Genzyme), Oxi-4500 (Oxigene), ATN-161 [0324] In another embodiment, the fibrosis-inhibiting.com (Attenuon), WX-293 (Wilex), M-2025 (Metris Therapeu pound is an AKT inhibitor (e.g., PKB inhibitors from Develo tics), Alphastatin (BioActa), YH-16 (Yantai Rongchang), Gen, AKT inhibitors from Array BioPharma, Celgene, Merck BIBF-1120 (Boehringer Ingelheim), BAY-57-9352 (Bayer), & Co, Amphora, NeoGenesis Pharmaceuticals, A-443654 AS-1404 (Cancer Research Technology), SC-77964 (Pfizer), (Abbott Laboratories), erucylphosphocholine (AEterna Zen glycomimetics (BioTie Therapies), TIE-2 Inhibitors (Onto taris), KRX-401 (Keryx), protein kinase B inhibitors from gen), DIMI, Octamer (Octamer), ABR-215050 (Active Bio Astex Technology, PX-316 (ProDO, or an analogue orderiva tech), ABT-518 (Abbott), KDR inhibitors (Abbott), BSF tive thereof). 466895 (Abbott), SCH-221153 (Schering-Plough), DAC: [0325] 77. Alpha 2 Integrin Antagonist antiangiogenic (Conjuchem), TFPI (EntreMed), AZD-2171 [0326] In another embodiment, the fibrosis-inhibiting.com (Astra-Zenaca), CDC-394 (Celgene), LY290293 (Eli Lilly), pound is an alpha 2 integrin antagonist (e.g., Pharmaprojects IDN-5390 (Indena), Kdr Kinase Inhibitors (Merck), No. 5754 (Merck KGaA), or an analogue or derivative CT-113020, CT-116433, CT-116563, CT-31890, CT-32228) thereof). (Cell Therapeutics), A-299620 (Abbott), TWEAK Inhibitor [0327] 78. Alpha 4 Integrin Antagonist (Amgen), VEGF modulators (Johnson and Johnson), Tum [0328] In another embodiment, the fibrosis-inhibiting.com N53, tumstatin (Genzyme), Thios-1, Thios-2 (Thios Pharma pound is an alpha 4 integrin antagonist (e.g. T 0047 (Tanabe ceuticals), MV-6401 (Miravant Medical Technologies), Seiyaku), VLA-4 antagonists from Sanofi-Aventis, Merck & Spisulosine (PharmaMar), CEP-7055 (Cephalon), AUV-201 Co Biogen Idec, Uriach, and Molecumetics, alpha 4 integrin (Auvation), LM-609 (Eli Lilly), SKF-106615 (AnorMED), antagonists from Genentech), BIO-2421 (Biogenidec), cell Oglu?anide disodium (Cytran), BW-114 (Phaminox), Calreti adhesion inhibitors from Kaken Pharmaceuticals, CT-737 culin (NIH), WX-678 (Wilex), SD-7784 (Pfizer), WX-UK1 (Wyeth), CT-767 (Elan), CY-9652 (Epimmune), CY-9701 (Wilex), SH-268 (Schering AG), 2-Me-PGA (Celgene), (Epimmune), fibronectin antagonists from Uriach, integrin S-137 (Pfizer), ZD-6126 (Angiogene Pharmaceuticals), alpha+57 antagonists frin Wilex, Pharmaprojects No. 5972 SG-292 (SignalGen), Benefin (Lane Labs), A6, A36 (Ang US 2009/0226500 A1 Sep. 10, 2009

strom), SB-2723005 (GlaxoSmithKline), SC-7 (Cell Thera [0336] 83. Beta 1 Integrin Antagonist peutics), ZEN-014 (AEterna Zentaris), 2-methoxyestradiol [0337] In another embodiment, the fibrosis-inhibiting com (EntreMed), NK-1301.19 (Nippon Kayaku), CC-10004 (Cel pound is a beta 1 integrin antagonist (e.g., fl-1 integrin antago gene), AVE-8062A (Ajinomoto). Tacedinaline (Pfizer), Acti nists, Berkeley Lab, or an analogue or derivative thereof). nonin (Tokyo Metropolitan Institute of Medical Science), [0338|| 84. Beta Tubulin Inhibitor Lenalidomide (Celgene), VGA-1155, BTO-956 (SRI Inter [0339] In another embodiment, the fibrosis-inhibiting com national), ER-68203-00 (Eisai), CT-6685 (UCB), JKC-362 pound is a beta tubulin inhibitor (e.g., ZEN-017 (AEterna (Phoenix Pharmaceuticals), DMI-3798 (DMI Biosciences, Zentaris), laulimalide (Kosan Biosciences), oran analogue or Angiomate (Ipsen), ZD-6474 (AstraZeneca), CEP-5214 derivative thereof). (Cephalon), Canstatin (Genzyme), NM-3 (Mercian), Ori [0340] 85. Blockers of Enzyme Production in Hepatitis C digm (MediQuest Therapeutics), Exherin (Adherex), BLS [0341] In another embodiment, the fibrosis-inhibiting com 0597 (Boston Life Sciences), PTC-299 (PTC Therapeutics), pound is an agent that blocks enzyme production in hepatitis NPI-2358 (Nereus Pharmaceuticals), CGP-79787 (Novartis), C (eg, merimepodib (Vertex Pharmaceuticals), or an ana AEE-788 (Novartis), CKD-732 (Chong Kun Dang), logue or derivative thereof). CP-564959 (OSI Pharmaceuticals), CM-101 (CarboMed), [0342] 86. Bruton’s Tyrosine Kinase Inhibitor CT-2584, CT3501 (Cell Therapeutics), combretastatin and [0343] In another embodiment, the fibrosis-inhibiting com analogues and derivatives thereof (such as combretastatin pound is a Bruton’s tyrosine kinase inhibitor (e.g., a Btk A-1, A-2, A-3, A-4, A-5, A-6, B-1, B-2, B-3, B-4, D-1, D-2, inhibitor from Cellular Genomics, or an analogue or deriva and combretastatin A-4 phosphate (Oxigene)), Rebimastat tive thereof). (Bristol-Meyers Squibb), Dextrin 2-sulfate (ML Laborato [0344) 87. Calcineurin Inhibitors ries), Cilengitide (Merk KGaA), NSC-706704 (Phaminox), [0345] In another embodiment, the fibrosis-inhibiting com KRN-951 (Kirin Brewery), Ukrain, NSC-631570 (Nowicky pound is a calcineurin inhibitor (e.g., tacrolimus (LifeCycle Pharma), Tecogalan sodium (Daiichi Pharmaceutical), Tz-93 Pharma), or an analogue or derivative thereof). (Tsumura), TBC-1635 (Encysive Pharmaceuticals), [0346) 88. Caspase 3 Inhibitors TAN-1120 (Takeda), Semaxanib (Pfizer), BDI-7800 (Biop [0347] In another embodiment, the fibrosis-inhibiting com harmacopae), SD-186, SD-983 (Bristol-Meyers Squibb), pound is a caspase 3 inhibitor (e.g., NM-3 (Mercian), or an SB-223245 (GlaxoSmithKline), SC–236 (Pfizer), analogue or derivative thereof). RWJ-590973 (Johnson and Johnson), ILX-1850 (Genzyme), [0348] 89. CC Chemokine Receptor Antagonists SC-68488, S-836 (Pfizer), CG-55069-11 (Curagen), [0349] In another embodiment, the fibrosis-inhibiting com Ki-23057 (Kirin Brewery), CCX-700 (Chemoentryx), pound is a CC chemokine receptor antagonist (e.g., a Pegaptanib octasodium (Giled Sciences), or an analogue or chemokine receptor 3 antagonist, a chemokine receptor 6 derivative thereof). In other embodiments, the angiogenesis antagonist, and a chemokine receptor 7 antagonist). Repre inhibitor may be a recombinant anti-angiogenic compound sentative examples of CC chemokine receptor antagonists such as ANGIOCOL (available from Biostratum Inc., include chemokine antagonists such as the CCR7 antagonists Durham, N.C.). from Neurocrine Biosciences. [0333] 81. Apoptosis Antagonists [0350] In a related embodiment, the fibrosis-inhibiting [0334] In another embodiment, the fibrosis-inhibiting.com compound is a CC chemokine receptorantagonist (CCR) 1, 3, pound is an apoptosis antagonist (e.g., didemnin B, RGB & 5 (e.g., peptide T (Advanced Immuni T), a CCR3 antago 286199 (GPC Biotech), 5F-DF-203 (Cancer Research Tech nist from GlaxoSmithKline, a chemokine antagonist (Phar nology), aplidine, bongkrekic acid, triammonium salt, [6] maprojects No. 6322) from Neurocrine Biosciences or Merck gingerol (CAS No. 23513-14-6), or an analogue or derivative & Co., an HIV therapy agent from ReceptoPharm (Nutra thereof). Pharma), Pharmaprojects No. 6129 (Sangamo BioSciences), or an analogue or derivative thereof) 82. Apoptosis Activators [0351] In certain embodiments, the CCCR antagonist is a [0335] In another embodiment, the fibrosis-inhibiting.com CCR2b chemokine receptor antagonist such as RS 102895 pound is an apoptosis activator (e.g., aplidine (CAS No. (CAS No. 300815-41-2) 137219-37-5) (PharmaMar), canfosfamide hydrochloride [0352] 90. Cell Cycle Inhibitors (CAS No. 58382-37-74 and 39943-59-6) (Telik), idronoxil [0353] In another embodiment, the fibrosis-inhibiting com (CAS No. 81267-65-4) (Novogen), OSI-461 (OSI Pharma pound is a cell cycle inhibitor (e.g., SNS-595 (Sunesis), ceuticals), DE-098 (Santen), ARQ-550RP (Ar(Jule), ABJ homoharringtonine, or an analogue or derivative thereof). 879 (Novartis), adaphostin (NIH), anticancer agents from [0354] In certain embodiments, the cell cycle inhibitor is an Apogenix Biotechnology and Momenta Pharmaceuticals, anti-microtubule agent (e.g., synthadotin, or an analogue or anti-PARP-1 or anti-PARP-2 (Octamer), BA-1037 (BioAx derivative thereof). one), CP-248 (CAS No. 200803-37-8) (OSI Pharmaceuti [0355] In certain embodiments, cell cycle inhibitor is a cals), EM-1421 (Erimos), IPI-504 (Infinity Pharmaceuticals), microtubule stimulant (e.g., KRX-0403, or an analogue or KP-372-1 (QLT), MPC-6827 (Maxim), MT-103 (Medisyn derivative thereof). Technologies), MX-116407 or MX-126374 (Maxim), NPI [0356] 91. Cathepsin B Inhibitor 0052 (Nereus Pharmaceuticals), NVP-AEW541 (Novartis), [0357] In another embodiment, the fibrosis-inhibiting com PARP inhibitor from Agouron (Pfizer), R-306.465 (Johnson & pound is a cathepsin B inhibitor (e.g., AM-4299A (Asahi Johnson), TG-100-33 (TargeCºen), a XIAP inhibitor from Kasei Pharma), BDI-7800 (Biopharmacopae), a cathepsin B AEgera, ZEN-011 (AEterna Zentaris), canertinib dihydro inhibitor from Axys (Celera Genomics), MDL-104903 (CAS chloride (CAS No. 289499-45-2) (Pfizer), BH31-1,3 No. 180799-56-8) (Sanofi-Aventis), NC-700 (Nippon BAABE, or an analogue or derivative thereof). Chemiphar), Pharmaprojects No. 2332 (Hoffmann-La US 2009/0226500 A1 Sep. 10, 2009 39

Roche), Pharmaprojects No. 4884 (Takeda), Pharmaprojects inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from No. 5134 (Nippon Chemiphar), or an analogue or derivative Amgen, a CDK2 inhibitor from SUGEN-2 (Pfizer), a hearing thereof). loss therapy agent (Sound Pharmaceuticals), PD-033.2991 [0358] 92. Cathepsin K Inhibitor (Pfizer), RGB-286199 (GPC Biotech), Ro-0505124 (Hoff [0359] In another embodiment, the fibrosis-inhibiting.com mann-La Roche), a Ser/Thr kinase inhibitor from Lilly (Eli pound is a cathepsin K inhibitor (e.g., 462795 (GlaxoSmith Lilly), CVT-2584 (CAS No. 199986-75-9) (CV Therapeu Kline), INPL-022-D6 (Amura Therapeutics), or an analogue tics), CGP 74514A, bohemine, olomoucine (CAS No. or derivative thereof). [0360] 93. Cathepsin L Inhibitor 101622-51-9), indole-3-carbinol (CAS No. 700-06-1), and an [0361] In another embodiment, the fibrosis-inhibiting.com analogue or derivative thereof. pound is a cathepsin L Inhibitor (eg, a cathepsin Linhibitor [0375] 100. Cyclooxygenase Inhibitors from Takeda, INPL-022-E10 (Amura Therapeutics), Phar [0376] In another embodiment, the fibrosis-inhibiting com maprojects No 5447 (Taiho), or an analogue or derivative pound is a cyclooxygenase inhibitor (eg. NS-398 (CAS No. thereof) 123653-11-2), ketoprofen, or an analogue or derivative [0362) 94. CD40 Antagonists thereof) In some embodiments, the cyclooxygenase inhibitor [0363] In another embodiment, the fibrosis-inhibiting.com is a COX-1 inhibitor such as triflusal, or an analogue or pound is a CD40 antagonists (e.g., 5D12 (Chiron), ABI-793 derivative thereof). (Novartis), an anticancer antibody from Chiron, anti-CD40 [0377| 101. Dihydroorotate Dehydrogenase Inhibitor MAb-2 (Kirin Brewery), anti-CD40 (Eli Lilly), anti-CD40L (DHFR) Inhibitors antibody (UCB), a CD40 inhibitor from Apoxis, CD40 ligand [0378] In another embodiment, the fibrosis-inhibiting com inhibitor from Millennium Pharmaceuticals, a CD40/CAP pound is a DHFR inhibitor (e.g., PDX (Allos Therapeutics), inhibitor from Snow Brand, CGEN-40 (Compugen), CHIR SC12267, sulfamerazine (CAS No. 127-79-7), or an ana 12.12 (Chiron), Pharmaprojects No. 5163 (Nippon Kayaku), logue or derivative thereof). ruplizumab (Biogen Idec), SGN-40 (Seattle Genetics), TNX 100 (AkzoNobel), toralizumab (CAS No 252662-47-8)(Bio [0379] 102. Dual Integrin Inhibitor gen Idec), or an analogue or derivative thereof). [0380] In another embodiment, the fibrosis-inhibiting com [0364] 95. Chemokine Receptor Agonists pound is a dual integrin inhibitor (e.g., R411 (Roche Pharma [0365] In another embodiment, the fibrosis-inhibiting.com ceuticals), or an analogue or derivative thereof). pound is a chemokine receptor agonist (e.g., a chemokine [0381] 103. Elastase Inhibitors agonist from NeuroTarget, or an analogue or derivative [0382] In another embodiment, the fibrosis-inhibiting com thereof). pound is an elastase inhibitor (e.g., orazipone, depelestat [0366] 96. Chymase Inhibitors (CAS No. 506433-25-6) (Dyax), AE-3763 (Dainippon), oran [0367] In another embodiment, the fibrosis-inhibiting.com analogue or derivative thereof). pound is a chymase inhibitor (e.g., BL-3875 (Dainippon), [0383] 104. Elongation Factor-1 Alpha Inhibitors LEX-043 (SuperGen), NK-3201 (CAS No. 204460-24-2) [0384] In another embodiment, the fibrosis-inhibiting com (Nippon Kayaku), or an analogue or derivative thereof). pound is an elongation factor-1alpha inhibitor (e.g., aplidine, [0368] 97. Collagenase (Interstitial) Antagonists or an analogue or derivative thereof). [0369] In another embodiment, the fibrosis-inhibiting.com pound is a collagenase (interstitial) antagonist (e.g., IBFB [0385) 105. Endothelial Growth Factor Antagonists 212543 (IBFB Pharma), Pharmaprojects No 3762 (Sanofi [0386] In another embodiment, the fibrosis-inhibiting com Aventis), S-0885 (CAS No 117517-22-3) (Sanofi-Aventis), pound is an endothelial growth factor (EGF) antagonist (e.g., SC-40827 (CAS No 101470-42-2) (Pfizer), or an analogue or neovastat, NM-3 (Mercian), or an analogue or derivative derivative thereof) thereof). [0370] 98. CXCR (2, 4) Antagonists (0387] 106. Endothelial Growth Factor Receptor Kinase [0371] In another embodiment, the fibrosis-inhibiting.com Inhibitors pound is a CXCR (24) antagonist (e.g., SB-656933 (Glaxo [0388] In another embodiment, the fibrosis-inhibiting com SmithKline), AMD3100 octahydrochloride (CAS No. pound is an endothelial growth factor receptor (EGF-R) 155148-31-5), or an analogue or derivative thereof). kinase inhibitor (e.g., sorafenib tosylate (Bayer), AAL-993 [0372] 99. Cyclin Dependent Kinase Inhibitors (Novartis), ABP-309 (Novartis), BAY-57-9352 (Bayer), [0373) In another embodiment, the fibrosis-inhibiting.com BIBF-1120 (Boehringer Ingelheim), E-7080 (Eisai), pound is a cyclin dependent kinase (CDK) inhibitor. In cer EG-3306 (Ark Therapeutics), EXEL-2880 (Exelixis), tain embodiments, the cyclin dependent kinase inhibitor is a GW-654652 (GlaxoSmithKline), lavendustin A (CAS No. CDK-1 inhibitor. In certain embodiments, the cyclin depen 125697-92-9), a KDR inhibitor from LG Life Sciences, dent kinase inhibitoris a CDK-2 inhibitor. In certain embodi CT-6685 or CT-6729 (UCB), KRN-633 or KRN-951 (Kirin ments, the cyclin dependent kinase inhibitor is a CDK-4 Brewery), OSI-930 (OSIPharmaceuticals), SP-5.2 (Supratek inhibitor. In certain embodiments, the cyclin dependent Pharma), SU-11657 (Pfizer), a Tie-2 antagonist (Hybrigen kinase inhibitor is a CDK-6 inhibitor. Representative ics), a VEGF-R inhibitorsuch as SU 1498, a VEGFR-2kinase examples of cyclin dependent kinase inhibitors include inhibitor (Bristol-Myers Squibb), XL-647 (Exelixis), a KDR CAK1 inhibitors from GPC Biotech and Bristol-Myers inhibitor from Abbott Laboratories, or an analogue or deriva Squibb, RGB-286199 (GPC Biotech), or an analogue or tive thereof). derivative thereof. [0389). In another embodiment, the fibrosis-inhibiting com [0374] Additional exemplary cyclin dependent protein pound is an endothelial growth factor receptor 2 kinase kinase inhibitors include an anticancer agent from Astex inhibitor (e.g., sorafenib tosylate, oran analogue orderivative Technology, a CAK1 inhibitor from GPC Biotech, a CDK thereof). US 2009/0226500 A1 Sep. 10, 2009 40

[0390) 107. Endotoxin Antagonists ester), trichostatin A from Streptomyces sp. (CAS No. 58880 [0391] In another embodiment, the fibrosis-inhibiting.com 19-6), or an analogue or derivative thereof). pound is an endotoxin antagonist (e.g., E5564 (Eisai Pharma [0412] 118. HMGCoA Reductase Inhibitors ceuticals), or an analogue or derivative thereof). [0413] In another embodiment, the fibrosis-inhibiting com [0392] 108. Epothilone and Tubulin Binders pound is an HMGCoA reductase inhibitor (e.g., an athero [0393] In another embodiment, the fibrosis-inhibiting.com sclerosis therapeutic from Lipid Sciences, ATI-16000 (ARYX pound is an epothilone or tubulin binder (e.g., ixabepilone Therapeutics), KS-01-019 (Kos Pharmaceuticals), Phar (BMS), or an analogue or derivative thereof. maprojects No 2197 (Sanofi-Aventi), RP 61969 (Sanofi [0394] 109. Estrogen Receptor Antagonists Aventis), cerivastatin Na) CAS No. 14320.1-11-0), or an ana [0395] In another embodiment the fibrosis-inhibiting com logue or derivative thereof) pound is an estrogen receptor antagonist (e.g. ERB-041 (Wy [0414] 119. ICAM Inhibitors eth), or an analogue or derivative thereof). [0415] In another embodiment, the fibrosis-inhibiting com [0396] 110. FGF Inhibitors pound is an ICAM inhibitor (e.g., alicaforsen (CAS No. [0397] In another embodiment, the fibrosis-inhibiting.com 185229-68-9) (ISISPharmaceuticals), an ICAM-5 modulator pound is a FGF inhibitor (e.g., IDN-5390 (Indena), or an (such as ICAM-4 from ICOS), or an analogue or derivative analogue or derivative thereof). thereof). [0398] 111. Farnexy! Transferase Inhibitors [0416) 120. IL-1, ICE & IRAK Antagonists [0399] In another embodiment, the fibrosis-inhibiting.com pound is an inhibitor of farmexyl transferase (FTI). In certain [0417] In another embodiment, the fibrosis-inhibiting com embodiments, the FTI inhibits the RAS oncogene family pound is an IL-1, ICE & IRAK antagonist (e.g., CJ-14877 or Examples of FTI’s include SARASAR (from Schering Cor CP-424174 (Pfizer), NF-61 (Negma-Lerads), or an analogue poration, Kenilworth, N.J.), or an analogue or derivative or derivative thereof). thereof. [0418] 121. IL-2 Inhibitors [0400) 112. Farnesyltransferase Inhibitors [0419). In another embodiment, the fibrosis-inhibiting com [0401] In another embodiment, the fibrosis-inhibiting.com pound is an IL-2 inhibitor (e.g., AVE 8062 (Sanofi-Aventis), pound is a farnesyltransferase inhibitor (e.g., A-197574 (Ab or an analogue or derivative thereof). bott), a farnesyltransferase inhibitor from Servier, FPTIII [0420) 122. Immunosuppressants (Strathclyde Institute for Drug R), LB-42908 (LG Life Sci [0421] In another embodiment, the fibrosis-inhibiting com ences), Pharmaprojects No. 5063 (Genzyme), Phar pound is an immunosuppressant (e.g., teriflunomide (Sanofi maprojects No. 5597 (Ipsen), Yissum Project No. B-1055 Aventis), chlorsulfaquinoxalone (NSC-339004), chlorsul (Yissum), or an analogue or derivative thereof). faquinoxalone sulfate, CS-712 (Sankyo), ismomultin alfa [0402] 113. FLT-3 Kinase Inhibitors (CAS No. 457913-93-8) (Akzo Nobel), antiallergics from [0403] In another embodiment, the fibrosis-inhibiting.com Genpat77, anti-inflammatories or AT-005 (Androclus Thera pound is a FLT-3 kinase inhibitor (e.g., Amphora, or an ana peutics), autoimmune disease therapeutics from Epi Vax, logue or derivative thereof). BN-007 (Bone), budesonide (CAS No. 51333-22-3) (MAP Pharmaceuticals), CO-14 (Genzyme), edratide (CAS No. [0404] 114. FGF Receptor Kinase Inhibitors 433922-67-9) (Teva), EP-314 (Enanta), eprovafen (CAS No. [0405] In another embodiment, the fibrosis inhibiting com 101.335-99-3) (Sanofi-Aventis), HWA-131 (CAS No. pound is a FGF receptor kinase inhibitor (e.g., MED-A300 118788-41-3) (Sanofi-Aventis), immunomodulators from (Gerolymatos). SSR-128129 (Sanofi-Aventis), TBC-2250 MerLion Pharmaceuticals, immunosuppressives from (Encysive Pharmaceuticals), XL-999 (Exelixis), or a FGF Alchemia, IPL-12 (inflazyme), MDL-9563 (CAS No. 27086 receptor kinase inhibitor from Paradigm Therapeutics, or an 86-8) (Sanofi-Aventis), Pharmaprojects No 2330 (Sanofi analogue or derivative thereof). Aventis), Pharmaprojects No. 6426 (Abgenix). PXS-25 [0406] 115. Fibrinogen Antagonists (Pharmaxis), rosmarinic acid (CAS No 20283-92-5) (Sanofi [0407] In another embodiment, the fibrosis-inhibiting.com Aventis), RP 42927 or RP 54745 (CAS No. 135330-08-4) pound is a fibrinogen antagonist (e.g., AUV-201 (Auvation), (Sanofi-Aventis), SGN-35 (Seattle Genetics), ST-1959 MG-13926 (Sanofi-Aventis), plasminogen activator (CAS (Sigma-Tau), type I diabetes therapy from SYNX Pharma, No. 105913-11-9) (from Sanofi-Aventis or UCB), plasmino UNIL-88 (Debiopharm), VP-025 (Vasogen), VR-694 (Vec gen activator-2 (tPA-2) (Sanofi-Aventis), pro-urokinase tura), PRTX-001 (Protalex), or an analogue or derivative (CAS No. 82657-92-9) (Sanofi-Aventis), mevastatin, or an thereof). analogue or derivative thereof). [0422] 123. IMPDH (Inosine Monophosphate) [0408] 116. Heat Shock Protein 90 Antagonists [0409] In another embodiment, the fibrosis-inhibiting.com [0423] In another embodiment, the fibrosis-inhibiting com pound is a heat shock protein 90 antagonist (e.g., SRN-005 pound is IMPDH (inosine monophosphate) (e.g., ribavirin (Sirenade), geldanamycin or a derivative thereof, such as (Hoffmann-La Roche) or an analogue or derivative thereof). NSC-33050 (17-allylaminogeldanamycin; 17-AAG) or [0424] 124. Integrin Antagonists 17-dimethylaminoethylamino-17-demethoxy-geldanamycin [0425] In another embodiment, the fibrosis-inhibiting com (17-DMAG), rifabutin (rifamycin XIV, 1,4-didehydro-1 pound is an integrin antagonist (e.g., 683699 from Glaxo deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxo-), radicicol, Smith Kline, integrin antagonists from Jerina AG (Germany), Humicola fuscoatra (CAS No. 12772-57-6), or an analogue or an analogue or derivative thereof). or derivative thereof). [0426] 125. Interleukin Antagonists [0410) 117. Histone Deacetylase Inhibitors [0427] In another embodiment, the fibrosis-inhibiting com [0411] In another embodiment, the fibrosis-inhibiting.com pound is an interleukin antagonist (e.g., dersalazine, or an pound is a histone deacetylase inhibitor (e.g., FK228 (Glouc analogue or derivative thereof). US 2009/0226500 A1 Sep. 10, 2009

[0428] In another embodiment, the fibrosis-inhibiting.com nade), AEG-3482 (AEgera), ARRY-142886 (Array BioP pound is an interleukin 1 antagonist (e.g., NPI-1302a-3, or an harma), CDP-146 (UCB), or analogue or derivative thereof). analogue or derivative thereof). [0447] 135. Matrix Metalloproteinase Inhibitors (MMPI) [0429] 126. Inhibitors of Type III Receptor Tyrosine [0448] In another embodiment, the fibrosis-inhibiting com Kinases pound is a matrix metalloproteinase inhibitor. A variety of [0430] In another embodiment, the fibrosis-inhibiting.com MMPI’s may be used in the practice of the invention. In one pound is an inhibitor of type III receptor tyrosine kinase such embodiment, the MMPI is a MMP-1 inhibitor. In another as FLT3, PDGRF and c-KIT (e.g., MLN518 (Millenium embodiment, the MMPI is a MMP-2 inhibitor. In other Pharmaceuticals), or an analogue or derivative thereof). embodiments, the MMPI is a MMP-4, MMP-5, MMP-6, [0431] 127. Irreversible Inhibitors of Enzyme Methionine MMP-7, or MMP-8 inhibitor. Representative examples of Aminopeptidase Type 2 MMPI’s include glucosamine sulfate, neovastat, GM1489 [0432] In another embodiment, the fibrosis-inhibiting.com (CAS No 170905-75-6). XL784 (EXEL-01370784). TNF-a pound is an irreversible Inhibitor of enzyme methionine ami Protease Inhibitor-1 or 2 (TAPI-1 or TAPI-2), galardin, or an nopeptidase type 2 (e.g., PPI-2458 (Praecis Pharmaceuti analogue or derivative thereof. cals), or analogue or derivative thereof). [0449) 136. MCP-CCR2 Inhibitors [0433) 128. Isozyme-Selective Delta Protein Kinase C [0450] In another embodiment, the fibrosis-inhibiting com Inhibitors pound is a MCP-CCR2 inhibitor (e.g., MLN1202 (Millen [0434] In another embodiment, the fibrosis-inhibiting.com nium Pharmaceuticals) or an analogue or derivative thereof). pound is an isozyme-selective delta protein kinase Cinhibitor [0451] 137. mTOR Inhibitor (e.g., KAI-9803 (Kai Pharmaceuticals), or an analogue or [0452] In another embodiment, the fibrosis-inhibiting com derivative thereof). pound is an mTOR inhibitor (e.g., temsirolimus (CAS No. [0435] 129. JAK3 Enzyme Inhibitors 162635-04-3) (Wyeth), or an analogue or derivative thereof). [0453] 138. mTOR Kinase Inhibitor [0436] In another embodiment, the fibrosis-inhibiting.com [0454] In another embodiment, the fibrosis-inhibiting com pound is a JAK3 enzyme inhibitor (e.g., CP-690,550 (Pfizer), pound is an mTOR kinase inhibitor (e.g., ABT-578 (Abbott), or an analogue or derivative thereof). temsirolimus (Wyeth), AP-23573 (Ariad), or an analogue or [0437] 130. JNK Inhibitors derivative thereof). [0438] In another embodiment, the fibrosis-inhibiting.com [0455] 139. Microtubule Inhibitors pound is a JNK inhibitor (e.g., BF-67192 (BioFocus), [0456] In another embodiment, the fibrosis-inhibiting com XG-101 or XG-102 (Xigen), or an analogue or derivative pound is a microtubule inhibitor (e.g., antibody-maytansi thereof). noid conjugates from Biogen Idec, colchicines (MantiGore [0439] 131. Kinase Inhibitors Pharmaceuticals), anticancer immunoconjugates from [0440] In another embodiment, the fibrosis-inhibiting.com Johnson & Johnson, DIME from Octamer, gni-1f (GNI), pound is a kinase inhibitor (e.g., a kinase inhibitors from huC242-DM4 or huMy9-6-DM1 (ImmunoGen), IDN-5404 EVOTEC, or an analogue or derivative thereof). (Indena), IMO-098 or IMOderm (Imotep), mebendazole (In [0441] 132. Kinesin Antagonist trogen Therapeutics), microtubule poisons from Cambridge [0442] In another embodiment, the fibrosis-inhibiting.com Enterprise, paclitaxel such as LOTAX from Aphios (CAS No. pound is a kinesin antagonist (e.g., SB-715992 and an anti 33069-62-4), Genexol-PM from Samyang, Pharmaprojects fungal from Cytokinetics, or an analogue or derivative No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi thereof). Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Star [0443) 133. Leukotriene Inhibitors and Antagonists pharma), SSR-2504.11 (Sanofi-Aventis), trastuzumab-DM1 [0444] In another embodiment, the fibrosis-inhibiting.com (Genentech), vinorelbine dolastatin 15 (CAS No 123884-00 pound is a leukotriene Inhibitor or antagonist (e.g., ambicro 4) or an analogue or derivative thereof) mil (CAS No 58805-38-2) (Sanofi-Aventis), amelubant (CAS [0457] In certain embodiments, the microtubule inhibitoris No. 346735-24-8) (Boehringer Ingelheim), DW-1141 (Dong a microtubule polymerization inhibitor such as vincamine, or Wha), ebselen (Daiichi Pharmaceutical), ibudilast (Kyorin), an analogue or derivative thereof). leucotriene inhibitors from Sanofi-Aventis, lymphotoxin [0458] 140. MIF Inhibitors beta receptor (LT-3) from Biogen Idec, Pharmaprojects No. [0459] In another embodiment, the fibrosis-inhibiting com 1535 or 2728 (CAS No. 119340-33-9) (Sanofi-Aventis), pound is a MIF inhibitor (e.g., AVP-13546 (Avanir), an MIF R-112 (Rigel), Rev-5367 (CAS No. 92532-05-3) (Sanofi inhibitor from Genzyme, migration stimulation factor D, or Aventis), RG-14893 (CAS No. 141835-49-6) (Sanofi-Aven an analogue or derivative thereof). tis), RG-5901-A (CAS No. 101910-24-1), 92532-23-5, RP [0460) 141. MMP (Stromolysin) Inhibitors 66153 (CAS No. 142422-79-5), RP 66364 (CAS No. [0461] In another embodiment, the fibrosis-inhibiting com 186912-92-5), or RP 69698 (CAS No. 141748-00-7) (Sanofi pound is a MMP (stromolysin) inhibitor (e.g., anticancer Aventis), SC-41 1930 (Pfizer), SC-41930 (CAS No. 120072 tetracycline from Tetragenex, rhostatin (BioAxone), TIMP’s 59-5) (Pfizer), SC-50605 (CAS No. 138828-39-4) (Pfizer), from Sanofi-Aventis (CAS No. 86102-31-0), and MMP SC-51146 (CAS No. 141059-52-1) or SC-53228 (CAS No. inhibitors form Cognosci and Tetragemex, or an analogue or 153633-01-3) (Pfizer), spaglumic acid (ZY-15106) (CAS No. derivative thereof). 3106-85-2) or 80619-64-3 (Novartis), tipredane (CAS No. [0462]. 142. Neurokinin (NK) Antagonist 85197-77-9) (Bristol-Myers Squibb), U-75302 (CAS No. [0463] In another embodiment, the fibrosis-inhibiting com 119477-85-9) (Pfizer), or analogue or derivative thereof). pound is a neurokinin (NK) antagonist (e.g., anthrotainin [0445] 134. MAP Kinase Inhibitors (CAS No. 148084-40-6) (Sanofi-Aventis), an IBS thereapeu [0446] In another embodiment, the fibrosis-inhibiting.com tic such as SLV-332 from Ar(Jule, MDL-105212A (CAS No. pound is a MAP kinase inhibitor (e.g., SRN-003-556 (Sire 167261-60-1) (Ssanofi-Aventis), Pharmaprojects No. 2744, US 2009/0226500 A1 Sep. 10, 2009 42

3258 (CAS No. 1391.67-47-8) 4006, 4201, or 5986 (Sanofi imatinib (CAS No. 152459-95-5) (Novartis), OSI-930 (OSI Aventis), RP 67580 (CAS No. 135911-02-3), SR-144190 Pharmaceuticals), RPR-1279.63E (Sanofi-Aventis), (CAS No. 201152-86-5), SSR-240600 or SSR-241586 RWJ-540973 (Johnson & Johnson), sorafenib tosylate (Sanofi-Aventis), TKA-457 (Novartis), vestipitant mesylate (Bayer), SU-11657 (Pfizer), tandutinib (CAS No. 387867 (CAS No. 334476-64-1) (GlaxoSmithKline), Win-64821 13-2) (Millennium Pharmaceuticals), vatalanib (Novartis), (Sanofi-Aventis), PRX-96026 (Predix Pharmaceuticals), or ZK-CDK (Schering AG), or an analogue or derivative an analogue or derivative thereof). thereof). [0464] 143. NF kappa B Inhibitors [0476] 149. Peroxisome Proliferator-Activated Receptor [0465] In another embodiment, the fibrosis-inhibiting.com Agonists pound is a NF kappa B (NFKB) inhibitor (e.g., emodin (CAS [0477] In another embodiment, the fibrosis-inhibiting com No. 518-82-1), AVE-0545 or AVE-0547 (Sanofi-Aventis), pound is a peroxisome proliferator-activated receptor (PPAR) bortezomib (CAS No. 179324-69-7) (Millennium Pharma agonists (e.g., (-)-halofenate (Metabolex), AMG-131 (Am ceuticals), dexanabinol (CAS No. 112924-45-5) (Pharmos), gen), antidiabetics from Japan Tobacco, AZD-4619, AZD dexlipotam (Viatris), Pharmaprojects No. 6283 (INDRA) 8450, or AZD-8677 (AstraZeneca), DRF-10945 or balaglita (OXiGENE), IPL-576092 (CAS No. 137571-30-3) (Infla zone (Dr Reddy’s), CS-00088 or CS-00098 (Chipscreen zyme), NFKB decoy (Corgentech), NFKB decoy oligo (An Biosciences), E-3030 (Eisai), etalocib (CAS No. 161172-51 Ges MG), NFKB's from Ariad, osteoporosis treatments or S5 6) (Eli Lilly), GSK-641597 (Ligand), GSK-677954 (Glaxo (FOO5) from Fulcrum Pharmaceuticals, P61 (Phytopharm), SmithKline), GW-409544 (Ligand), GW-590735 (Glaxo R-flurbiprofen (CAS No. 5104-49-4) (Encore Pharmaceuti SmithKline), K-111 (Hoffmann-La Roche), LY-518674 (Eli cals), Bay 11-7085, or an analogue or derivative thereof). Lilly), LY-674 (Ligand), LY-929 (Ligand), MC-3001 or [0466] 144. Nitric Oxide Agonists MC-3002 (MaxoCore Pharmaceuticals), mefformin HC1+pi [0467] In another embodiment, the fibrosis-inhibiting.com oglitazone (CAS No. 1115-70-4 and 112529-15-4) (such as pound is a nitric oxide agonist (e.g., Acclaim, Angx-1039 or ACTOPLUS MET from Andrx), muraglitazar (CAS No. Angx-3227 (Angiogenix), CAS-1609 (CAS No. 158590-73 331741–94-7) (Bristol-Myers Squibb), naveglitazar 9) (Sanofi-Aventis), GCI-503 (Spear Therapeutics), HCT (Ligand), oleoylethanolamide (Kadmus Pharmaceuticals), 3012 (CAS No. 163133–43–5) (Nicox), hydralazine HISDN ONO-5129, pioglitazone hydrochloride (CAS No. 11:1025 (NitroMed), isosorbide dinitrate, Diffutab (CAS No. 87-33 46-8 and 112529-15-4) (Takeda), PLX-204 (Plexxikon), 2) (Eurand), isosorbide mononitrate (CAS No. 16051-77-7) PPAR agonists from Genfit, PPAR delta agonists from Eli from AstraZeneca, Schering AGor Schwarz Pharma, LA-419 Lilly, PPAR-alpha agonists from CrystalGenomics, PPAR (Lacer), molsidomine (CAS No. 25717-80-0) (from Takeda gamma modulators and PPAR-3 modulators from C are X, and Therabel), NCX-1000, NCX-2057, or NCX4040 rosiglitazone maleate (CAS No. 122320-73-4 or 155141-29 (Nicox), nitric oxide (ProStrakan), nitroglycerin in the form 0) (GlaxoSmithKline), rosiglitazone maleate/glimepir (CAS of a nitroglycerin patch, such as DERMATRANS from (Rot No. 155141-29-0 and 93479-97-1), such as AVANDARYL or tapharm), nitroglycerin (CAS No. 55-63-0) (from Cellegy rosiglitazone maleate/metformin extend (CAS No. 155141 Pharmaceuticals, Forest Laboratories, NovaL)el, Schwarz 29-0 and 657-24-9) such as AVANDAMET, or rosiglitazone Pharma, and Watson), NO-releasing prodrugs (Inotek), maleate+metformin, such as AVANDAMET (GlaxoSmith OM-294DP (OM PHARMA), oxdralazine (CAS No. 27464 Kline), tesaglitazar (AstraZeneca), LBM642, WY-14,643 23-9) (Sanofi-Aventis), pirsidomine (CAS No. 132722-74-8) (CAS No. 50892-23-4), or an analogue orderivative thereof). (Sanofi-Aventis), prostaglandin and NO donor (Cellegy Phar [0478] In certain embodiments, the PPAR Agonist is a maceuticals), upidosin derivatives (Recordati), or an ana PPARO agonist such as GW7647 orfenofibric acid (CAS No. logue or derivative thereof). 42017-89-0), a PPAR Y agonist such as MCC-555 (CAS No. [0468] 145. Ornithine Decarboxylase Inhibitors 161600-01-7), GW9662 or GW1929, a PPAERö agonist such [0469] In another embodiment, the fibrosis-inhibiting.com as GW501516, a PPARB and PPARö agonist such L-165,041 pound is an ornithine decarboxylase inhibitor (e.g. aplidine, (CAS No. 79558-09-1), or an analogue or derivative thereof. or an analogue or derivative thereof). [0479] 150. Phosphatase Inhibitor [0470) 146. p38 MAP Kinase Inhibitors [0480] In another embodiment, the fibrosis-inhibiting com [0471] In another embodiment, the fibrosis-inhibiting.com pound is a phosphatase inhibitor (e.g., diabetes therapy such pound is a p38 MAP kinase inhibitor (e.g., AZD-6703 (Astra as SQMO3, SQDM38, SODM60 from Sequenom, Phar Zeneca), JX-401 (Jexys Pharmaceuticals), BMS-2 (Bristol maprojects No 4191 (Sanofi-Aventis), PRL-3 inhibitors from Myers Squibb), a p38 MAP kinase inhibitor from Novartis, a Genzyme, WIP1 inhibitors from Amgen, or an analogue or p38-alpha MAP kinase inhibitor from Amphora, Phar derivative thereof). maprojects No. 5704 (Pharmacopeia), SKF86002 (CAS No. [0481] 151. Phosphodiesterase (PDE) Inhibitors 72873-74-6), RPR-200765A (Sanofi-Aventis), SD-282 [0482] In another embodiment, the fibrosis-inhibiting com (Johnson & Johnson), TAK-715 (Takeda), or an analogue or pound is a phosphodiesterase (PDE) inhibitor (e.g., avanafil derivative thereof). (Tanabe Seiyaku), dasantafil (CAS No. 569351-91-3) (Scher [0472] 147. Palmitoyl-Protein Thioesterase Inhibitors ing-Plough), A-906119 (CAS No. 134072-58-5) or DL-850 [0473] In another embodiment, the fibrosis-inhibiting.com (Sanofi-Aventis), GRC-3015, GRC-3566, or GRC-3886 pound is a palmitoyl-protein thioesterase inhibitor (e.g., apli (Glenmark), HWA-153 (CAS No. 56395-66-5) (Sanofi dine, or an analogue or derivative thereof). Aventis), hydroxypumafentrine (Altana), IBFB-130011, [0474] 148. PDGF Receptor Kinase Inhibitors IBFB-14-016, IBFB-140301, IBFB-150007, or IBFB [0475] In another embodiment, the fibrosis-inhibiting.com 211913 (IBFB Pharma), L-826141 (Merck & Co), pound is a PDGF receptor kinase inhibitors (e.g., AAL-993, medorinone (CAS No. 88296-61-1) (Sanofi-Aventis), MEM AMN-107, or ABP-309 (Novartis), AMG-706 (Amgen), 1917 (Memory Pharmaceuticals), ND-1251 (Neuro3d), PDE BAY-57-9352 (Bayer), CDP-860 (UCB), E-7080 (Eisai), inhibitors from ICOS, PDE IV inhibitors from Memory Phar US 2009/0226500 A1 Sep. 10, 2009

maceuticals and CrystalGenomics, Pharmaprojects No 2742 formulations thereof, such as MYLINAX from Serone SA and 6141 (Sanofi-Aventis), QAD-171 (Novartis), RHC-2963 and IVAX Research Inc. (Miami, Fla.), or an analogue or (CAS No. 76993-12-9 and 76993-14-1), RPR-117658, RPR derivative thereof). 122818 derivatives, SR-24870, and RPR-132294 (Sanofi [0501) 160. Purinoreceptor P2XAntagonist Aventis), SK-350 (In?3Gen), stroke therapy agents from [0502] In another embodiment, the fibrosis-inhibiting com deCODE Genetics, TAS-203 (Taiho), tofimilast (CAS No. pound is a purinoreceptor P2X antagonist (e.g., AZD-9056 185954-27-2) (Pfizer), UK-37.1800 (Pfizer), WIN-65579 (AstraZeneca), R-1554 (Hoffmann-La Roche), (CAS No. 158020-82-7) (Sanofi-Aventis), IBFB-130020 AR-C118925XX (AstraZeneca), suramin (CAS No. 129-46 (IBFB Pharma), OPC-6535 (CAS No. 145739-56-6) (Ot 4), P2Y4 receptor from Euroscreen, or an analogue orderiva suka), theobromine (CAS No. 83-67-0), papverine hydro tive thereof). chloride (CAS No. 61–25-6), quercetin dehydrate (CAS No. [0503] 161. Raf Kinase Inhibitors 6151-25-3), YM 976 (CAS No. 191219-80-4), irsogladine [0504] In another embodiment, the fibrosis-inhibiting com (CAS No 57381-26-7), or an analogue or derivative thereof). pound is a Rafkinase inhibitor (e.g., Sorafenib tosylate, or an [0483] In one embodiment, the phosphodiesterase inhibitor analogue or derivative thereof). is a phosphodiesterase III inhibitor (e.g., enoximone, or an analogue or derivative thereof). In other embodiments, the [0505] 162. Reversible Inhibitors of ErbB1 and ERbB2 phosphodiesterase inhibitor is a phosphodiesterase IV inhibi [0506] In another embodiment, the fibrosis-inhibiting com tor (e.g., fosfosal, Atopik (Barrier Therapeutics), triflusal or pound is a reversible inhibitor (e.g., lapatinib (GSK), or an an analogue orderivative thereof). In other embodiments, the analogue or derivative thereof) phosphodiesterase inhibitor is a phosphodiesterase V inhibi [0507] 163. Ribonucleoside Triphosphate Reductase tor Inhibitors [0484] 152. PKC Inhibitor [0508] In another embodiment, the fibrosis-inhibiting com [0485] In another embodiment, the fibrosis-inhibiting.com pound is a cytoplasmic tyrosine kinase inhibitor such as a pound is a PKC inhibitor (e.g., HMR-105509 or P-10050 SRC inhibitor (e.g., SRN-004 (Sirenade), gallium maltolate (Sanofi-Aventis), JNJ-10164830 (Johnson & Johnson), (Titan Pharmaceutcals), or an analogue orderivative thereof), Ro-31-8425 (CAS No. 131848-97-0), NPC-15437 dihydro or an analogue or derivative thereof) chloride (CAS No. 136449-85-9), or an analogue or deriva [0509] 164. SDF-1 Antagonists tive thereof). [0510] In another embodiment, the fibrosis-inhibiting com [0486] In one embodiment, the PKC inhibitor is an inhibi pound is a SDF-1 antagonist (e.g., CTCE-9908 (Chemokine tor of PKC beta (e.g., ruboxistaurin (Eli Lilly), or an analogue Therapeutics), or an analogue or derivative thereof). or derivative thereof). [0511] 165. Sheddase Inhibitor [0487] 153. Platelet Activating Factor Antagonists [0512] In another embodiment, the fibrosis-inhibiting com [0488] In another embodiment, the fibrosis-inhibiting.com pound is a sheddase inhibitor (e.g., INCB-7839 (Incyte Cor pound is a platelet activating factor antagonist (e.g., dersala poration), or an analogue or derivative thereof). [0513] 166. SRC Inhibitors zine, or an analogue or derivative thereof). [0514] In another embodiment, the fibrosis-inhibiting com [0489] 154. Platelet-Derived Growth Factor Receptor pound is a SRC inhibitor (e.g., SRN-004 (Sirenade), or an Kinase Inhibitors analogue or derivative thereof). [0490] In another embodiment, the fibrosis-inhibiting.com [0515] In certain embodiments, the SRC inhibitor is a SRC pound is a platelet-derived growth factor receptor kinase kinase inhibitor (e.g., AZD0530 (AstraZeneca), or an ana inhibitor (e.g., sorafenib tosylate, Raf or Ras inhibitors such logue or derivative thereof). as sorafenib tosylate from Bayer and Onyx Pharmaceuticals, [0516] 167. Stromelysin Inhibitors or an analogue or derivative thereof). [0517] In another embodiment, the fibrosis-inhibiting com [0491] 155. Prolyl Hydroxylase Inhibitors pound is a stromelysin inhibitor (e.g., glucosamine sulfate, or [0492] In another embodiment, the fibrosis-inhibiting.com an analogue or derivative thereof). pound is a prolyl hydroxylase inhibitor (e.g., FG-2216 (CAS [0518) 168. Syk Kinase Inhibitors No. 11096-26-7) or HIF agonists from FibroGen, or an ana [0519) In another embodiment, the fibrosis-inhibiting com logue or derivative thereof). pound is a syk kinase inhibitor (eg. R406 (Rigel), or an [0493] 156. Polymorphonuclear Neutrophil Inhibitors analogue or derivative thereof) [0494] In another embodiment, the fibrosis-inhibiting.com pound is a polymorphonuclear neutrophil inhibitor (e.g., [0520) 169. Telomerase Inhibitors orazipone, or an analogue or derivative thereof) [0521] In another embodiment, the fibrosis-inhibiting com pound is a telomerase inhibitor (e.g., AS-1410 (Antisoma), or [0495] 157. Protein Kinase B Inhibitors an analogue or derivative thereof). [0496) In another embodiment, the fibrosis-inhibiting.com [0522] 170. TGF Beta Inhibitors pound is a protein kinase B inhibitor (e.g., Akt-1 inhibitors [0523] In another embodiment, the fibrosis-inhibiting com from Amphora, or an analogue or derivative thereof). pound is a TGF beta inhibitor (e.g., pirfenidone (CAS No. [0497] 158. Protein Kinase C Stimulants 53179-13-8) (MARNAC), tranilast (CAS No. 53902-12-8) [0498] In another embodiment, the fibrosis-inhibiting.com (Kissei), IN-1130 (In 2Gen), mannose-6-phosphate (BTG), pound is a protein kinase C stimulant (e.g., bryostatin-1, or TGF-3 antagonists from Inflazyme (Pharmaprojects No. analogue or derivative thereof). 6075), TGF-5 antagonists (e.g., 1090 and 1091 from Sydney; [0499] 159. Purine Nucleoside Analogues non-industrial source), TGF-31 receptor kinase inhibitors [0500] In another embodiment, the fibrosis-inhibiting.com from Eli Lilly, TGF-5 receptor inhibitors from Johnson & pound is a purine nucleoside analogue (e.g., cladrinbine and Johnson, or an analogue or derivative thereof). US 2009/0226500 A1 Sep. 10, 2009 44

[0524] 171. TNFo. Antagonists and TACE Inhibitors [0532] 175. Tyrosine Kinase Inhibitors [0525] In another embodiment, the fibrosis-inhibiting.com [0533] In another embodiment, the fibrosis-inhibiting com pound is a TNFO antagonist or TACE inhibitors (e.g., adali pound is a tyrosine kinase inhibitor (e.g., SU-01.1248 (e.g., mumab (CAS No. 331731-18-1) (Cambridge Antibody Tech SUTENT from Pfizer Inc. (New York, N.Y.), BMS-354825, nology), AGDK-4207 (AtheroGenics), AGT-1 (Advanced PN-355 (Paracelsian Pharmaceuticals), AGN-199659 (Aller Biotherapy), an anti-inflammatory from Borean Pharma, gan), (e.g., AAL-993 or ABP-309 (Novartis), adaphostin Celizome, or Paradigm Therapeutics, anti-inflammatory vac (NIH), AEE-788 (Novartis), AG-013736 (OSI Pharmaceuti cine (TNF-alpha kinoid) from Neovacs, humanized anti-TNF cals), AG-13736 (Pfizer), ALT-110 (Alteris Therapeutics), antibody or an anti-TNF MAb (CB0006) Celitech (UCB), AMG-706 (Amgen), anticancer MAbs from Xencor, anti apratastat (CAS No. 287405-51-0) (Wyeth), BMS-561392 EGFrv?II MAbs from Abgenix, anti-HER2MAb from Abio (Bristol-Myers Squibb), BN-006 (Bone), certolizumab pegol gen, AZD-2171 or AZD-9935 (AstraZeneca), BAY-57-9352 (CAS No. 428863-50-7 or CH-138 (UCB), cilomilast (CAS (Bayer), BIBF-1120 (Boehringer Ingelheim), CEP-5214 No. 153259-65-5) (GlaxoSmithKline), CR-1 (Nuada Phar (Cephalon), CEP-7055 (Cephalon), cetuximab (ImClone maceuticals), CRx-119 (CombinatoRx), D-5410 (UCB), dacopa?ant (CAS No. 125372-33-0) (Sanofi-Aventis), der Systems), CHIR-200131 and CHIR-258 (Chiron), salazine (CAS No. 188913-57-7/188913-58-8) (Uriach), CP-547632 (OSI Pharmaceuticals), CP-724714 (Pfizer), etanercept (CAS No 185243-69-0) (Amgen), ethyl pyruvate CT-301 (Creabilis Therapeutics), D-69491 (Baxter Interna (Critical (Critical Therapeutics), golimumab (CAS No. tional), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EGFR/ 476181-74-5) (Johnson & Johnson), hormono-immuno ErbB2 inhibitors from Array BioPharma, erlotinib (CAS No. therapy from Ipsen, CDP571 (e.g. humicade from UCB), 183319-69-9) (OSI Pharmaceuticals), EXEL-2880 (Ex IC-485 (ICOS), infliximab (CAS No 170277-31-3) (Johnson elixis), FK-778 (Sanofi-Aventis), gefitinib (CAS No 184475 & Johnson), IP-751 (Manhattan Pharmaceuticals), ISIS 35-2) (Astraeneca), GW-2286 or GW-654652 (GlaxoSmith 104838 (CAS No. 250755-32-9) (ISIS Pharmaceuticals), Kline), her2/neu antigen from Alpha\Wax, HER-21 neu lenalidomide (CAS No. 191732–72-6) (Celgene), lentinan inhibitor from Generex, Herzyme (Medipad) (Sirna Thera (CAS No. 37339-90-5) (Ajinomoto), MDL-201112 (CAS peutics), HKI-272 (Wyeth), HuMax-EGFr (Genmab), idron No. 142130-73-2) (Sanofi-Aventis), medroxyprogesterone oxil (CAS No.81267-65-4) (Novogen), IGF-1 inhibitors from (CAS No. 520-85-4) (Inkine Pharmaceutical), N-acetylcys Ontogen, IMC-11F8 (ImClone Systems), kahalalide F (CAS teine (CAS No. 616-91-1) (Zambon), NBE-P2 (DIREVO No. 149204-42-2) (PharmaMar), KDR inhibitor from LG Biotech), merelimomab (CAS No. 162774-06-3) (Chiron), Life Sciences, KDR inhibitors from Abbott Laboratories, OM-294DP (OM PHARMA), onercept (CAS No. 199685 KDR kinase inhibitors (UCB), Kdr kinase inhibitors from 57-9) (Yeda), PASSTNF-alpha (Verigen), pentoxifylline or Merck & Co, KRN-633 and KRN-951 (Kirin Brewery), oxypentifylline (Sanofi-Aventis), Pharmaprojects No. 4091, KSB-102 (Xenova), lapatinib ditosylate (CAS No. 388082 4241, 4295, or 4488 (Sanofi-Aventis), Pharmaprojects No. 78-8) (GlaxoSmithKline), matuzumab (Merck KGaA), 5480 (Amgen), Pharmaprojects No. 6749 (Cengent), pirfeni MDX-214 (Medarex), ME-103 (Pharmexa), MED-A300 done (CAS No. 53179-13-8) (MARNAC), RPR-132294 (Gerolymatos), MNAC-13 (Lay Line Genomics), nimotu (Sanofi-Aventis), S5 (F002) (Fulcrum Pharmaceuticals), sim vastatin (CAS No. 79902-63-9) (Merck & Co), STA-6292 zumab (Center of Molecular Immunology), NSC-330507 or (Synta Pharmaceuticals), tacrolimus (CAS No. 104987-11-3) NSC-707545 (NIH), NV-50 (Novogen), OSI-930 (OSI Phar (from Fujisawa LifeCycle Pharma), talactoferrin alfa (CAS maceuticals), panitumumab (Abgenix), pelitinib (CAS No. No. 308240-58-6) (Agennix), thalidomide (CAS No. 50-35 287933-82-7) (Wyeth), pertuzumab (CAS No. 380610-27-5) 1) (Celgene), TNF antagonists form ProStrakan, and Syner (Genentech), Pharmaprojects No. 3985 (Sanofi-Aventis), gen, TNF inhibitors (Amgen), TNF-alpha antagonists from prostate cancer therapeutics from Sequenom (SQPC35, Dynavax Technologies and Jerina AG (Germany), TNF-alpha SQPC36, SQPC90), removab and remoxab (Trion Pharma), inhibitors from IBFB Pharma and Xencor (Xencor), torbafyl RG-13022 (CAS No. 136831-48-6), RG-13291 (CAS No. line (CAS No. 105102-214) (Sanofi-Aventis), UR-1505 (Uri 138989-50-1), or RG-14620 (CAS No. 136831-49-7) ach), VT-346 (Viron Therapeutics), YSIL6 (Y’s Therapeu (Sanofi-Aventis), RM-6427 (Romark), RNAi breast cancer tics), YSTH2 (Y’s Therapeutics), NPI-1302a-3 (Nereus therapy from Benitec, RP 53801 (CAS No 125882-88-4) Pharmaceuticals, a TNF antagonist from Jerina AG (Ger (Sanofi-Aventis), sorafenib tosylate (Bayer), SU-11657 many), dersalazine, or an analogue or derivative thereof). (Pfizer), Tie-2 antagonists from Semaia (Hybrigenics), Tie-2 [0526) 172. Tumor Necrosis Factor Antagonists inhibitors from Ontogen, trastuzumab (CAS No. 180288-69 [0527] In another embodiment, the fibrosis-inhibiting.com 1) (Genentech), tyrosine kinase inhibitors from Sanofi-Aven pound is a tumor necrosis factor (TNF) antagonist (eg anti tis, U3-1287, U3-1565, U3-1784, or U3-1800 (U3 Pharma), inflammatory compounds from Biota Inc. or an analogue or vatalanib (Novartis), VEGFR-2 kinase inhibitor from Bristol derivative thereof). Myers Squibb, XL-647 (Exelixis), ZD-6474 (AstraZeneca), [0528] 173. Toll Receptor Antagonists ZK-CDK (Schering AG), herbimycin A, or an analogue or [0529) In another embodiment, the fibrosis-inhibiting.com derivative thereof). pound is a Toll receptor antagonist (e.g., E5564 (Eisai Phar [0534] In certain embodiments, the tyrosine kinase inhibi maceuticals), or an analogue or derivative thereof). tor is an EGFR tyrosine kinase inhibitor such as EKB-569 [0530) 174. Tubulin Antagonist (Wyeth), or an analogue or derivative thereof). [0531] In another embodiment, the fibrosis-inhibiting.com [0535] 176. VEGF Inhibitors pound is a tubulin antagonist (e.g., synthadotin, KRX-0403 [0536] In another embodiment, the fibrosis-inhibiting com (Keryx Biopharmaceuticals), or an analogue or derivative pound is a VEGF Inhibitor (e.g., AZD2171 (AstraZeneca), or thereof). an analogue or derivative thereof) US 2009/0226500 A1 Sep. 10, 2009

[0537] 177. Vitamin D Receptor Agonists examples of anti-psychotic compounds include thioxanthines [0538] In another embodiment, the fibrosis-inhibiting.com such as chlorprothixene and thiothixene, clozapine, loxapine pound is a vitamin D receptor agonist (e.g., BXL-628, BXL succinate, and olanzapine. 922 (BioXell), or an analogue or derivative thereof). [0545] 181. CaM Kinase II Inhibitor [0539] 178. Histamine Receptor Antagonists [0546) In another embodiment, the fibrosis-inhibiting com [0540] In another embodiment, the fibrosis-inhibiting.com pound is CaM kinase II inhibitor, such as a lavendustin C, or pound is an histamine receptor antagonist. Certain embodi an analogue or derivative thereof. ments, the histamine receptor antagonists, such as H1, H2, (0547] 182. CaM Kinase II Inhibitor and H3 histamine receptor antagonists, block the production [0548] In another embodiment, the fibrosis-inhibiting com of pro-inflammatory cytokines such as TNFa and IL-1 (e.g., pound is CaM kinase II inhibitor, such as a lavendustin C, or IL-13). In certain embodiments, the histamine receptor an analogue or derivative thereof. antagonist inhibit NFkB activation. Representative examples [0549] 183. G Protein Agonist of H1 histamine receptor antagonists include phenothiazines, [0550] In another embodiment, the fibrosis-inhibiting com such as promethazine, and alkylamines, such as chlorphe pound is G protein agonist, such as aluminum fluoride, or an niramine (CAS No. 7054-11-7), brompheniramine (CAS No. analogue or derivative thereof. 980–71-2), fexofenadine hydrochloride, promethazine [0551] 184. Antibiotics and Anti-Microbials hydrochloride, loratadine, ketotifen fumarate salt, and acriv [0552] In another embodiment, the fibrosis-inhibiting com astine. Other examples of histamine receptor antagonists pound is an antibiotic, such as apigenin (Cas No. 520-36-5), include broad spectrum histamine receptor antagonists such ampicillin sodium salt (CAS No. 69-52–3), puromycin, or an as methylxanthines (e.g., theophylline, theobromine, and caf analogue or derivative thereof. feine). Representative examples of H2 receptor antagonists [0553] In another embodiment, the fibrosis-inhibiting com include those with a histamine-like structure including cime pound is an anti-microbial agent, such as brefeldin A (CAS tidine (available under the tradename TAGAMET from No. 20350-15-6), terbinafine, benzoyl peroxide, pentami SmithKline Beecham Phamaceutical Co., Wilmington, Del.), dine, ornidazole, tinidazole, ketocanazole, sulconazole ranitidine (available under the tradename ZANTAC from nitrate salt, or an analogue or derivative thereof. Warner Lambert Company, Morris Plains, N.J.), famotidine [0554] 185. DNA Topoisomerase Inhibitors (available under the tradename PEPCID from Merck & Co., [0555] In another embodiment, the fibrosis-inhibiting com Whitehouse Station, N.J.), nizatidine (available under the pound is DNA topoisomerase I inhibitor, such as fl-lapachone tradename AXID from Reliant Pharmaceuticals, Inc., Liberty (CAS No. 4707-32-8), or an analogue or derivative thereof. Corner, N.J.), nizatidine, and roxatidine acetate (CAS No [0556] In another embodiment, the fibrosis-inhibiting com 78628-28-1) Additional examples include H3 receptor pound is DNA topoisomerase II inhibitor, such as (...)-arcti antagonists (e.g., thioperamide and thioperamide maleate genin (CAS No 7770-78-7), aurintricarboxylic acid, or an salt) and anti-histamines such as tricyclic dibenozoxepins, analogue or derivative thereof ethanolamines, ethylenediamines, piperizines, piperidines, [0557] 186. Thromboxane A2 Receptor Inhibitor and pthalazinones. [0558] In another embodiment, the fibrosis-inhibiting com [0541] 179. Alpha Adrenergic Receptor Antagonists pound is thromboxane A2 receptor inhibitor, such as BM-531 [0542] In another embodiment, the fibrosis-inhibiting.com (CAS No. 284464–46-6), ozagrel hydrochloride (CAS No. pound is an alpha adrenergic receptor antagonist. Alpha adr 78712-43-3), or an analogue or derivative thereof. energic receptor antagonists may inhibit the production of [0559) 187. D2-Dopamine Receptor Antagonist pro-inflammatory cytokines such as TNFa. The alpha adren [0560] In another embodiment, the fibrosis-inhibiting com ergic receptor antagonist may be an alpha-1 and/oran alpha-2 pound is a D2 dopamine receptor antagonist, such as cloza adrenergic receptor antagonist. Representative examples of pine (CAS No. 5786-21-0), mesoridazine benzenesulfonate, alpha-1/alpha-2 antagonists include phenoxybenzamine. In or an analogue or derivative thereof. certain embodiments, the alpha adrenergic receptor antago [0561] 188. Peptidyl-Prolyl Cis/Trans Isomerase Inhibitor nist is a haloalkylamine compound ora catecholamine uptake [0562] In another embodiment, the fibrosis-inhibiting com inhibitor. Representative examples of alpha-1 adrenergic pound is a Peptidyl-Prolyl Cis/Trans Isomerase Inhibitor, receptor antagonists include phenoxybenzamine hydrochlo such as juglone (CAS No. 481-39-0), or an analogue or ride and prazosin, a piperizinyl quinazoline. Representative derivative thereof. examples of alpha-2 adrenergic receptor antagonists include [0563] 189. Dopamine Antagonists imadazole based compounds such as idazoxan (CAS No. [0564] In another embodiment, the fibrosis-inhibiting com 79944–56-2), idazoxan hydrochloride, and loxapine succi pound is a dopamine antagonist, such as thiothixene, thior nate salt (CAS No. 27833-64-3). Additional examples of idazine hydrochloride, or an analogue or derivative thereof. alpha adrenergic receptor antagonists include prazosin [0565] 190. Anesthetics hydrochloride. [0566] In another embodiment, the fibrosis-inhibiting com [0543) 180. Anti-Psychotic Compounds pound is an anesthetic compound, such as lidocaine (CAS [0544] In another embodiment, the fibrosis-inhibiting.com No. 137-58-6), or an analogue or derivative thereof. pound is an anti-psychotic compound, such as a phenothiaz [0567] 191. Clotting Factors ine compound or an analogue or derivative thereof. In some [0568] In another embodiment, the fibrosis-inhibiting com embodiments, the fibrosis-inhibiting compound is a phe pound is a clotting factor, such as menadione (CAS No. nothiazine derivative capable of suppressing the production 58-27-5), or an analogue or derivative thereof of pro-inflammatory cytokines such as TNFa and/or IL-1. [0569] 192. Lysyl Hydrolase Inhibitor Representative examples of phenothiazine compounds [0570] In another embodiment, the fibrosis-inhibiting com include chlorpromazine, fluphenazine, trifluorphenazine, pound is a lysyl hydrolase inhibitor, such as minoxidil (CAS mesoridazine, thioridazine, and perphenazine. Other No. 38304-91-5), or an analogue or derivative thereof. US 2009/0226500 A1 Sep. 10, 2009 46

[0571] 193. Muscarinic Receptor Inhibitor [0592] 203. Anti-Neoplastic Agents [0572] In another embodiment, the fibrosis-inhibiting.com [0593] In another embodiment, the fibrosis-inhibiting com pound is a muscarinic receptor inhibitor, such as perphena pound is an anti-neoplastic agent, such as tirapazamine (CAS zine (CAS No. 58-39–9), or an analogue orderivative thereof. No. 27314-97-2), fludarabine (CAS No. 21679-14-1), [0573] 194. Superoxide Anion Generator cladribine, imatinib mesilate, or an analogue or derivative [0574] In another embodiment, the fibrosis-inhibiting.com thereof. pound is a superoxide anion generator, such as plumbagin [0594) 204. DNA Synthesis Inhibitors (CAS No 481-42-5), or an analogue or derivative thereof. [0595] In another embodiment, the fibrosis-inhibiting com (0575] 195. Steroids pound is a DNA synthesis inhibitor, such as S-(2-hydroxy-5 [0576] In another embodiment, the fibrosis-inhibiting.com nitrobenzyl)-6-thioguanosine or uracilfludarabine phosphate pound is a steroid, such as prednisolone, prednisolone 21-ac (CAS No. 75607-67-9), 6,11-dihydroxy-5,12-naphthacene etate (CAS No. 52-21-1), loteprednol etabonate, (CAS No. dione, or an analogue or derivative thereof. 82034-46-6), clobetasol propionate, or an analogue orderiva [0596] 205. DNA Alkylating Agents tive thereof. [0597] In another embodiment, the fibrosis-inhibiting com [0577] 196. Anti-Proliferative Agents pound is a DNA alkylating agent, such as dacarbazine (CAS [0578] In another embodiment, the fibrosis-inhibiting.com No. 4342-03-4), temozolomide, procarbazine HCl, or an ana pound is an anti-proliferative agent, such as silibinin (CAS logue or derivative thereof. No. 22888-70-6), silymarin (CAS No. 65666-07-1), 1,2-hex [0598) 206. DNA Methylation Inhibitors anediol, dioctyl phthalate (CAS No. 117-81-7), zirconium [0599] In another embodiment, the fibrosis-inhibiting com (IV) oxide, glycyrrhizic acid, spermidine trihydrochloride or pound is a DNA methylation inhibitor, such as decitabine tetrahydrochloride, CGP 74514A, spermine tetrahydrochlo (CAS No. 2353-33-5), or an analogue or derivative thereof. ride, NG-methyl-L-arginine acetate salt, galardin, halofugi [0600] 207. NSAID Agents none hydrobromide (HBr), fascaplysin, or an analogue or [0601] In another embodiment, the fibrosis-inhibiting com derivative thereof. pound is a NSAID agent, such as nabumetone, benzydamine hydrochloride, or an analogue or derivative thereof. [0579] 197. Diuretics [0602) 208. Peptidylglycine Alpha-Hydroxylating [0580] In another embodiment, the fibrosis-inhibiting.com Monooxygenase Inhibitors pound is a diuretic, such as spironolactone (CAS No. 52-01 [0603] In another embodiment, the fibrosis-inhibiting com 7), or an analogue or derivative thereof. pound is a peptidylglycine alpha-hydroxylating monooxyge [0581] 198. Anti-Coagulants nase inhibitor, such as trans-styrylacetic acid, or an analogue [0582] In another embodiment, the fibrosis-inhibiting.com or derivative thereof. pound is an anti-coagulant, such as fucoidan from Fucus [0604] 209. MEK1/MEK2 Inhibitors vesiculosus (CAS No. 9072-19-9) or an analogue or deriva [0605] In another embodiment, the fibrosis-inhibiting com tive thereof. pound is a MEK1/MEK2 inhibitor, such as U0126 (CAS No. [0583) 199. Cyclic GMP Agonists 1095.11-58-2), or an analogue or derivative thereof. [0584] In another embodiment, the fibrosis-inhibiting.com [0606] 210. NO Synthase Inhibitors pound is a cyclic GMP agonist, such as sinitrodil (CAS No. [0607] In another embodiment, the fibrosis-inhibiting com 143248-63-9), or an analogue or derivative thereof. pound is an NO synthase inhibitor, such as L-NAME (CAS [0585] 200. Adenylate Cyclase Agonist No. 53308-83-1), NG-Methyl-L-arginine acetate salt, or an [0586] In another embodiment, the fibrosis-inhibiting.com analogue or derivative thereof. pound is an adenylate cyclase agonist, such as histamine [0608] 211. Retinoic Acid Receptor Antagonists (CAS No. 51-45-6), or an analogue or derivative thereof. [0609] In another embodiment, the fibrosis-inhibiting com [0587] 201. Antioxidants pound is retinoic acid receptorantagonist, such as isotretinoin [0588] In another embodiment, the fibrosis-inhibiting.com (CAS No. 4759-48-2), or an analogue or derivative thereof. pound is an antioxidant, such as morpholine, phytic acid [0610] 212. ACE Inhibitors dipotassium salt, (–)-epigallocatechin or (–)-epigallocat [0611] In another embodiment, the fibrosis-inhibiting com echin gallate from green tea (CAS Nos. 970-74-1 and 1257 pound is an ACE inhibitor, such as quinapril hydrochloride 08-5, respectively), (–)-epigallocatechin gallate (CAS No. (CAS No 85441-61-8), enalapril, or an analogue orderivative 989-51-5), nobiletin (CAS No 478-01-3), probucol (CAS No thereof 23288-49-5), phosphorous acid, hesperetin. L-ascorbyl-2 [0612] 213. Glycosylation Inhibitors phosphate, magnesium salt (CAS No. 84309-23-9), catechin, [0613] In another embodiment, the fibrosis-inhibiting com (+)-maringenin (CAS No. 67604-48-2), (–)-epicatechin, (-) pound is a glycosylation inhibitor, such as aminoguanidine epicatechin gallate, 3-hydroxyflavone, (-)-arctigenin, or an hydrochloride, castanospermine, or an analogue orderivative analogue or derivative thereof. thereof [0589] 202. Nitric Oxide Synthase Inhibitors [0614] 214. Intracellular Calcium Influx Inhibitors [0590] In another embodiment, the fibrosis-inhibiting.com [0615] In another embodiment, the fibrosis-inhibiting com pound is a nitric oxide synthase inhibitor, such as ammonium pound is an intracellular calcium influx inhibitor, such as pyrrolidinedithiocarbamate (CAS No. 5108-96-3), or an ana TAS-301 (CAS No. 193620-69-8), or an analogue or deriva logue or derivative thereof. tive thereof. [0591] In another embodiment, the fibrosis-inhibiting.com [0616] 215. Anti-Emetic Agents pound is a reversible nitric oxide synthase inhibitor, such as [0617] In another embodiment, the fibrosis-inhibiting com NB-methyl-L-arginine acetate salt (L-NMMA) (CAS No. pound is an anti-emetic agent, such as amifostine (CAS No. 53308-83-1), or an analogue or derivative thereof. 20537-88-6), or an analogue or derivative thereof. US 2009/0226500 A1 Sep. 10, 2009 47

[0618] 216. Acetylcholinesterase Inhibitors [0646] 230. Anti-Spasmodic Agents [0619. In another embodiment, the fibrosis-inhibiting.com [0647] In another embodiment, the fibrosis-inhibiting com pound is an acetylcholinesterase inhibitor, such as (–)-hu pound is an anti-spasmodic agent, such as 2-hydroxy-4,6 perzine A (CAS No. 102518-79-6), or an analogue or deriva dimethoxyacetophenone, or an analogue or derivative tive thereof. thereof. [0620) 217. ALK-5 Receptor Antagonists [0648] 231. Protein Synthesis Inhibitors [0621] In another embodiment, the fibrosis-inhibiting.com [0649] In another embodiment, the fibrosis-inhibiting com pound is an ALK-5 receptor antagonist, such as SB 431542 pound is a protein synthesis inhibitor, such as oxytetracycline (CAS No. 301836-41-9), orananalogue orderivative thereof. hydrochloride, or an analogue or derivative thereof. [0622] 218. RAR/RXR Antagonists [0650] 232. Cº-Glucosidase Inhibitors [0623] In another embodiment, the fibrosis-inhibiting.com [0651] In another embodiment, the fibrosis-inhibiting com pound is a RAR/RXT antagonist, such as 9-cis-retinoic acid, pound is a C-glucosidase inhibitor, such as myricetin (CAS or an analogue or derivative thereof No. 529-44-2), or an analogue or derivative thereof. [0624] 219. EIF-2a Inhibitors [0652] 233. Calcium Channel Blockers [0625] In another embodiment, the fibrosis-inhibiting.com [0653] In another embodiment, the fibrosis-inhibiting com pound is a eIF-2a inhibitor, such as salubrinal, or an analogue pound is a calcium channel blocker, such as verapamil, nitren or derivative thereof. dipine, or an analogue or derivative thereof. [0626] 220. S-Adenosyl-L-Homocysteine Hydrolase [0654] In another embodiment, the fibrosis-inhibiting com Inhibitors pound is a L-type calcium channel blocker, such as nifedipine [0627] In another embodiment, the fibrosis-inhibiting.com (CAS No. 21829-25-4), (+)-cis-diltiazem hydrochloride, or pound is a S-adenosyl-L-homocysteine hydrolase inhibitor, an analogue or derivative thereof. such as 3-deazaadenosine, or an analogue or derivative [0655] In another embodiment, the fibrosis-inhibiting com thereof. pound is a T-type calcium channel blocker, such as penfluri [0628] 221. Estrogen Agonists dol (CAS No. 26864-56-2), or an analogue or derivative [0629] In another embodiment, the fibrosis-inhibiting.com thereof. pound is an estrogen agonist, such as coumestrol, bisphenol [0656] 234. Pyruvate Dehydrogenase Activators A, 1-linoleoyl-rac-glycerol (CAS No. 2277–28-3), daidzein [0657] In another embodiment, the fibrosis-inhibiting com (4,7-dihydroxy-iso-flavone), dihexyl phthalate, kaempferol, pound is a pyruvate dehydrogenase activator, such as dichlo formononetin, or an analogue or derivative thereof. roacetic acid, or an analogue or derivative thereof. [0630) 222. Serotonin Receptor Inhibitors [0658] 235. Prostaglandin Inhibitors [0631] In another embodiment, the fibrosis-inhibiting.com [0659] In another embodiment, the fibrosis-inhibiting com pound is a serotonin receptor inhibitor, such as amitriptyline pound is a prostaglandin inhibitor, such as betulinic acid, or hydrochloride, or an analogue or derivative thereof. an analogue or derivative thereof. [0632] 223. Anti-Thrombotic Agents [0660] 236. Sodium Channel Inhibitors [0633] In another embodiment, the fibrosis-inhibiting.com [0661] In another embodiment, the fibrosis-inhibiting com pound is an anti-thrombotic agent, such as geniposidic acid, pound is a sodium channel inhibitor, such as amiloride hydro geniposide, or an analogue or derivative thereof. chloride hydrate, or an analogue or derivative thereof. [0634] 224. Tryptase Inhibitors [0662] 237. Serine Protease Inhibitors [0635] In another embodiment, the fibrosis-inhibiting.com [0663] In another embodiment, the fibrosis-inhibiting com pound is a tryptase inhibitors, such as 2-azetidinone, or an pound is a serine protease inhibitor, such as gabexate mesy analogue or derivative thereof. late, or an analogue or derivative thereof. [0636] 225. Pesticides [0637] In another embodiment, the fibrosis-inhibiting.com [0664] 238. Intracellular Calcium Flux Inhibitors pound is a pesticide, such as allyl disulfide, or an analogue or [0665] In another embodiment, the fibrosis-inhibiting com derivative thereof. pound is an intracellular calcium flux inhibitor, such as [0638] 226. Bone Mineralization Promotor thapsigargin, or an analogue or derivative thereof. [0639] In another embodiment, the fibrosis-inhibiting.com [0666] 239. JAK2 Inhibitors pound is a bone mineralization promotor, such as glycerol [0667] In another embodiment, the fibrosis-inhibiting com 2-phosphate disodium salt hydrate, or an analogue or deriva pound is a JAK2 inhibitor (e.g., AG490 (CAS No. 134036 tive thereof. 52-5), or an analogue or derivative thereof). [0640] 227. Bisphosphonate Compounds [0668] 240. Androgen Inhibitors [0641] In another embodiment, the fibrosis-inhibiting.com [0669] In another embodiment, the fibrosis-inhibiting com pound is a bisphosphonate compound, such as risedronate, or pound is an androgen inhibitor (e.g., tibolone (CAS No. an analogue or derivative thereof. 5630-53-5), or an analogue or derivative thereof). [0642] 228. Anti-Inflammatory Compounds [0670] 241. Aromatase Inhibitors [0643] In another embodiment, the fibrosis-inhibiting.com [0671] In another embodiment the fibrosis-inhibiting com pound is an anti-inflammatory compound, such as aucubin, pound is an aromatase inhibitor (e.g. Ietrozole, oran analogue cepharanthine, or an analogue or derivative thereof. or derivative thereof) [0644] 229. DNA Methylation Promotors [0672] 242. Anti-Viral Agents [0645] In another embodiment, the fibrosis-inhibiting.com [0673] In another embodiment, the fibrosis-inhibiting com pound is a DNA methylation promotor, such as 5-azacytidine, pound is an anti-viral agent, such as imiquimod, or an ana or an analogue or derivative thereof. logue or derivative thereof. US 2009/0226500 A1 Sep. 10, 2009 48

[0674] 243. 5-HT Inhibitors [0698] 1. Secondary Therapeutic Agents [0675] In another embodiment, the fibrosis-inhibiting.com [0699] Within various embodiments of the invention, a pound is a 5-HT inhibitor, such as ketanserin tartrate, amox therapeutic composition may include an agent that inhibits apine, or an analogue or derivative thereof. fibrosis and a second composition or compound which acts to [0676] 244. FXR Antagonists have an inhibitory effect on pathological processes in or [0677] In another embodiment, the fibrosis-inhibiting.com around the site where a suture has been, is being, or is to be pound is a FXR antagonist, such as guggulsterone (CAS No. implanted. Representative examples of additional therapeu 95975-55-6), or an analogue or derivative thereof. tically active agents include, by way of example and not [0678] 245. Actin Polymerization and Stabilization Promo limitation, anti-thrombotic agents, anti-infective agents, anti torS proliferative agents, anti-inflammatory agents, neoplastic [0679] In another embodiment, the fibrosis-inhibiting.com agents, enzymes, receptor antagonists or agonists, hormones, pound is an actin polymerization and stabilization promotor, antibiotics, antimicrobial agents, antibodies, cytokine inhibi such as jasplakinolide, or an analogue or derivative thereof. tors, IMPDH (inosine monophosplate dehydrogenase) [0680] 246. AXOR12 Agonists inhibitors, tyrosine kinase inhibitors, MMP inhibitors, p38 [0681] In another embodiment, the fibrosis-inhibiting.com MAP kinase inhibitors, immunosuppressants, apoptosis pound is an AXOR12 agonist, such as metastin (KiSS-1 (112 antagonists, caspase inhibitors, and JNK inhibitors 121), or an analogue or derivative thereof. [0700] In certain embodiments, the composition may [0682] 247. Angiotensin II Receptor Antagonists include an anti-thrombotic agent and/or antiplatelet agent [0683] In another embodiment, the fibrosis-inhibiting.com and/or a thrombolytic agent, which reduces the likelihood of pound is an angiotensin II receptor agonist, such as losartan thrombotic events upon implantation of a medical implant potassium, or an analogue or derivative thereof. Representative examples of anti-thrombotic and/or antiplate [0684] 248. Platelet Aggregation Inhibitors let and/or thrombolytic agents include heparin, heparin frag [0685] In another embodiment, the fibrosis-inhibiting.com ments, organic salts of heparin, heparin complexes (e.g., ben pound is a platelet aggregation inhibitor, such as clopidogrel, zalkonium heparinate, tridodecylammonium heparinate), or an analogue or derivative thereof. dextran, sulfonated carbohydrates such as dextran sulfate, [0686] 249. CB1/CB2 Receptor Agonists coumadin, coumarin, heparinoid, danaparoid, argatroban chi [0687] In another embodiment, the fibrosis-inhibiting.com tosan sulfate, chondroitin sulfate, danaparoid, lepirudin, hiru pound is a CB1/CB2 receptor agonist, such as HU-210 (CAS din, AMP adenosine, 2-chloroadenosine, acetylsalicylic No. 112830-95-2), or an analogue or derivative thereof. acid, phenylbutazone, indomethacin, meclofenamate, hydro [0688] 250. Norepinephrine Reuptake Inhibitors chloroquine, dipyridamole, iloprost, streptokinase, factor Xa [0689] In another embodiment, the fibrosis-inhibiting.com inhibitors, such as DX9065a, magnesium, and tissue plasmi pound is a norepinephrine reuptake inhibitor, such as nortrip nogen activator. Further examples include plasminogen, lys plasminogen, alpha-2-antiplasmin, urokinase, aminocaproic tyline hydrochloride, or an analogue or derivative thereof. acid, ticlopidine, clopidogrel, trapidil (triazolopyrimidine), [0690] 251. Selective Serotonin Reuptake Inhibitors naftidrofuryl, auriritricarboxylic acid and glycoprotein IIb/ [0691] In another embodiment, the fibrosis-inhibiting.com IIIa inhibitors such as abcizamab, eptifibatide, and tirogiban. pound is a selective serotonin reuptake inhibitor, such as Other agents capable of affecting the rate of clotting include paroxetine maleate, or an analogue or derivative thereof. glycosaminoglycans, danaparoid, 4-hydroxycourmarin, war [0692] 252. Reducing Agents farin sodium, dicumarol, phenprocoumon, indan-1,3-dione, [0693] In another embodiment, the fibrosis-inhibiting.com acenocoumarol, anisindione, and rodenticides including bro pound is a reducing agent such as WW-85 (Inotek), or an madiolone, brodifacoum, diphenadione, chlorophacinone, analogue or derivative thereof. and pidnone. [0694] 253. Immuno-Modulators [0701] Representative examples of secondary therapeutic [0695] In another embodiment, the fibrosis-inhibiting.com agents include: anti-inflammatory agents (e.g., dexametha pound is an immunomodulators such as Bay 11-7085, (-) sone, cortisone, fludrocortisone, prednisone, prednisolone, arctigenin, idazoxan hydrochloride, or an analogue orderiva 60-methylprednisolone, triamcinolone, and betamethasone); tive thereof. matrix metalloproteinase (MMP) inhibitors (e.g., marimistat, [0696) In certain embodiments, two or more anti-scarring batimistat, TIMP’s representative examples of which are agents may be used in combination with sutures according to included in U.S. Pat. Nos. 5,665,777; 5,985,911; 6,288,261: the present invention. The effectiveness of various combina 5,952,320; 6,441,189; 6,235,786; 6,294,573; 6,294,539; tions of anti-scaring agents in using in combination with 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502; sutures (e.g., reducing surgical adhesion) may be determined 6,160,132: 6,197.791; 6,172,057; 6,288,086; 6,342,508; according to the methods described in the examples. 6,228,869; 5,977,408, 5,929,097; 6,498,167; 6,534,491; B. Therapeutic Compositions 6,548,524; 5,962,481; 6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080: [0697] Anti-scarring agents as described above may be 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; used in combination with other therapeutic agents or compo 5,789.434; 5,932,763; 6,500,847; 5,925,637; 6,225,314: ments to form therapeutic compositions. In certain embodi 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; ments, such compositions may be used in making sutures that 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; comprise anti-scarring agents, such as used as a coating or 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; dipping solution. In other embodiments, anti-scarring agent 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; containing therapeutic compositions may be used to infiltrate 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976: tissue into which a suture has been, is being, or is to be 5,968,795; 5,789.434; 5,932,763; 6,500,847; 5,925,637; implanted. 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; US 2009/0226500 A1 Sep. 10, 2009 49

5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 03/053958A1, WO 03/055447A2, WO 03/059269A2, WO 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 03/063573A2, WO 03/087071A1, WO 99/001545A1, WO 6,642,255; 6,495,548; 6.479,502; 5,696,082; 5,700,838; 97/40028A1, WO 97/41211A1, WO 98/40381A1, and WO 5,861,436; 5,691.382; 5,763,621; 5,866,717; 5,902.791; 99/55663A1), p38 MAP kinase inhibitors (MAPK) (e.g., 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739: GW-2286, CGP-52411, BIRB-798, SB220025, RO-320 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 1195, RWJ-67657, RWJ-68354, SCIO-469) (Representative 5,917,090; 6,124.329; 6,329,373; 6,344,457; 5,698,706; examples are included in U.S. Pat. Nos. 6,300,347; 6,316, 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491; 464; 6,316,466; 6,376.527; 6,444,696; 6,479,507; 6,509,361: 5,955,435; 6,090,840; 6,114,372: 6,566,384; 5,994,293; 6,579,874; and 6,630,485, and US Patent Application Publi 6,063,786; 6,469,020; 6,118,001: 6,187,924; 6,310,088; cation Nos 2001/0044538A1, 2002/0013354A1, 2002/ 5,994,312: 6,180,611; 6,110,896; 6,380,253, 5,455,262: 0049220A1, 2002/0103245A1, 2002/0151491A1, 2002/ 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 0156114A1, 2003/0018051A1, 2003/0073832A1, 2003/ 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 0.130257A1, 2003/0130273A1, 2003/013031941, 2003/ 5,239,078; 5,892,112, 5,773,438; 5,696,147; 6,066,662; 0139388A1, 2003/01394.62A1, 2003/0149031A1, 2003/ 6,600,057; 5,990,158; 5,731,293; 6,277.876; 6,521,606: 0166647A1, and 2003/0181411A1, and PCT Publication 6,168,807; 6,506,414; 6,620,813; 5.684,152; 6,451,791; Nos. WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; WO 01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 6,403,644; 6,177,466; 6,569,899: 5,594,006; 6,417,229; 02/083622A2, WO 02/094842A2, WO 02/096426A1, WO 5,861,510; 6,156,798; 6.387,931; 6,350,907; 6,090,852; 02/101015A2, WO 02/103000A2, WO 03/008413A1, WO 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016: 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO 5,804,593; 5,847,153; 5,859,061; 6,194,451; 6,482,827; 03/031431A1, WO 03/040103A1, WO 03/053940A1, WO 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472.396; 6,548,667; 03/053941A2, WO 03/063799A2, WO 03/079986A2, WO 5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657; 03/080024A2, WO 03/082287A1, WO 97/44467A1, WO 5,773,428; 6,037,472: 6,579,890; 5,932,595; 6,013,792; 99/01449A1, and WO 99/58523A1), and immunomodula 6,420,415: 5,532,265; 5,639,746; 5,672,598; 5,830,915; tory agents (rapamycin, everolimus, ABT-578, azathioprine 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; azithromycin, analogues of rapamycin, tacrolimus and 5,595,885; 6,093,398; 6,379,667; 5,641,636; 5,698,404; derivatives thereof (e.g., EP 0184162B1 and those described 6,448,058; 6,008,220; 6,265,432: 6,169,103: 6,133,304; in U.S. Pat. No. 6,258,823) and everolimus and derivatives 6,541,521; 6,624, 196; 6,307,089; 6,239,288; 5,756,545; thereof (e.g., U.S. Pat. No. 5,665,772). Further representative 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; examples of sirolimus analogues and derivatives include 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284.513; ABT-578 and those found in PCT Publication Nos. WO 5,977,141; 6,153,612; 6.297,247; 6,559,142; 6,555,535: 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 6,350,885; 5,627,206, 5,665,764; 5,958,972; 6,420,408; 96/00282, WO95/16691, WO95/15328, WO95/07468, WO 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 95/04738, WO95/04060, WO 94/25022, WO 94/21644, WO 6,531,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 5,183,900; 5,189,178; 6.511,993; 6,617,354; 6,331,563: 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 5,962,466; 5,861,427; 5,830,869, and 6,087,359), cytokine 93/18043, WO 93/13663, WO 93/11130, WO 93/101.22, WO inhibitors (chlorpromazine, mycophenolic acid, rapamycin, 93/04680, WO 92/14737, and WO92/051.79 and in U.S. Pat. 10-hydroxy vitamin Ds), IMPDH (inosine monophosplate Nos. 6,342,507; 5,985,890; 5,604,234, 5,597,715; 5,583,139; dehydrogenase) inhibitors (e.g., mycophenolic acid, ribavi 5,563,172; 5,561,228; 5,561,137; 5,541,193; 5,541,189: ran, aminothiadiazole, thiophenfurin, tiazofurin, viramidine) 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182: (Representative examples are included in U.S. Pat. Nos. 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,536,747; 5,807,876; 5,932,600; 6,054,472: 6,128,582: 5,258,389: 5,252,732; 5,247,076; 5.225,403; 5,221,625; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 5,210,030: 5,208,241; 5,200,411; 5,198.421; 5,147,877; 6,498.178; 6,514,979; 6,518,291; 6,541,496; 6,596,747; 5,140,018; 5,116,756; 5,109,112; 5,093,338; and 5,091,389. 6,617,323; and 6,624,184, U.S. Patent Application Nos. [0702] Other examples of therapeutic agents that may be 2002/0040022A1, 2002/0052513A1, 2002/0055483A1, included include tyrosine kinase inhibitors (e.g., imantinib, 2002/0068346A1, 2002/011 1378A1, 2002/0111495A1, ZK-222584, CGP-52411, CGP-53716, NVP-AAK980-NX, 2002/0123520A1, 2002/0143176A1, 2002/0147160A1, CP-127374, CP-564959, PD-171026, PD-173956, 2002/0161038A1, 2002/0173491A1, 2002/0183315A1, PD-180970, SU-0879, and SKI-606), MMP inhibitors (e.g., 2002/0193612A1, 2003/0027845A1, 2003/0068302A1, nimesulide, PKF-241-466, PKF-242-484, CGS-27023A, 2003/0105073A1, 2003/0130254A1, 2003/0143197A1, SAR-943, primomastat, SC-77964, PNU-171829, AG-3433, 2003/0144300A1, 2003/0166201A1, 2003/0181497A1, PNU-142769, SU-5402, and dextipotam), p38 MAP kinase 2003/0186974A1, 2003/0186989A1, and 2003/0195202A1. inhibitors (e.g., CGH-2466 and PD-98-59), immunosuppres and PCT Publication Nos. WO 00/24725A1, WO sants (e.g., argyrin B, macrocyclic lactone, ADZ-62-826, 00/25780A1, WO 00/26197A1, WO 00/51615A1, WO CCI-779, tilomisole, amcinonide, FK-778, AVE-1726, and 00/56331A1, WO 00/73288A1, WO 01/00622A1, WO MDL-28842), TNF-484A, PD-172084, CP-293121, 01/66706A1, WO 01/79246A2, WO 01/81340A2, WO CP-353164, and PD-168787, NFKB inhibitors, (e.g., AVE 01/85952A2, WO 02/16382A1, WO 02/18369A2, WO 0547, AVE-0545, and IPL-576092), HMGCOA reductase 02/051814A1, WO 02/057287A2, WO 02/057425A2, WO inhibitors (e.g., pravestatin, atorvastatin, fluvastatin, dalvas 02/060875A1, WO 02/060896A1, WO 02/060898A1, WO tatin, glenvastatin, pitavastatin, CP-83101, U-20685), apop 02/068058A2, WO 03/020298A1, WO 03/037349A1, WO tosis antagonists (e.g., troloxamine, TCH-346 (N-methyl-N 03/0395.48A1, WO 03/045901A2, WO 03/047512A2, WO propargyl-10-aminomethyl-dibenzo(b,f)oxepin), caspase US 2009/0226500 A1 Sep. 10, 2009 50 inhibitors (e.g., PF-5901 (benzenemethanol, alpha-pentyl-3 [0708] a. Anti-Infective Agents—Antibiotics (2-quinolinylmethoxy)-), and JNK inhibitor (e.g., [0709| Antibiotics and combinations of antibiotics that are AS-602801). used by those skilled in the medical art include the following [0703] In certain embodiments, a polymeric composition exemplary antibiotics: fourth generation penicillins such as comprising a fibrosis-inhibiting agent is combined with an meziocillin and piperacillin (ureidopenicillins), carbenicillin agent that can modify metabolism of the agent in vivo to and ticarcillin (carboxypenicillins), and analogues and enhance efficacy of the fibrosis-inhibiting agent. One class of derivatives thereof; first generation cephalosporins such as cephazolin, Cephazolin Sodium, Cephalexin (Keflex), Cefa therapeutic agents that can be used to alter drug metabolism zolin (Ance?), Cephapirin (Cefady!), and Cephalothin (Kef includes agents capable of inhibiting oxidation of the anti lin), and analogues and derivatives thereof; Ticarcillin; sec scarring agent by cytochrome P450 (CYP). In one embodi ond generation cephalosporins such as Cefuroxime (Ceftin ment, compositions are provided that include a fibrosis-in (oral) and Zinocef), Cefotetan (Cefotan), and Cefoxitin (Me hibiting agent (e.g., ZD-6474, AP-23573, Synthadotin, foxin), and analogues and derivatives thereof; third genera S-0885, Aplidine, Ixabepilone, IDN-5390, SB-2723005, tion cephalosporin such as Naxcel (Ceftiofur Sodium), Cef ABT-518, Combretastatin, Anecortave acetate, SB-715992, dinir (Omnicef), Cefoperazone (Cefobid), Ceftazidime Temsirolimus, Adalimumab, erucyiphosphocholine, alph (Fortaz), and Ceftriaxone (Rocephin), and Cefotaxime astatin, BXT-51072, Etanercept, Humicade, Gefitinib, rapa (Claforan), and analogues and derivatives thereof; and fourth mycin, everolimus) and a CYP inhibitor, which may be com generation cephalosporins such as Cefepime (Maxipime) and bined (e.g., coated) with any of the sutures described herein. analogues and derivatives thereof, monobactams such as Representative examples of CYP inhibitors include flavones, aztreonam and analogues and derivatives thereof; carbapen azole antifungals, macrolide antibiotics, HIV protease inhibi ems such as imipenem, ertapenem and meropenem, and ana tors, and anti-sense oligomers. logues and derivatives thereof. Also included are inhibitors of [0704] In certain embodiments, the therapeutic composi protein synthesis such as aminoglycosides including strepto tion may comprise one or more anti-infective agents, which mycin, gentamicin, gentamicin sulfate, tobramycin, and ami kacin, amikacin sulfate, and analogues and derivatives may reduces the likelihood of infections at the site where a thereof; inhibitors of protein synthesis such as the MSL group suture is implanted. An “anti-infective agent” refers to an including macrolides (Erythromycin), long acting macrolides agent that reduces the likelihood of an infection. An agent is (Azithromycin) and lincosamides (Clindamycin) and strep demonstrated to be an active anti-infective agent toward a togramins (Syneroid), clarithromycin, kanamycin, kanamy microorganism by assays routinely practiced by persons cin sulfate, and analogues and derivatives thereof. Other skilled in the art, for example, an in vitro assay determining exemplary antibiotics include inhibitors of DNA snthesis inhibition of bacterial growth as indicated by the M.I.C. (min such as the quinolones including ciprofloxacin, ofioxacin, imimum inhibitory concentration). In certain embodiments, gatifloxacin, moxifloxacin, levofloxacin, trovafloxacin, and anti-infective agents are chemotherapeutic agents that have analogues and derivatives thereof, as well as other inhibitors antimicrobial activity at low doses (e.g., anthracyclines, fluo of DNA synthesis such as metronidazole and analogues and ropyrimidines, folic acid antagonists, podophylotoxins, derivatives thereof. Other antibiotics include inhibitors of camptothecins, hydroxyureas, and platinum complexes. folate metabolism such as sulfonamides and trimethoprim, [0705] In certain embodiments, the anti-infective agent and analogues and derivatives thereof. Additional agents may be an anti-septic agent. An “anti-septic agent” refers to include but are not limited to cefixime, spectinomycin, tetra an agent or substance that is capable of effective antisepsis, cycline, nitrofurantoin, doxycycline, polymyxin B, neomy that is, prevention of infection by inhibiting the growth of an cin, neomycin sulfate, and analogues and derivatives thereof. infectious organism without necessarily killing the organism. In certain embodiments, the anti-infective agent is gentami Representative examples of anti-septic agents include chlo cin sulfate, amikacin sulfate, kanamycin sulfate, polymyxin rhexadine, triclosan, and chloroxylenol. B, neomycin sulfate, cephazolin sodium, metronidazole, [0706] In certain other embodiments, the anti-infective ciprofloxacin, piperacillin, cefoxitin, cefepime, azithromy agent may be an antibiotic. An “antibiotic” refers to an agent cin, or trimethoprim-sulfamethoxazole. that kills or inhibits the growth of microorganisms. Antibiot [0710] Furthermore, additional therapeutic agents may be ics may have a narrow or wide range of activity against either delivered in combinations. Such combinations include, by one or both of Gram-positive and Gram-negative organisms. way of example, but are not limited to amoxicillin and clavu Antibiotic agents can be identified through in vitro inhibition lanate, ampicillin and sulbactam, trimethoprom-sul of bacterial growth as shown in the M.I.C. assay described famethoxazole, ampicillin and probenecid, amoxicillin and herein. Representative examples of antibiotics include gen probenecid, penicillin G and probenecid, and penicillin and a tamicin sulfate, amikacin sulfate, kanamycin sulfate, poly penicillinase inhibitor. myxin B, neomycin sulfate, cephazolin sodium, metronida [0711] b. Anti-Infective Agents—Chemotherapeutic zole, Ciprofloxacin, piperacillin, Cefoxitin, Cefepime, Agents Azithromycin, and Trimethoprom-sulfamethoxazole. [0712] In certain embodiments, anti-infective agents useful [0707] In certain embodiments, the anti-infective agent in the present invention may be chemotherapeutic agnets, may be further combined with anti-thrombotic and/or anti which have potent antimicrobial activity at extremely low platelet agents (for example, heparin, dextran sulfate, danap doses. Discussed in more detail below are several represen aroid, lepirudin, hirudin, AMP adenosine, 2-chloroadenos tative examples of such agents: (A) anthracyclines (e.g., ine, aspirin, phenylbutazone, indomethacin, meclofenamate, doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopi 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) dogrel, abcizamab, eptifibatide, tirofiban, streptokinase, and/ podophylotoxins (e.g., etoposide), (E) camptothecins, (F) or tissue plasminogen activator) to enhance efficacy hydroxyureas, and (G) platinum complexes (e.g., cisplatin). US 2009/0226500 A1 Sep. 10, 2009

[0713] i. Anthracyclines [0714] Anthracyclines have the following general struc ture, where the R groups may be a variety of organic groups:

[0715] According to U.S. Pat. No. 5,594,158, suitable R Doxorubicin: OCH, C(O)CH,OH OH out of ring groups are as follows: R is CH3 or CH2OH: R2 is daun plane osamine or H; Rs and Ra are independently one of OH, NO2, Epirubicin: OCHs C(O)CH2OH OH in ring plane (4! epimer of NH2, F, Cl, Br, I, CN, H or groups derived from these; Rs is doxorubicin) hydrogen, hydroxyl, or methoxy; and Rais are all hydrogen. Daunorubicin: OCHs C(O)CH3 OH out of ring plane Alternatively, Rs and Ra are hydrogen and R7 and Rs are alkyl Idarubicin: H C(O)CH3 OH out of ring or halogen, or vice versa. plane [0716] According to U.S. Pat. No. 5,843,903, R, may be a Pirarubicin: OCHs C(O)CH2OH conjugated peptide. According to U.S. Pat. No. 4,296,105, Rs may be an ether linked alkyl group. According to U.S. Pat. No. 4,215,062, Rs may be OH or an ether linked alkyl group. C R? may also be linked to the anthracycline ring by a group Zorubicin: OCH, C(CH2)(=NNHC(O)CeH, OH Carubicin: OH C(O)CH3 OH out of ring other than C(O), such as an alkyl or branched alkyl group plane having the C(O) linking moiety at its end, such as —CH2CH (CH2—X)C(O)—R1, wherein X is H or an alkyl group (see, e.g., U.S. Pat. No. 4,215,062). R, may alternately be a group [0718I. Other suitable anthracyclines are anthramycin, linked by the functional group N–NHC(O)—Y, where Y is a mitoxantrone, menogaril, nogalamycin, aclacinomycin A, group such as a phenyl or substituted phenyl ring. Alternately olivomycin A, chromomycin As, and plicamycin having the Rs may have the following structure: Structures:

OH O in which Rø is OH either in or out of the plane of the ring, or Mitoxantrone is a second sugar moiety such as Rs. Rio may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Pat. No. 5,843, 903). Alternately, Rio may be derived from an amino acid, having the structure –C(O)CH(NHR, )(R12), in which R, , is H, or forms a Cs a membered alkylene with R12, R12 may be H, alkyl, aminoalkylamino, hydroxyl mercapto, phenyl, ben zyl or methylthio (see U.S. Pat. No. 4,296,105) [0717] Exemplary anthracyclines are doxorubicin, dauno rubicin, idarubicin epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the structures: US 2009/0226500 A1 Sep. 10, 2009 52

1995), cephalosporin doxorubicin derivatives (Vrudhula et -continued al. JMed Chem 38(3):1380-5, 1995), hydroxyrubicin (Solary et al., Int. J. Cancer 56(1):85-94, 1994), methoxymorpholino R1 R2 R3 R4 doxorubicin derivative (Kuhlet al., Cancer Chemother. Phar Olivomycin A COCH(CH3), CH3 COCH3 H macol. 33(1):10-16, 1993), (6-mateimidocaproyl)hydrazone Chromomycin As COCH, CHs COCH, CHs doxorubicin derivative (Willner et al., Bioconjugate Chem. Plicamycin H H H CH3 4(6):521-7, 1993), N-(5,5-diacetoxypent-1-yl) doxorubicin R1 R2 R3 (Chemf & Farquhar, J. Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ri Menogaril H OCH3 H Nogalamycin O-sugar H COOCH3 pamonti et al., Br. J. Cancer 65(5):703-7, 1992), N-hydrox

ysuccinimide ester doxorubicin derivatives (Demant et al., Biochim. Biophys. Acta 1118(1):83-90, 1991), polydeoxy nucleotide doxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta 1129(3):294-302, 1991), morpholinyl doxoru bicin derivatives (EPA 434960), mitoxantrone doxorubicin analogue (Krapcho et al., J. Med. Chem. 34(8):2373-80, 1991), AD 198 doxorubicin analogue (Traganos et al., Cancer Res. 51(14):3682-9, 1991), 4-demethoxy-3'-N-trifluoro acetyldoxorubicin (Horton et al., Drug Des. Delivery 6(2): 123-9, 1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et al., Eur J. Cancer Clin. Oncol. 2007):919–26, 1984), alkylating cya nomorpholino doxorubicin derivative (Scudder et al., J. Nat’l Cancer Inst. 80016): 1294–8, 1988), deoxydihydroiodooxoru bicin (EPA 275966), adriblastin (Kalishevskaya et al., Vestn. Mosk, Univ., 16(Biol. 1):21-7, 1988), 4'-deoxydoxorubicin (Schoelzel et al., Leuk. Res. 10(12): 1455-9, 1986), 4-dem H3C O ethyoxy-4'-O-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemother 16:285-70–285-77, 1983), 3'-deamino-3' N(CH3)2 hydroxydoxorubicin (Horton et al., J. Antibiot. 37(8):853-8, 1984), 4-demethyoxy doxorubicin analogues (Barbieri et al., H3C O Drugs Exp. Clin. Res. 10(2):85-90, 1984), N-L-leucyl doxo rubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. OH Symp. Tumor Pharmacother), 179-81, 1983), 3'-deamino-3' O (4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. Pat. No. 4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin H3C O derivatives (U.S. Pat. No. 4,301,277), 4'-deoxydoxorubicin O and 4'-O-methyldoxorubicin (Giuliani et al., Int. J. Cancer Aclacinomycin A 27(1):5-13, 1981), aglycone doxorubicinderivatives (Chan & Watson, J. Pharm. Sci 67(12) 1748 52, 1978), SM 5887 (Pharma Japan 1468 20, 1995). MX-2 (Pharma Japan 1420 [0719) Other representative anthracyclines include, FCE 19, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP 23762, a doxorubicin derivative (Quaglia et al., J. Liq. Chro 275966), morpholinyl doxorubicin derivatives (EPA matogr 17(18):3911-3923, 1994), annamycin (Zou et al., J. 434960), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxoru Pharm. Sci. 82(11):1151-1154, 1993), ruboxyl (Rapoport et bicin derivatives (U.S. Pat. No. 4,314,054), doxorubicin-14 al., J. Controlled Release 58(2):153-162, 1999), anthracy valerate, morpholinodoxorubicin (U.S. Pat. No. 5,004,606), cline disaccharide doxorubicin analogue (Pratesi et al., Clin. 3'-deamino-3'-(3"-cyano-4"-morpholinyl doxorubicin; Cancer Res. 4(11):2833–2839, 1998), N-(trifluoroacetyl) 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3'-dihydroxorubi doxorubicin and 4'-O-acetyl-N-(trifluoroacetyl)doxorubicin cin; (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubi (Berube & Lepage, Synth. Commun. 28(6):1109–1116, cin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihy 1998), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat’l Acad. drodaunorubicin; and 3'-deamino-3'-(4"-morpholinyl-5 Sci. U.S.A. 95(4):1794-1799, 1998), disaccharide doxorubi iminodoxorubicin and derivatives (U.S. Pat. No. 4,585,859), cin analogues (Arcamone et al., J. Nat'l Cancer Inst. 89(16): 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin 1217-1223, 1997), 4-demethoxy-7-O-[2,6-dideoxy-4-O-(2, derivatives (U.S. Pat. No. 4,314,054) and 3-deamino-3-(4 3,6-trideoxy-3-amino-O-L-lyxo-hexopyranosyl)-O-L-lyxo morpholinyl) doxorubicin derivatives (U.S. Pat. No. 4,301, hexopyranosyl]-adriamicinone doxorubicin disaccharide 277). analogue (Monteagudo et al., Carbohydr. Res. 3000): 11-16, [0720) ii. Fluoropyrimidine Analogues 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat’l Acad. [0721] In another aspect, the therapeutic agent is a fluoro Sci. U.S.A. 94(2):652-656, 1997), morpholinyl doxorubicin pyrimidine analog, such as 5-fluorouracil, or an analogue or analogues (Duran et al., Cancer Chemother. Pharmacol. derivative thereof, including carmofur, doxifluridine, emite 38(3):210-216, 1996), enaminomalonyl-[3-alanine doxorubi fur, tegafur, and floxuridine. Exemplary compounds have the cin derivatives (Seitz et al., Tetrahedron Lett. 36(9) 1413-16, Structures: US 2009/0226500 A1 Sep. 10, 2009

dihydro-6-alkoxyuracil (Van der Wilt et al., Br. J. Cancer 68(4):702-7, 1993), cyclopentane 5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem. 70(4):1162-9, 1992), O A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye R2 F Zazhi 20011):513-15, 1989), N4-trimethoxybenzoyl-5 SN | deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):998-1003, 1990), 1-hexyl carbamoyl-5-fluorouracil (Hoshi et al. J Pharmacobio-Dun º 3(9):478-81, 1980; Maehara et al., Chemotherapy (Basel) R 34(6):484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2):151-4, R1 R2 1988), uracil-1-(2-tetrahydrofuryl)-5-fluorouracil (Anai et al., Oncology 45(3): 144-7, 1988), 1-(2'-deoxy-2'-fluoro-fl-D 5-Fluorouracil H H Carmofur C(O)NH(CH,);CH, H arabinofuranosyl)-5-fluorouracil (Suzuko et al., Mol. Phar Doxifluridine A1 H macol. 31(3)-301-6, 1987), doxifluridine (Matuura et al., Oyo Floxuridine A2 H Yakuri 29(5):803-31, 1985), 5'-deoxy-5-fluorouridine (Bol Emitefur CH2OCH2CH3 B lag & Hartmann, Eur, J. Cancer 16(4):427–32, 1980), Tegafur C H 1-acetyl-3-O-toluyl-5-fluorouracil (Okada, Hiroshima J. CN Med. Sci. 28(1):49-66, 1979), 5-fluorouracil-m-formylben O 2. O O zene-sulfonate (JP 55059173), N'-(2-furanidyl)-5-fluorou S racil (JP 53149985) and 1-(2-tetrahydrofuryl)-5-fluorouracil O N O CH3 (JP 52089680). [0724] These compounds are believed to function as thera peutic agents by serving as antimetabolites of pyrimidine. B [0725] iii. Folic Acid Antagonists CH3 [0726] In another aspect, the therapeutic agent is a folic acid antagonist, such as methotrexate or derivatives or ana O logues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin. Methotrex C ate analogues have the following general structure:

[0722] Other suitable fluoropyrimidine analogues include 5-FudR (5-fluoro-deoxyuridine), or an analogue orderivative thereof, including 5-iododeoxyuridine (5-ludk),5-bromode oxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP). Exem plary compounds have the structures:

[0727] The identity of the R group may be selected from organic groups, particularly those groups set forthin U.S. Pat. Nos. 5,166,149 and 5,382,582. Forexample, R, may be N, R2 may be NorC(CH3), R3 and Rs' may Horalkyl, e.g., CH3, Ra may be a single bond or NR, where R is H or alkyl group. Rs.6 s may be H, OCHs, or alternately they can behalogens or hydro groups. R7 is a side chain of the general structure:

OH O 5-Fluoro-2'-deoxyuridine: R = F 5-Bromo-2'-deoxyuridine: R = Br NH CH3 5-Iodo-2'-deoxyuridine: R = I HO

O [0723] Other representative examples of fluoropyrimridine O OH analogues include N3-alkylated analogues of 5-fluorouracil # (Kozai et al., J. Chem. Soc., Perkin Trans. 1(19):3145-3146, 1998), 5-fluorouracil derivatives with 1,4-oxaheteroepane wherein n=1 for methotrexate, n=3 for pteropterin. The car moieties (Gomez et al., Tetrahedron 54(43):13295-13312, boxyl groups in the side chain may be esterified or form a salt 1998), 5-fluorouracil and nucleoside analogues (Li, Antican such as a Znºt salt. Ro and Rio can be NH2 or may be alkyl cer Res. 17(1A):21-27, 1997), cis- and trans-5-fluoro-5,6 substituted. US 2009/0226500 A1 Sep. 10, 2009

[0728] Exemplary folic acid antagonist compounds have the structures:

RI N NH2 R5 S sº R4 2 2N R6 R3 R3 Ro R; R8 Ro RI R2 R3 R4 Rs Ré R7 Rs Methotrexate NH, N N H N(CH3) H H A (n = 1) H Edatrexate NH, N N H CH(CH2CH3) H H A (n = 1) H Trimetrexate NH, CH C(CH3) H NH H OCH OCHs OCHs Pteropterin OH N N H NH H H A (n = 3) H Denopterin OH N N CHs N(CH3) H H A (n = 1) H Peritrexin NH, N C(CH3) H single bond OCHs H H OCH3

A: O

NH CH3 HO

O O OH # HoocºS O º | Nsº CH3 Hoocº : SNii \ S / N NH O Tomudex

[0729) Other representative examples include 6-S-aminoa Chem. 39(1):56-65, 1996), methotrexate tetrahydroquinazo cyloxymethyl mercaptopurine derivatives (Harada et al., line analogue (Gangjee, et al., J. Heterocycl. Chem. 32(1): Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine 243-8, 1995), N-(o-aminoacyl) methotrexate derivatives (6-MP) (Kashida et al., Biol. Pharm. Bull, 18(11):1492-7, (Cheung et al., Pteridines 3(1-2):101-2, 1992), biotin meth 1995), 7,8-polymethyleneimidazo-1,32-diazaphosphorines otrexate derivatives (Fan et al., Pteridines 3(1-2): 131-2, (Nilov et al. Mendeleev Commun 2:67, 1995), azathioprine 1992), D-glutamic acid or D-erythrou, threo-4-fluoro (Chifotides et al., J Inorg Biochem. 56(4):249-64, 1994), glutamic acid methotrexate analogues (McGuire et al., Bio methyl-D-glucopyranoside mercaptopurine derivatives (Da chem. Pharmacol. 42(12):2400-3, 1991), 5,7-methano meth Silva et al., Eur, J. Med. Chem. 29(2):149-52, 1994) and otrexate analogues (Rosowsky et al., Pteridines 2(3):133-9, s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim. 1991), 10-deazaminopterin (10-EDAM) analogue (Braa Farm. Zh. 15(8), 65-7, 1981); indoline ring and a modified khuis et al., Chem. Biol. Pteridines, Proc. Int. Symp. Pte ornithine or glutamic acid-bearing methotrexate derivatives ridines Folic Acid Deriv., 1027-30, 1989), Y-tetrazole meth (Matsuoka et al., Chem. Pharm. Bull. 45(7):1146-1150, otrexate analogue (Kalman et al., Chem. Biol. Pteridines, 1997), alkyl-substituted benzene ring C bearing methotrexate Proc. Int. Symp. Pteridines Folic Acid Deriv., 1154-7, 1989), derivatives (Matsuoka et al., Chem. Pharm. Bull. 44(12): N-(L-O-aminoacyl) methotrexate derivatives (Cheung et al., 2287–2293, 1996), benzoxazine or benzothiazine moiety Heterocycles 28(2):751-8, 1989), meta and ortho isomers of bearing methotrexate derivatives (Matsuoka et al., J. Med. aminopterin (Rosowsky et al., J. Med. Chem. 32(12) 2582, Chem. 40(1):105-111, 1997), 10-deazaminopterin analogues 1989), hydroxymethylmethotrexate (DE 267495). Y-fluo (DeGraw et al., J. Med. Chem, 40(3):370-376, 1997), 5-dea romethotrexate (McGuire et al., Cancer Res.49(16):45.17–25, zaminopterin and 5,10-dideazaminopterin methotrexate ana 1989), polyglutamyl methotrexate derivatives (Kumar et al., logues (Piper et al., J. Med Chem, 40(3):377-384, 1997), Cancer Res. 46(10):5020-3, 1986), gem-diphosphonate indoline moiety-bearing methotrexate derivatives (Matsuoka methotrexate analogues (WO 88/06158), Cº- and Y-substituted et al., Chem. Pharm. Bull. 44(7):1332-1337, 1996), lipophilic methotrexate analogues (Tsushima et al., Tetrahedron amide methotrexate derivatives (Pignatello et al., World Meet. 44(17):5375-87, 1988), 5-methyl-5-deaza methotrexate ana Pharm. Biopharm. Pharm. Technol., 563-4, 1995), L-threo logues (U.S. Pat. No. 4,725,687), Nô-acyl-No-(4-amino-4 (2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic deoxypteroyl)-L-ornithine derivatives (Rosowsky et al., J. acid-containing methotrexate analogues (Hart et al., J. Med. Med. Chem. 31(7): 1332-7, 1988), 8-deaza methotrexate ana US 2009/0226500 A1 Sep. 10, 2009

logues (Kuehl et al., Cancer Res.48(6):1481-8, 1988), acivi [0731] iv. Podophyllotoxins cin methotrexate analogue (Rosowsky et al., J. Med. Chem. [0732] In another aspect, the therapeutic agent is a Podo 30(8): 1463-9, 1987), polymeric platinol methotrexate deriva phyllotoxin, or a derivative or an analogue thereof. Exem tive (Carraher et al., Polym. Sci. Technol. (Plenum), 35(Adv. plary compounds of this type are etoposide or teniposide, Biomed. Polym.):311-24, 1987), methotrexate-Y-dimyris which have the following structures: toylphophatidylethanolamine (Kinsky et al., Biochim. Bio phys. Acta 917(2):211-18, 1987), methotrexate poly glutamate analogues (Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 985-8, 1986), poly-Y-glutamyl methotrexate derivatives (Kis liuk et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate methotr exate derivatives (Webber et al., Chem. Biol. Pteridines, Pte ridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analogue (Delcamp et al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9, 1986), 2,-omega-diaminoalkanoid acid-con H3CO OCH3 taining methotrexate analogues (McGuire et al., Biochem. Pharmacol. 35(15):2607-13, 1986), polyglutamate methotr exate derivatives (Kamen & Winick, Methods Enzymol. 122 (Vitam. Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza Etoposide CHs analogues (Piper et al., J. Med. Chem. 29(6):1080–7, 1986), quinazoline methotrexate analogue (Mastropaolo et al., J. Temposide S CH3 Med. Chem. 29(1): 155-8, 1986), pyrazine methotrexate ana logue (Lever & Vestal, J. Heterocycl. Chem. 22(1):5-6, 1985), cysteic acid and homocysteic acid methotrexate analogues (U.S. Pat. No. 4,490,529), Y-tert-butyl methotrexate esters (Rosowsky etal, JMed Chem 28(5):660-7, 1985), fluorinated [0733] Other representative examples of podophyllotoxins methotrexate analogues (Tsushima et al., Heterocycles 23(1): include Cu(II)-VP-16 (etoposide) complex (Tawa et al., 45-9, 1985), folate methotrexate analogue (Trombe, J Bacte Biocrg Med. Chem. 6(7):1003-1008, 1998), pyrrolecarboxa riol. 160(3):849-53, 1984), phosphonoglutamic acid ana midino-bearing etoposide analogues (Ji et al., Bioorg. Med. logues (Sturtz & Guillamot, Eur, J. Med Chem.-Chim. Ther. Chem. Lett. 7(5):607-612, 1997), 43-amino etoposide ana 19(3):267-73, 1984), poly(L-lysine) methotrexate conjugates logues (Hu, University of North Carolina Dissertation, 1992), (Rosowsky et al., J. Med. Chem. 27(7):888-93, 1984), dil y-lactone ring-modified arylamino etoposide analogues ysine and trilysine methotrexate derivates (Forsch & (Zhou et al., J. Med. Chem, 37(2):287-92, 1994), N-glucosyl Rosowsky, J. Org. Chem, 49(7):1305-9, 1984), 7-hy etoposide analogue (Allevi et al., Tetrahedron Lett. 34(45): droxymethotrexate (Fabre et al., Cancer Res. 43(10):4648 7313-16, 1993), etoposide A-ring analogues (Kadow et al., 52, 1983), poly-Y-glutamyl methotrexate analogues (Piper & Biodrq. Med. Chem. Lett. 2(1):17-22, 1992), 4'-deshydroxy Montgomery, Adv. Exp. Med. Biol., 163(Folyl Antifolyl Poly 4'-methyl etoposide (Saulnier et al., Biocrg. Med. Chem. Lett. glutamates):95-100, 1983), 3',5'-dichloromethotrexate 2(10): 1213-18, 1992), pendulum ring etoposide analogues (Rosowsky & Yu, J. Med. Chem. 26(10): 1448-52, 1983), (Sinha et al., Eur, J. Cancer 26(5):590-3, 1990) and E-ring diazoketone and chloromethylketone methotrexate ana desoxy etoposide analogues (Saulnier et al., J. Med. Chem. logues (Gangjee et al., J. Pharm. Sci. 71(6):717-19, 1982), 32(7):1418-20, 1989). 10-propargylaminopterin and alkyl methotrexate homologs [0734] These compounds are believed to act as topoi (Piper et al., J. Med. Chem. 25(7):877-80, 1982), lectin somerase II inhibitors and/or DNA cleaving agents. derivatives of methotrexate (Lin et al., JNCI 66(3):523-8, [0735] v. Camptothecins 1981), polyglutamate methotrexate derivatives (Galivan, [0736] In another aspect, the therapeutic agent is camptoth Mol. Pharmacol. 17(1):105-10, 1980), halogentated methotr ecin, or an analogue or derivative thereof. Camptothecins exate derivatives (Fox, JNCI 58(4):J955-8, 1977), 8-alkyl-7, have the following general structure. 8-dihydro analogues (Chaykovsky et al., J. Med. Chem. 20010):J1323-7, 1977), 7-methyl methotrexate derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 17(12):J1308-11, 1974), lipophilic methotrexate derivatives and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10):J1190–3, 1973), deaza amethopterin analogues (Montgomery et al., Ann. N.Y. Acad. Sci. 186:J227–34, 1971), MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and homocysteic acid methotrexate analogues (EPA 0142220); [0730] These compounds are believed to act as antimetabo lites offolic acid. US 2009/0226500 A1 Sep. 10, 2009 56

[0737] In this structure, X is typically 0, but can be other for example N-[3-[5-(4-fluorophenylthio)-furyl]-2-cyclo groups, eg., NH in the case of 21-lactam derivatives. R1 is penten-1-yl]N-hydroxyurea; R2 is Horan alkyl group having typically H or OH, but may be other groups, e.g., a terminally 1 to 4 carbons and Rs is H; X is H or a cation. hydroxylated C1-s alkane. R2 is typically H or an amino con taining group such as (CH3)2NHCH2, but may be other [0745] Other suitable hydroxyureas are disclosed in, e.g., groups e.g., NO2, NH2, halogen (as disclosed in, e.g., U.S. U.S. Pat. No. 4,299,778, wherein R, is a phenyl group sub Pat. No. 5,552,156) or a short alkane containing these groups. stituted with one or more fluorine atoms; R2 is a cyclopropyl Rs is typically H or a short alkyl such as C2Hs. Ra is typically group; and Rs and X is H. H but may be other groups, e.g., a methylenedioxy group with [0746] Other suitable hydroxyureas are disclosed in, e.g., Ri U.S. Pat. No. 5,066,658, wherein R, and Rs together with the [0738] Exemplary camptothecin compounds include topo adjacent nitrogen form: tecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lac tam-20(S)-camptothecin, 10, 11-methylenedioxycamptoth ecin, SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. Exemplary compounds have the structures:

wherein m is 1 or 2, n is 0–2 and Y is an alkyl group. [0747] In one aspect, the hydroxyurea has the structure: Js on R1 R2 R3 Hydroxyurea Camptothecin: H H H Topotecan: OH (CH3)2NHCH2 H SN-38: OH H C2H5 [0748] These compounds are thought to function by inhib X: O for most analogs, NH for 21-lactam analogs iting DNA synthesis [0739] Camptothecins have the five rings shown here. The [0749) vii. Platinum Complexes ring labeled E must be intact (the lactone rather than carboxy [0750] In another aspect, the therapeutic agent is a platinum late form) for maximum activity and minimum toxicity. compound In general, suitable platinum complexes may be of [0740] Camptothecins are believed to function as topoi Pt(II) or Pt(IV) and have this basic structure: somerase I inhibitors and/or DNA cleavage agents. [0741] vi. Hydroxyureas [0742] The therapeutic agent of the present invention may be a hydroxyurea. Hydroxyureas have the following general Structure:

wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen, R, and R2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(II) complexes Z! and Z, are non-existent. For Pt(IV) Zi and Z, may be anionic [0743) Suitable hydroxyureas are disclosed in, for groups such as halogen, hydroxyl, carboxylate, ester, sulfate example, U.S. Pat. No. 6,080,874, wherein R, is: or phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4,250, 189. [0751] Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Pat. Nos. 5,409,915 and 5,380,897. For example bisplatinum and triplatinum complexes of the type: and R2 is an alkyl group having 1-4 carbons and Rs is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a meth ylether. [0744] Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No. 5,665,768, wherein R, is a cycloalkenyl group, US 2009/0226500 A1 Sep. 10, 2009 57

2-methyl-1,4-butanediamineplatinum(II) and cis-diammine -continued (glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Z1 Biochem. 26(4):257-67, 1986; Fanet al., Cancer Res.48(11): 3135-9, 1988; Heiger-Bernays et al., Biochemistry 29(36): 8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res. 12(4):233-40, 1993; Murray et al., Biochemistry 31(47): 11812-17, 1992; Takahashi et al., Cancer Chemother. Pharmacol. 33(1):31-5, 1993), cis-amine-cyclohexylamine dichloroplatinum(II) (Yoshida et al., Biochem. Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyphe nyl)ethylenediamine) dichloroplatinum(II) (Bednarski et al., [0752) Exemplary platinum compounds are cisplatin, car J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues boplatin, oxaliplatin, and miboplatin having the structures: containing a tethered dansyl group (Hartwig et al., J. Am. Chem. Soc. 114(21):8292-3, 1992), platinum(II) polyamines (Siegmann et al., Inorg. Met.-Containing Polym. Mater., NH3 O Os] (Proc. Am. Chem. Soc. Int Symp), 335-61, 1990), cis-(3H) ºts dichloro(ethylenediamine)platinum(II) (Eastman, Anal. Bio NH3 | `NH, chem. 197(2):311-15, 1991), trans-diamminedichloroplati | O num(II) and cis-(Pt(NH3)2(N3-cytosine)C1) (Bellon & Lippard, Biophys. Chem. 35(2-3):179-88, 1990), 3H-cis-1,2 a-rºwC| O diaminocyclohexanedichloroplatinum(II) and 3H-cis-1,2-di Cisplatin Carboplatin aminocyclohexane-malonatoplatinum (II) (Oswald et al., Res. Commun. Chem. Pathol. Pharmacol. 64(1):41-58, O H. H. 1989), diaminocarboxylatoplatinum (EPA 296321), trans O o \{ (D,1)-1,2-diaminocyclohexane carrier ligand-bearing plati O. NH2 \ S. num analogues (Wyrick & Chaney, J. Labelled Compa. \/t Pt*. / N **** d/ *.N H. Radiopharm. 25(4):349–57, 1988), aminoalkylaminoan O NH3 trº thraquinone-derived cisplatin analogues (Kitov et al., Eur J. O O Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al., Oxaliplatin Miboplatin Eur, J. Cancer Clin. Oncol. 24(8): 1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbellet [0753] Other representative platinum compounds include al., Inorg. Chim. Acta 152(2):125-34, 1988), platinum(II), platinum(IV) (Liu & Wang, Shandong Yike Daxue Xuebao (CPA),Pt|DOLYM) and (DACH)Pt[DOLYM) cisplatin 24(1):35-41, 1986), cis-diammine(1,1-cyclobutanedicar (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), boxylato-)platinum(II) (carboplatin, JM8) and ethylenediam Cis-[PtCl2(4,7-H-5-methyl-7-oxol 1,2,4-?triazolo[1,5-alpy mine-malonatoplatinum(II) (JM40) (Begg et al., Radiother. rimidine), (Navarro et al., J. Med. Chem. 41(3):332-338, Oncol. 9(2):157-65, 1987), JM8 and JM9 cisplatin analogues 1998), [Pt(cis-1,4-DACH)(trans-C1,)(CBDCA)].9%MeoH (Harstricket al., Int. J. Androl. 10(1): 13945, 1987), (NPr4), cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969 ((PtCL4).cis-(PtCl2-(NH2Me)2) (Brammer et al., J. Chem. 5971, 1997), 4-pyridoxate diammine hydroxyl platinum Soc., Chem. Gommun. 6:443-5, 1987), aliphatic tricarboxy (Tokunaga et al., Pharm Sci. 3(7):353–356, 1997), Pt(II) . . . lic acid platinum complexes (EPA 185225), and cis-dichloro Pt(II) (Pt.[NHCHN(C(CH2)(CH3))|a) (Navarro et al., Inorg (amino acid) (tert-butylamine)platinum(II) complexes Chem. 35(26).7829–7835, 1996), 254-S cisplatin analogue (Pasini & Bersanetti, Inorg. Chim. Acta 107(4):259-67, (Koga et al. Neurol. Res. 18(3):244-247, 1996), o-phenylene 1985). These compounds are thought to function by binding diamine ligand bearing cisplatin analogues (Koeckerbauer & to DNA, i.e., acting as alkylating agents of DNA. Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, cis-[Pt(OaC),I2(en)] (Kratochwil et al., J. Med. Chem. [0754) viii. Combination Therapy 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenedi [0755] It should be readily evident based upon the discus amine ligand (with sulfur-containing amino acids and glu sions provided herein that combinations of anthracyclines tathione) bearing cisplatin analogues (Bednarski, J. Inorg. (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., Biochem. 62(1):75, 1996), cis-1,4-diaminocyclohexane cis 5-fluorouracil), folic acid antagonists (e.g., methotrexate and/ platin analogues (Shamsuddin et al., J. Inorg. Biochem. 61(4): or podophylotoxins (e.g., etoposide) can be utilized to 291-301, 1996), 5' orientational isomer of cis-[Pt(NH3)(4 enhance the antibacterial activity of the suture coating. Simi aminoTEMP-O){d(GpG)}] (Dunham & Lippard, J. Am. larly anthracyclines (e.g., doxorubicin or mitoxantrone), Chem. Soc. 117(43): 10702-12, 1995), chelating diamine fluoropyrimidines (e.g., 5-fluorouracil), folic acid antago bearing cisplatin analogues (Koeckerbauer & Bednarski, J. nists (e.g., methotrexate and/or podophylotoxins (e.g., etopo Pharm. Sci. 84(7):819-23, 1995), 1,2-diarylethyleneamine side) can be combined with traditional antibiotic and/or anti ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. fungal agents to enhance efficacy Clin. Oncol. 121(1):31-8, 1995), (ethylenediamine)platinum [0756] Dosages (II) complexes (Pasini et al., J. Chem. Soc., Dalton Trans. [0757] As sutures are made in a variety of configurations 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al., Int.J. and sizes, the exact dose of anti-infective agent administered Oncol. 5(3):597–602, 1994), cis-diaminedichloroplatinum will vary with suture size, length, diameter, surface area, (II) and its analogues cis-1,1-cyclobutanedicarbosylato(2R) design and portions of the suture coated. However, certain US 2009/0226500 A1 Sep. 10, 2009 principles can be applied in the application of this art. Drug dosing parameters should be utilized in combination with the dose can be calculated as a function of dose per unit area (of release rate of the drug from the suture surface such that a the portion of the suture being coated), or total drug dose. minimum concentration of 107-107* M of doxorubicin is Total drug dose administered can be measured and appropri maintained on the surface for the required duration of thera ate surface concentrations of active drug can be determined. peutic effect It is necessary to insure that surface drug con Regardless of the method of application of the drug to the centrations exceed concentrations of doxorubicin known to suture, the preferred agents, used alone or in combination, be lethal or inhibitory to the growth of multiple species of should be administered under the following dosing guide bacteria and/or fungi (i.e., are in excess of 107* M: although lines: for some embodiments lower concentrations are sufficient). [0758] Anti-infective agents are to be used at concentra In a preferred embodiment, doxorubicin is released from the tions that range from several times more than, to 50%, 20%, surface of the suture such that anti-infective activity is main 10%, 5%, or even less than 1% of the concentration typically tained for a period ranging from several hours to several used in a single anti-infective systemic dose application. In months. In a particularly preferred embodiment the drug is certain embodiments, the anti-infective agent is released from the composition in effective concentrations in a time period released in effective concentrations for a period ranging from that may be measured from the time of infiltration into tissue 1 week-6 months. It should be readily evident based upon the adjacent to the suture, which ranges from about less than 1 discussions provided herein that analogues and derivatives of day to about 180 days. Generally, the release time may also be doxorubicin (as described previously) with similar functional from about less than 1 day to about 180 days; from about 7 activity can be utilized for the purposes of this invention; the days to about 14 days; from about 14 days to about 28 days; above dosing parameters are then adjusted according to the from about 28 days to about 56 days; from about 56 days to relative potency of the analogue or derivative as compared to about 90 days; from about 90 days to about 180 days. the parent compound (e.g., a compound twice as potent as [0759] The exemplary anti-infective agents, used alone or doxorubicin is administered at half the above parameters, a in combination, should be administered under the following compound half as potent as doxorubicin is administered at dosing guidelines. The total amount (dose) of anti-infective twice the above parameters, etc.). agent in the composition can be in the range of about 0.01 [0761] Utilizing mitoxantrone as another example of an pig-1 pig, or about 1 pug-10 pig, or about 10 pig-100 pig or about anthracycline, whether applied as a polymer coating, incor 100 pig-1 mg or about 1 mg to 10 mg. of about 10 mg-100 mg, porated into the polymers that make up the suture (plain or of about 100 mg to 250 mg for coating a suture or a portion self-retaining), or applied without a carrier polymer, the total thereof or for infiltrating a tissue where a suture has been, is dose of mitoxantrone applied should not exceed 5 mg (range being, or is to be, implanted, or about 250 mg-1000 mg for of 0.01 pig to 5 mg). In a particularly preferred embodiment, infiltrating a tissue where a suture has been, is being, or is to the total amount of drug applied should be in the range of 0.05 be, implanted. The dose (amount) of anti-infective agent per pig to 1 mg. The dose per unit area (i.e., the amount of drug as unit area of suture or tissue surface to which the agent is a function of the surface area of the portion of the suture to applied may be in the range of about 0.01 pg/mm3-1 |g/mm3, which drug is applied and/or incorporated) should fall within or about 1 pg/mm2-10 pg/mm3, or about 10 pg/mm3-100 the range of 0.01 p.g-20 pig per mm of surface area. In a pg/mm3, or about 100 pg/mm to 250 pg/mm3. As different particularly preferred embodiment, mitoxantrone should be compositions will release the anti-infective agent at differing applied to the suture surface at a dose of 0.05 mg/mm3-3 rates, the above dosing parameters should be utilized in com Hg/mm3. As different polymer and non-polymer coatings will bination with the release rate of the drug from the composi release mitoxantrone at differing rates, the above dosing tion such that a minimum concentration of about 107* M to parameters should be utilized in combination with the release 107M, or about 107M to 107°Morabout 107°M to 107* M rate of the drug from the suture surface such that a minimum or about 107* M to 107* M of the agent is maintained in the concentration of 10°-107°M of mitoxantrone is maintained vicinity of or on the tissue surface to maintain the desired on the surface for the required duration of therapeutic effect. therapeutic effect for the required period of time. The It is necessary to insure that drug concentrations on the suture required minimum concentration is dependent on the potency surface exceed concentrations of mitoxantrone known to be of the agent under consideration and can be determined using lethal or inhibitory to the growth of multiple species of bac standard tests such as the Minimum Inhibitory Concentration teria and/or fungi (i.e., are in excess of 10 M, although for (M.I.C.) test. some embodiments lower drug levels will be sufficient). In a [0760) (a) Anthracyclines Utilizing the anthracycline doxo preferred embodiment, mitoxantrone is released from the rubicin as an example, whether applied as a polymer coating, surface of the suture such that anti-infective activity is main incorporated into the polymers which make up the suture tained for a period ranging from several hours to several (plain or self-retaining), or applied without a carrier polymer, months. In a particularly preferred embodiment the drug is the total dose of doxorubicin applied to the suture should not released in effective concentrations for a period ranging from exceed 25 mg (range of 0.1 pig to 25 mg). In a particularly 1 week-6 months. It should be readily evident based upon the preferred embodiment, the total amount of drug applied discussions provided herein that analogues and derivatives of should be in the range of 0.5 pig to 5 mg. The dose per unit area mitoxantrone (as described previously) with similar func (i.e., the amount of drug as a function of the surface area of the tional activity can be utilized for the purposes of this inven portion of the suture to which drug is applied and/or incorpo tion; the above dosing parameters are then adjusted according rated) should fall within the range of 0.01 pig-100 pig permm” to the relative potency of the analogue or derivative as com of surface area. In a particularly preferred embodiment, doxo pared to the parent compound (e.g., a compound twice as rubicin should be applied to the suture surface at a dose of 0.1 potent as mitoxantrone is administered at half the above Hg/mm3-10 pg/mm3. As different polymer and non-polymer parameters, a compound half as potent as mitoxantrone is coatings will release doxorubicinat differing rates, the above administered at twice the above parameters, etc.). US 2009/0226500 A1 Sep. 10, 2009 59

[0762] (b) Fluoropyrimidines Utilizing the fluoropyrimi a period ranging from several hours to several months. In a dine 5-fluorouracil as an example, whether applied as a poly particularly preferred embodiment the drug is released in mer coating, incorporated into the polymers which make up effective concentrations for a period ranging from 1 week-6 the suture (plain or self-retaining), or applied without a carrier months. It should be readily evident based upon the discus polymer, the total dose of 5-fluorouracil applied should not sions provided herein that analogues and derivatives of eto exceed 20 mg (range of 0.1 pig to 20 mg). In a particularly poside (as described previously) with similar functional preferred embodiment, the total amount of drug applied activity can be utilized for the purposes of this invention, the should be in the range of 10 pig to 10 mg. The dose per unit above dosing parameters are then adjusted according to the area (i.e., the amount of drug as a function of the surface area relative potency of the analogue or derivative as compared to of the portion of the suture to which drug is applied and/or the parent compound (e.g., a compound twice as potent as incorporated) should fall within the range of 0.01 pug-0.1 mg etoposide is administered at half the above parameters, a per mm”, of surface area. In a particularly preferred embodi compound half as potent as etoposide is administered at twice ment, 5-fluorouracil should be applied to the suture surface at the above parameters, etc.). a dose of 0.1 pg/mm3-100 pg/mm”. As different polymer and [0764] 2. Polymers non-polymer coatings will release 5-fluorouracil at differing [0765] In certain embodiments, the compositions of the rates, the above dosing parameters should be utilized in com present invention may comprise a polymer that facilitates the bination with the release rate of the drug from the suture delivery of a therapeutic agent or forms a sustained release surface such that a minimum concentration of 10 °-107 Mof formulation for a therapeutic agent. In certain embodiments, 5-fluorouracil is maintained for the required duration of compositions that comprise polymers may further comprise therapeutic effect. It is necessary to insure that surface drug additional agents (e.g., pharmaceutical excipents, echogenic concentrations exceed concentrations of 5-fluorouracil agents, etc.). known to be lethal or inhibitory to the growth of numerous [0766] For instance, the composition may be or include a species of bacteria and/or fungi (i.e., are in excess of 10 “M, hydrophilic polymer gel that has anti-thrombogenic proper although for some embodiments lower drug levels will be ties. Such a composition can be in the form of a coating that sufficient). In a preferred embodiment, 5-fluorouracil is can comprise a hydrophilic, biodegradable polymer that is released from the suture surface such that anti-infective activ physically removed from the surface of the suture over time, ity is maintained for a period ranging from several hours to thus reducing adhesion of platelets to the suture surface. The several months. In a particularly preferred embodiment the gel composition can include a polymer or a blend of poly drug is released in effective concentrations for a period rang mers. Representative examples include alginates, chitosan ing from 1 week-6 months. It should be readily evident based and chitosan sulfate, hyaluronic acid, dextran sulfate, PLU upon the discussions provided herein that analogues and RONIC polymers (e.g., F-127 or F87), chain extended PLU derivatives of 5-fluorouracil (as described previously) with RONIC polymers, various polyester-polyether block copoly similar functional activity can be utilized for the purposes of mers of various configurations (e.g., AB, ABA, or BAB, this invention; the above dosing parameters are then adjusted where A is a polyester such as PLA, PGA, PLGA, PCL or the according to the relative potency of the analogue orderivative like), examples of which include MePEG-PLA PLA-PEG as compared to the parent compound (e.g., a compound twice PLA, and the like) In one embodiment, the anti-thrombotic as potent as 5-fluorouracil is administered at half the above composition can include a crosslinked gel formed from a parameters, a compound half as potent as 5-fluorouracil is combination of molecules (e.g., PEG) having two or more administered at twice the above parameters, etc.). terminal electrophilic groups and two or more nucleophilic [0763) (c) Podophylotoxins Utilizing the podophylotoxin groups. etoposide as an example, whether applied as a polymer coat [0767] Representative examples of biodegradable poly ing, incorporated into the polymers which make up the suture mers suitable for the delivery of the anti-scarring agent (or (plain or self-retaining), or applied without a carrier polymer, other therapeutic agents) include albumin, collagen, gelatin, the total dose of etoposide applied should not exceed 15 mg hyaluronic acid, starch, cellulose and cellulose derivatives (range of 0.1 pig to 15 mg). In a particularly preferred embodi (e.g., regenerated cellulose, methylcellulose, hydroxypropy ment, the total amount of drug applied should be in the range lcellulose, hydroxypropylmethylcellulose, carboxymethyl of 1 pig to 5 mg. The dose per unit area (i.e., the amount of drug cellulose, cellulose acetate phthalate, cellulose acetate succi as a function of the surface area of the portion of the suture to nate, hydroxypropylmethylcellulose phthalate), casein, which drug is applied and/or incorporated) should fall within dextrans, polysaccharides, fibrinogen, poly(ether ester) the range of 0.01 pig-100 pig per mm of surface area. In a multiblock copolymers, based on poly(ethylene glycol) and particularly preferred embodiment, etoposide should be poly(butylene terephthalate), tyrosine-derived polycarbon applied to the suture surface at a dose of 0.1 pg/mm3-10 ates (e.g., U.S. Pat. No. 6,120,491), poly(hydroxyl acids), Hg/mm3. As different polymer and non-polymer coatings will poly(D.L-lactide), poly(D.L-lactide-co-glycolide), poly(gly release etoposide at differing rates, the above dosing param colide), poly(hydroxybutyrate), polydioxanone, poly(alkyl eters should be utilized in combination with the release rate of carbonate) and poly(orthoesters), polyesters, poly(hydroxy the drug from the suture surface such that a concentration of valeric acid), polydioxanone, polyesters, poly(malic acid), 107°-107°Mofetoposide is maintained for the required dura poly(tartronic acid), poly(acrylamides), polyanhydrides, tion of therapeutic effect. It is necessary to insure that surface polyphosphazenes, poly(amino acids), poly(alkylene oxide) drug concentrations exceed concentrations of etoposide poly(ester) block copolymers (e.g., X—Y, X—Y—X, known to be lethal or inhibitory to the growth of a variety of Y—X—Y, R=(Y-X), or R-(X—Y), where X is a poly bacteria and fungi (ie, are in excess of 10° M, although for alkylene oxide (e.g., poly(ethylene glycol, poly(propylene some embodiments lower drug levels will be sufficient). In a glycol) and block copolymers of poly(ethylene oxide) and preferred embodiment, etoposide is released from the surface poly(propylene oxide) (e.g., PLURONIC and PLURONICR of the suture such that anti-infective activity is maintained for series of polymers from BASF Corporation, Mount Olive, US 2009/0226500 A1 Sep. 10, 2009 60

N.J.) and Y is a polyester, where the polyester may comprise lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, the residues of one or more of the monomers selected from gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, acid, beta-butyrolactone, gamma-butyrolactone, gamma gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric valerolactone, Y-decanolactone, Ö-decanolactone, trimethyl acid, beta-butyrolactone, gamma-butyrolactone, gamma ene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2One.), R valerolactone, Y-decanolactone, Ö-decanolactone, trimethyl is a multifunctional initiator and copolymers as well as blends ene carbonate, 1,4-dioxane-2-one or 15-dioxepan-2One (e.g., thereof), nitrocellulose, silicone rubbers, poly(styrene)block PLGA, PLA, PCL, polydioxanone and copolymers thereof) poly(isobutylene)-block-poly(styrene), poly(acrylate) poly and R is a multifunctional initiator), and the copolymers as mers and blends, admixtures, or co-polymers of any of the well as blends thereof (see generally, Illum, L., Davids, S. S. above. Other preferred polymers include collagen, poly(alky (eds.) “Polymers in Controlled Drug Delivery” Wright, Bris lene oxide)-based polymers, polysaccharides such as hyalu tol, 1987: Arshady, J. Controlled Release 17:1-22, 1991; Pitt, ronic acid, chitosan and fucans, and copolymers of polysac Int. J. Phar 59:173-196, 1990; Holland et al., J. Controlled charides with degradable polymers, as well as blends thereof. Release 4:155-0180, 1986). [0770] Other representative polymers capable of sustained [0768] Representative examples of non-degradable poly localized delivery offibrosis-inhibiting therapeutic agents (or mers suitable for the delivery offibrosis-inhibiting agents (or other therapeutic agents) include carboxylic polymers, poly other therapeutic agents) include poly(ethylene-co-vinyl acetates, polycarbonates, polyethers, polyethylenes, polyvi acetate) (“EVA”) copolymers, non-degradable polyesters, nylbutyrals, polysilanes, polyureas, polyoxides, polysty such as poly(ethylene terephthalate), silicone rubber, acrylic renes, polysulfides, polysulfones, polysulfonides, polymers (polyacrylate, polyacrylic acid, polymethylacrylic polyvinylhalides, pyrrolidones, rubbers, thermal-setting acid, polymethylmethacrylate, poly(butyl methacrylate)), polymers, cross-linkable acrylic and methacrylic polymers, poly(alkylcynoacrylate) (e.g., poly(ethylcyanoacrylate), poly ethylene acrylic acid copolymers, styrene acrylic copoly (butylcyanoacrylate) poly(hexylcyanoacrylate) poly(octyl mers, vinyl acetate polymers and copolymers, vinyl acetal cyanoacrylate)), acrylic resin, polyethylene, polypropylene, polymers and copolymers, epoxies, melamines, other amino polyamides (nylon 6,6), polyurethanes (e.g., CHRONOF resins, phenolic polymers, and copolymers thereof, water LEX AR, CHRONOFLEX AL, BIONATE, and PELLE insoluble cellulose ester polymers (including cellulose THANE), poly(ester urethanes), poly(ether urethanes), poly acetate propionate, cellulose acetate, cellulose acetate (ester-urea), cellulose esters (e.g., nitrocellulose), polyethers butyrate, cellulose nitrate, cellulose acetate phthalate, and (poly(ethylene oxide), poly(propylene oxide), polyoxyalky mixtures thereof), polyvinylpyrrolidone, polyethylene gly lene ether block copolymers based on ethylene oxide and cols, polyethylene oxide, polyvinyl alcohol, polyethers, propylene oxide such as the PLURONIC polymers (e.g., polysaccharides, hydrophilic polyurethane, polyhydroxy F-127 or F87) from BASF Corporation (Mount Olive, N.J.), acrylate, dextran, xanthan, hydroxypropyl cellulose, and and poly(tetramethylene glycol), styrene-based polymers homopolymers and copolymers of N-vinylpyrrolidone, N-vi (polystyrene, poly(styrene sulfonic acid), poly(styrene) nyllactam, N-vinylbutyrolactam, N-vinyl caprolactam, other block-poly(isobutylene)-block-poly(styrene), poly(styrene) vinyl compounds having polar pendant groups, acrylate and poly(isoprene) block copolymers), and vinyl polymers (poly methacrylate having hydrophilic esterifying groups, vinylpyrrolidone, poly(vinyl alcohol), poly(vinyl acetate hydroxyacrylate, and acrylic acid, and combinations thereof; phthalate) as well as copolymers and blends thereof. Poly cellulose esters and ethers, ethyl cellulose, hydroxyethyl cel mers may also be developed which are either anionic (e.g., lulose, cellulose nitrate, cellulose acetate, cellulose acetate alginate, carrageenan, carboxymethyl cellulose, poly(acryla butyrate, cellulose acetate propionate, natural and synthetic mido-2-methyl propane sulfonic acid) and copolymers elastomers, rubber, acetal, styrene polybutadiene, acrylic thereof, poly(methacrylic acid and copolymers thereof and resin, polyvinylidene chloride, polycarbonate, homopoly poly(acrylic acid) and copolymers thereof, as well as blends mers and copolymers of vinyl compounds, polyvinylchlo thereof, or cationic (e.g., chitosan, poly-L-lysine, polyethyl ride, and polyvinylchloride acetate. enimine, and poly(allyl amine)) and blends, copolymers and [0771] Representative examples of patents relating to drug branched polymers thereof (see generally, Dunn et al., J. delivery polymers and their preparation include PCT Publi Applied Polymer Sci 50:353–365, 1993; Cascone et al., J. cation Nos. WO 98/19713, WO 01/17575, WO 01/41821, Materials Sci.: Materials in Medicine 5770-774, 1994; WO 01/41822, and WO 01/15526 (as well as the correspond Shiraishi et al, Biol Pharm. Bull 16(11):1164-1168, 1993; ing U.S. applications), U.S. Pat. Nos. 4,500,676, 4,582,865, Thacharodi and Rao, Int'l J. Pharm. 120:115-118, 1995; 4,629,623, 4,636,524, 4,713,448, 4,795,741, 4,913,743. Miyazaki et al., Int’l J. Pharm. 118:257-263, 1995). 5,069,899, 5,099,013, 5,128,326, 5,143,724, 5,153,174, [0769] Some examples of preferred polymeric carriers 5,246,698, 5,266,563, 5,399,351, 5,525,348, 5,800,412, include poly(ethylene-co-vinyl acetate), polyurethanes (e.g., 5,837,226, 5,942,555, 5,997,517, 6,007,833, 6,071,447. CHRONOFLEX AR, CHRONOFLEX AL, BIONATE, and 6,090,995, 6,106,473, 6,110,483, 6,121,027, 6,156,345, PELLETHANE), poly(D.L-lactic acid) oligomers and poly 6,214,901, 6,368,611, 6,630,155, 6,528,080, RE37,950, mers, poly(L-lactic acid) oligomers and polymers, poly (gly 6,461,631, 6,143,314, 5,990,194, 5,792,469, 5,780,044, colic acid), copolymers of lactic acid and glycolic acid, poly 5,759,563, 5,744,153, 5,739,176, 5,733,950, 5,681,873, (caprolactone), poly(Valerolactone), polyanhydrides, 5,599,552, 5,340,849, 5,278,202, 5,278,201, 6,589,549, copolymers of poly(caprolactone) or poly (lactic acid) with a 6,287,588, 6,201,072, 6,117,949, 6,004,573, 5,702.717. polyethylene glycol (e.g., MepeG), poly(alkylene oxide) 6,413,539, 5,714,159, 5,612,052, and U.S. Patent Applica poly(ester) block copolymers (e.g., X—Y, X—Y—X or tion Publication Nos. 2003/0068377, 2002/0192286, 2002/ Y—X—Y, R=(Y-X), R=(X—Y), where X is a polyalky 0076441, and 2002/0090398. lene oxide and Y is a polyester (e.g., polyester can comprise [0772] It should be obvious to one of skill in the art that the the residues of one or more of the monomers selected from polymers as described herein can also be blended or copoly US 2009/0226500 A1 Sep. 10, 2009 merized in various compositions as required to deliver thera Swelling Behavior in Crosslinked N-isopropylacrylamide peutic doses of fibrosis-inhibiting agents. Networks: Cationic, Anionic and Ampholytic Hydrogels.” [0773) Polymeric carriers for fibrosis-inhibiting therapeu Dept. of Chemical & Biological Sci., Oregon Graduate Insti tic agents (or other therapeutic agents) can be fashioned in a tute of Science & Technology, Beaverton, Oreg., pp. 829-830; variety of forms, with desired release characteristics and/or Kim et al., Pharm. Res. 9(3):283-290, 1992; Bae et al., with specific properties depending upon the composition Pharm. Res. 8(5):624–628, 1991; Kono et al. J Controlled being utilized. For example, polymeric carriers may be fash Release 30:69-75, 1994, Yoshida et al. J Controlled Release ioned to release a therapeutic agent upon exposure to a spe 32:97-102, 1994: Okano et al., J. Controlled Release 36, cific triggering event such as pH (see, e.g., Heller et al., 125-133, 1995, Chun and Kim, J. Controlled Release 38:39 “Chemically Self-Regulated Drug Delivery Systems” in 47, 1996. D’Emanuele and Dinarvand, Int’l J Pharm. 118: Polymers in Medicine III, Elsevier Science Publishers B.V., 237-242, 1995; Katono et al. J Controlled Release 16.215 Amsterdam, 1988, pp. 175-188; Kang et al., J. Applied Poly 228, 1991; Hoffman, “Thermally Reversible Hydrogels merSci, 48:343-354, 1993; Dong et al., J. Controlled Release Containing Biologically Active Species,” in Migliaresi et al. 19:171-178, 1992; Dong and Hoffman, J. Controlled Release (eds.), Polymers in Medicine III, Elsevier Science Publishers 15:141-152, 1991; Kim et al., J. Controlled Release 28:143 B.V., Amsterdam, 1988, pp. 161-167; Hoffman, “Applications 152, 1994; Cornejo-Bravo et al., J. Controlled Release of Thermally Reversible Polymers and Hydrogels in Thera 33:223-229, 1995; Wu and Lee, Pharm. Res. 10(10):1544 peutics and Diagnostics,” in Third international Symposium 1547, 1993; Serres et al., Pharm. Res. 13(2):196-201, 1996; on Recent Advances in Drug Delivery Systems, Salt Lake Peppas, “Fundamentals of pH- and Temperature-Sensitive City, Utah, Feb. 24-27, 1987, pp. 297-305; Gutowska et al., J. Delivery Systems,” in Gurny et al. (eds.), Pulsatile Drug Controlled Release 22:95-104, 1992; Palasis and Gehrke, J. Delivery, Wissenschaftliche Verlagsgesellschaft mbH, Stut Controlled Release 18:1-12, 1992; Paavolaetal., Pharm. Res. tgart, 1993, pp. 41-55; Doelker, “Cellulose Derivatives.” 12(12):1997-2002, 1995). 1993, in Peppas and Langer (eds.), Biopolymers I, Springer [0775] Representative examples of thermogelling poly Verlag, Berlin). Representative examples of pH-sensitive mers, and the gelatin temperature (LCST (? C.)) include polymers include poly(acrylic acid) and its derivatives (in homopolymers such as poly(N-methyl-N-n-propylacryla cluding for example, homopolymers such as poly(aminocar mide), 19.8; poly(N-n-propylacrylamide), 21.5; poly(N-me boxylic acid); poly(acrylic acid); poly(methyl acrylic acid), thyl-N-isopropylacrylamide), 22.3; poly(N-n-propyl copolymers of such homopolymers, and copolymers of poly methacrylamide), 28.0; poly(N-isopropylacrylamide), 30.9; (acrylic acid) and/or acrylate or acrylamide monomers such poly(N, n-diethylacrylamide), 32.0; poly(N-isopropyl as those discussed above. Other pH sensitive polymers methacrylamide), 44.0; poly(N-cyclopropylacrylamide), include polysaccharides such as cellulose acetate phthalate; 45.5; poly(N-ethylmethyacrylamide), 50.0; poly(N-methyl hydroxypropylmethylcellulose phthalate; hydroxypropylm N-ethylacrylamide), 56.0; poly(N-cyclopropylmethacryla ethylcellulose acetate succinate; cellulose acetate trimelli mide), 59.0; poly(N-ethylacrylamide), 72.0. Moreover ther late; and chitosan. Yet other pH sensitive polymers include mogelling polymers may be made by preparing copolymers any mixture of a pH sensitive polymer and a water-soluble between (among) monomers of the above, or by combining polymer such homopolymers with other water-soluble polymers such [0774] Likewise, fibrosis-inhibiting therapeutic agents (or as acrylmonomers (e.g., acrylic acid and derivatives thereof, other therapeutic agents) can be delivered via polymeric car such as methylacrylic acid, acrylate monomers and deriva riers that are temperature sensitive (see, e.g., Chen et al., tives thereof, such as butyl methacrylate, butyl acrylate, lau “Novel Hydrogels of a Temperature-Sensitive PLURONIC ryl acrylate, and acrylamide monomers and derivatives Grafted to a Bioadhesive Polyacrylic Acid Backbone for thereof, such as N-butyl acrylamide and acrylamide). Vaginal Drug Delivery,” in Proceed. Intern. Symp. Control. [0776] Other representative examples of thermogelling Rel. Bioact. Mater, 22:167-168, Controlled Release Society, polymers include cellulose ether derivatives such as hydrox Inc., 1995; Okano, “Molecular Design of Stimuli-Responsive ypropyl cellulose, 41° C.; methyl cellulose, 55° C., hydrox Hydrogels for Temporal Controlled Drug Delivery,” in Pro ypropylmethyl cellulose, 66° C., and ethylhydroxyethyl cel ceed. Intern. Symp. Control. Ret Bioact. Mater, 22:111-112, lulose, polyalkylene oxide-polyester block copolymers of the Controlled Release Society, Inc., 1995; Johnston et al., structure X=Y, Y-X-Y and X?X-X where X in a poly Pharm. Res. 9(3):425-433, 1992; Tung, Int’l J. Pharm. 107: alkylene oxide and Y is a biodegradable polyester (e.g., PLG 85-90, 1994; Harsh and Gehrke, J. Controlled Release PEG-PLG) and PLURONICs such as F-127, 10-15° C.; 17:175-186, 1991; Bae et al., Pharm. Res. 8(4):531-537, L-122, 19°C.; L-92, 26°C.; L-81, 20° C.; and L-61, 24°C. 1991; Dinarvand and D’Emanuele, J. Controlled Release [0777] Representative examples of patents relating to ther 36:221-227, 1995; Yu and Grainger, “Novel Thermo-sensi mally gelling polymers and the preparation include U.S. Pat. tive Amphiphilic Gels: Poly N-isopropylacrylamide-co-so Nos. 6,451,346; 6,201,072: 6,117,949; 6,004,573; 5,702.717; dium acrylate-co-n-N-alkylacrylamide Network Synthesis and 5,484,610; and PCT Publication Nos. WO 99/07343; WO and Physicochemical Characterization.” Dept. of Chemical & 99/18142; WO 03/17972; WO 01/82970, WO 00/18821; WO Biological Sci., Oregon Graduate Institute of Science & 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651. Technology, Beaverton, Oreg., pp. 820–821; Zhou and Smid, [0778] Within another aspect of the present invention, poly “Physical Hydrogels of Associative Star Polymers.” Polymer meric carriers can be materials that are formed in situ. In one Research Institute, Dept. of Chemistry, College of Environ embodiment, the precursors can be monomers or macromers mental Science and Forestry, State Univ. of New York, Syra that contain unsaturated groups that can be polymerized and/ cuse, N.Y., pp. 822-823; Hoffman et al., “Characterizing Pore or cross-linked. The monomers or macromers can then, for Sizes and Water ‘Structure’ in Stimuli-Responsive Hydro example, be injected into the treatment area or onto the sur gels,” Center for Bioengineering, Univ. of Washington, face of the treatment area and polymerized in situ using a Seattle, Wash., p. 828; Yu and Grainger, “Thermo-sensitive radiation source (e.g., visible or UV light) or a free radical

US 2009/0226500 A1 Sep. 10, 2009

No. 5,242,073), liposome/gel (WO 94/26254), nanocapsules imaging may be achieved using an echogenic coating. (Bartoli et al., J. Microencapsulation 7(2):191-197, 1990), Echogenic coatings are described in, e.g., U.S. Pat. Nos. micelles (Alkan-Onyuksel et al., Pharm. Res. 11(2):206-212, 6,106,473 and 6,610,016. For visualization under MRI, con 1994), nanoparticles (Violante and Lanzafame PAACR), trast agents (e.g., gadolinium (III) chelates oriron oxide com nanoparticles-modified (U.S. Pat. No. 5,145,684), nanoparti pounds) may be incorporated into or onto the suture, such as cies (surface modified) (U.S. Pat. No. 5,399,363), micelle a componentina coating. In some embodiments, a suture may (surfactant) (U.S. Pat. No. 5,403,858), synthetic phospho include radio-opaque or MRI visible markers (e.g., bands) lipid compounds (U.S. Pat. No. 4,534,899), gas borne disper that may be used to orient and guide the suture during the sion (U.S. Pat. No. 5,301,664), liquid emulsions, foam, spray, implantation procedure. gel, lotion, cream, ointment, dispersed vesicles, particles or [0791) In certain embodiments, sutures may be pre-at droplets solid- or liquid-aerosols, microemulsions (U.S. Pat. tached to another device or element. For example, sutures No. 5,330,756), polymeric shell (nano- and micro-capsule) may be pre-attached to a needle or an anchor member for (U.S. Pat. No. 5,439,686), emulsion (Tarret al., Pharm Res.4: securing its placement in soft or hard tissues. In such embodi 62-165, 1987), and nanospheres (Hagan et al., Proc. Intern. ments, sutures themselves, the other devices or elements Symp. Control Rel. Bioact. Mater 22, 1995; Kwon et al., (e.g., needles and anchor members), or both the sutures and Pharm Res. 12(2): 192-195; Kwon et al., Pharm Res. 10(7): the other devices or elements may be coated with a radio 970-974; Yokoyama et al., J. Contr Rel. 32:269-277, 1994; opaque, echogenic, or magnetic resonance imaging (MRI) Gref et al., Science 263:1600-1603, 1994; Bazile et al., J. responsive material. Pharm. Sci. 84:493-498, 1994) and implants (U.S. Pat. No. [0792] Sutures may, alternatively, or in addition, be visual 4,882,168). ized under visible light, using fluorescence, or by other spec [0788] In certain embodiments of the invention, anti-scar troscopic means. Visualization agents that can be included for ring agents (or other therapeutic agents) can further comprise this purpose include dyes, pigments, and other colored agents a secondary carrier. The secondary carrier can be in the form In one aspect, the suture may further include a colorant to of microspheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin, improve visualization of the suture in vivo and/or ex vivo polydioxanone, poly(alkylcyanoacrylate)), nanospheres Frequently, sutures can be difficult to visualize upon inser (PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly tion, especially at the margins of suture. A coloring agent can (alkylcyanoacrylate)), liposomes, emulsions, microemul be incorporated into a suture to reduce or eliminate the inci sions, micelles (SDS, block copolymers of the form X-Y, dence or severity of this problem. The coloring agent provides Y—X—Y, R=(Y-X), R=(X–Y), and X-Y-X(where a unique color, increased contrast, or unique fluorescence X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly characteristics to the suture. In one aspect, a suture is pro (propylene glycol) and block copolymers of poly(ethylene vided that includes a colorant such that it is readily visible oxide) and poly(propylene oxide) (e.g., PLURONIC and (under visible light or using a fluorescence technique) and PLURONIC R series of polymers from BASF Corporation, easily differentiated from its implant site. In another aspect, a Mount Olive, N.J.) and Y is a biodegradable polyester, where colorant can be included in a liquid or semi-solid composi the polyester may comprise the residues of one or more of the tion. For example, a single component of a two-component monomers selected from lactide, lactic acid, glycolide, gly mixture may be colored, such that when combined ex-vivo or colic acid, e-caprolactone, gamma-caprolactone, hydroxyva in-vivo, the mixture is sufficiently colored. leric acid, hydroxybutyric acid, beta-butyrolactone, gamma [0793] The coloring agent may be, for example, an endog butyrolactone, gamma-valerolactone, Y-decanolactone, enous compound (e.g., an amino acid or vitamin) or a nutrient ô-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or food material and may be a hydrophobic or a hydrophilic or 1,5-dioxepan-2One (e.g., PLG-PEG-PLG) and R is a mul compound. Preferably, the colorant has a very low or no tifunctional initiator), zeolites or cyclodextrins. toxicity at the concentration used. Also preferred are colo [0789] Within certain embodiments of the invention, the rants that are safe and normally enter the body through therapeutic compositions may also comprise additional absorption such as fl-carotene. Representative examples of ingredients such as surfactants (e.g., PLURONICS, such as colored nutrients (under visible light) include fat soluble vita F-127, L-122, L-101, L-92 L-81, and L-61), preservatives, mins such as VitaminA (yellow); water soluble vitamins such and anti-oxidants. as Vitamin B12 (pink-red) and folic acid (yellow-orange); [0790] Within certain embodiments of the invention, the carotenoids such as fl-carotene (yellow-purple) and lycopene anti-scarring agent-containing compositions can also com (red). Other examples of coloring agents include natural prise radio-opaque, echogenic materials and magnetic reso product (berry and fruit) extracts such as anthrocyanin nance imaging (MRI) responsive materials (i.e., MRI contrast (purple) and saffron extract (dark red). The coloring agent agents) to aid in visualization of sutures under ultrasound, may be a fluorescent or phosphorescent compound such as fluoroscopy and/or MRI. For example, a suture may be made O-tocopherolquinol (a Vitamin E derivative) or L-tryptophan. with or coated with a composition which is echogenic or Derivatives, analogues, and isomers of any of the above col radiopaque (e.g., made with echogenic or radiopaque with ored compound also may be used. The method for incorpo materials such as powdered tantalum, tungsten, barium car rating a colorant into a suture ortherapeutic composition may bonate, bismuth oxide, barium sulfate, metrazimide, iopami be varied depending on the properties of and the desired dol, iohexyl, iopromide, iobitridol, iomeprol, iopentol, iover location for the colorant. For example, a hydrophobic colo sol, ioxilan, iodixanol, iotrolan, acetrizoic acid derivatives, rant may be selected for hydrophobic matrices. The colorant diatrizoic acid derivatives, iothalamic acid derivatives, may be incorporated into a carrier matrix, such as micelles. ioxithalamic acid derivatives, metrizoic acid derivatives, Further, the pH of the environment may be controlled to iodamide, lypophylic agents, iodipamide and ioglycamic acid further control the color and intensity or, by the addition of microspheres or bubbles which present [0794] In one aspect, the composition and sutures of the an acoustic interface). Visualization of a suture by ultrasonic present invention include one or more coloring agents, also US 2009/0226500 A1 Sep. 10, 2009 64 referred to as dyestuffs, which will be present in an effective 45° C., 50° C., 55° C. or 60° C.), and solid or semi-solid at amount to impart observable coloration to the composition, another temperature (e.g., ambient body temperature, or any e.g., the gel. Examples of coloring agents include dyes suit temperature lower than 37°C.). Such “thermopastes” may be able for food such as those known as F. D. & C. dyes and readily made utilizing a variety of techniques (see, e.g., PCT natural coloring agents such as grape skin extract, beet red Publication WO 98/24427). Other pastes may be applied as a powder, beta carotene, annato, carmine, turmeric, paprika, liquid, which solidify in vivo due to dissolution of a water and so forth. Derivatives, analogues, and isomers of any of the soluble component of the paste and precipitation of encapsu above colored compound also may be used. The method for lated drug into the aqueous body environment. These “pastes” incorporating a colorant into a suture or therapeutic compo and “gels” containing anti-scarring agents are particularly sition may be varied depending on the properties of and the useful for application to the surface of tissues that will be in desired location for the colorant. For example, a hydrophobic contact with the suture. colorant may be selected for hydrophobic matrices. The colo [0801] The fibrosis-inhibiting therapeutic agent (or another rant may be incorporated into a carrier matrix, such as therapeutic agent) may be delivered as a solution. The thera micelles. Further, the pH of the environment may be con peutic agent can be incorporated directly into the solution to trolled to further control the color and intensity. provide a homogeneous solution or dispersion. In certain [0795] In one aspect, the compositions of the present inven embodiments, the solution is an aqueous solution. The aque tion include one or more preservatives or bacteriostatic agents ous solution may further include buffer salts, as well as vis present in an effective amount to preserve the composition cosity modifying agents (e.g., hyaluronic acid, alginates, car and/or inhibit bacterial growth in the composition, for boxymethylcellulose (CMC), and the like). In another aspect example, bismuth tribromophenate, methyl hydroxyben of the invention, the solution can include a biocompatible zoate, bacitracin, ethyl hydroxybenzoate, propyl hydroxy solvent or liquid oligomers and/or polymers, such as ethanol, benzoate, erythromycin, chlorocresol, benzalkonium chlo DMSO, glycerol, PEG-200, PEG-300 or NMP. These com rides, and the like. Examples of additional preservative positions may further comprise a polymer such a degradable include paraoxybenzoic acid esters, chlorobutanol, benzyla polyester, where the polyester may comprise the residues of lcohol, phenethyl alcohol, dehydroacetic acid, and sorbic one or more of the monomers selected from lactide, lactic acid. In one aspect, the compositions of the present invention acid, glycolide, glycolic acid, e-caprolactone, gamma-capro include one or more bactericidal (also known as bacteri lactone, hydroxyvaleric acid, hydroxybutyric acid, beta-bu acidal) agents. tyrolactone, gamma-butyrolactone, gamma-valerolactone, [0796] In one aspect, the compositions and sutures of the Y-decanolactone, Ö-decanolactone, trimethylene carbonate, present invention include one or more antioxidants, presentin 1,4-dioxane-2-one or 1,5-dioxepan-2One, or block copoly an effective amount. Examples of the antioxidant include mers of the form X-Y, Y-X-Y, R=(Y-X), R=(X sulfites, alpha-tocopherol and ascorbic acid. Y), and X—Y—X (where X in a polyalkylene oxide (e.g., [0797] 4. Physical Forms poly(ethylene glycol, poly(propylene glycol) and block [0798] The compositions of the present invention may be in copolymers of poly(ethylene oxide) and poly(propylene various forms, such as microparticles or nanoparticles, oxide) (e.g., PLURONIC and PLURONIC R series of poly microspheres, microcapsules, pastes, gels, sprays, and liq mers from BASF Corporation, Mount Olive, N.J.) and Y is a uids. These can be applied to the surface of the suture or biodegradable polyester, where the polyester may comprise infiltrated into the tissues surrounding the suture. In certain the residues of one or more of the monomers selected from embodiments, anti-scarring agents may be linked by occlu factide, lactic acid, glycolide, glycolic acid, e-caprolactone, sion in the matrices of a polymer, bound by covalent linkages, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric, bound by ionic interactions, or encapsulated in microcap acid, beta-butyrolactone, gamma-butyrolactone, gamma sules. valerolactone, Y-decanolactone, Ö-decanolactone, trimethyl [0799] Within certain aspects of the present invention, enecarbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2One (e.g., therapeutic compositions may be fashioned in any size rang PLG-PEG-PLG) and R is a multifunctional initiator). ing from 20 nm to 1500 pum, depending upon the particular C. Sutures that Comprise Anti-Scarring Agents use. These compositions can be in the form of microspheres [0802] Various types of sutures (plain or self-retaining) (porous or non-porous), microparticles and/or nanoparticles. may be used in combination with anti-scarring agents accord These compositions can beformed by spray-drying methods, ing to the present invention. In certain embodiments, sutures milling methods, coacervation methods, W/O (water-oil) are absorbable (e.g. those that are degraded by the body’s emulsion methods, W/O/W emulsion methods, and solvent enzymatic pathways and generally lose tensile strength by 60 evaporation methods. In another embodiment, these compo days after implantation). In certain embodiments, the absorb sitions can include microemulsions, emulsions, liposomes able sutures are made of polymers or copolymers of glycolic and micelles. Alternatively, such compositions may also be and lactic acid. Exemplary absorbable sutures include catgut readily applied as a “spray”, which solidifies into a film or (both plain and chromic) (e.g., those with a trade name coating foruse as a suture surface coating or to line the tissues PROGUT from Dolphin Sutures, India), and those derived of the implantation site. Such sprays may be prepared from from polyglycolic acid with a trade name PETCRYL (Dol microspheres of a wide array of sizes, including for example, phin Sutures, India) and with a trade name DEXONTM (Sher from 0.1 pum to 3 pum, from 10 pum to 30 pum, and from 30 pum wood Services AG, Schaffhausen, Switzerland), from to 100 pum. poliglecaprone 25 with a trade name MONOCRYLR (co [0800] Therapeutic compositions of the present invention polymer of about 75% glycolide and about 25% caprolactone, may also be prepared in a variety of “paste” or gel forms. For Johnson & Johnson Co., New Brunswick, N.J.), from example, within one embodiment of the invention, therapeu polyglactin 910 (such as VICRYLR, coated VICRYLR, tic compositions are provided which are liquid at one tem coated VICRYLR Plus Antibacterial sutures that contain perature (e.g., temperature greater than 37°C., such as 40°C., antibacterial triclosan, and Coated VICRYL RAPIDE(R) US 2009/0226500 A1 Sep. 10, 2009

sutures, Johnson & Johnson Co., New Brunswick, N.J.), TEVDEKTM (braided polyester suture from J.A. Deknatel MULTIPASSR Needle Coating (Johnson & Johnson Co., and Son, Inc. New York, N.Y.), PROLENETM (polypropylene New Brunswick, N.J.), copolymer of about 67% glycolide suture from Ethicon, Inc., Somerville, N.J.), FLUOROFILTM and about 33% trimethylene carbonate sold as MAXONTM, (polypropylene suture from Pitman-Moore, Inc. Lake Forest, Wyeth, Madison, N.J., and from polydioxanone with a trade Ill.), and MERSILENETM (polyester fiber suture from Ethi name PDS IIR (Johnson & Johnson Co., New Brunswick, con, Inc., Somerville, N.J.). N.J.). [0806] Additional exemplary sutures that may be used in [0803] In addition to the sutures described above, degrad combination with anti-scarring agents according to the able sutures can be made from polymers such as polyglycolic present invention are various sutures available from Surgical acid, copolymers of glycolide and lactide, copolymers of Specialities Co., Reading, Pa.), including monoderm undyed trimethylene carbonate and glycolide with diethylene glycol or dyed monofilament sutures, clear or dyed PCL monofila (e.g., MAXONTM, Tyco Healthcare Group), terpolymer com ment sutures, dyed polypropylene monofilament sutures, posed of glycolide, trimethylene carbonate, and dioxanone undyed braided POLYSYN FA sutures, dyed or undyed (e.g., BIOSYNTM [glycolide (60%), trimethylene carbonate braided PGA sutures, dyed or undyed braided polysyn suture, (26%), and dioxanone (14%)], Tyco Healthcare Group), dyed monofilament polysyn sutures, dyed braided poloyester copolymers of glycolide, caprolactone, trimethylene carbon sutures, braided silk sutures, dyed braided polyviolene ate, and lactide (e.g., CAPROSYNTM, Tyco Healthcare sutures, plain or chromic gut sutures, dyed or undyed Group). Other sutures that can be used in this invention monofilament nylon sutures, and dyed pliable nylon sutures. include sutures composed of a polymer that comprises the Additional exemplary sutures that may be used in combina residues of one or more of the monomers selected from lac tion with anti-scarring agents, according to the present inven tide, lactic acid, glycolide, glycolic acid, e-caprolactone, tion are various sutures available from Tyco International gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric Ltd., Bermuda or its companies. Such sutures include SUR acid, beta-butyrolactone, gamma-butyrolactone, gamma GITIETM (single use ligating loops with delivery system) and valerolactone, Y-decanolactone, Ö-decanolactone, trimethyl SURGIWIPTM (single use sutrue ligatures with delivery sys ene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2One. tem), absorbable sutures such as POLYSORBTM (suturtes These sutures can be in either a braided multifilament form or composed of LACTOMERTM glycolide/lactide copolymer, a a monofilament form. The polymers used in the present synthetic polyester composed of glycolide and lactide (de invention can be linear polymers, branched polymers or rived from glycolic and lactic acids), DEXONTM II (synthetic multi-axial polymers. Examples of multi-axial polymers used suture composed of homopolymer of glycolic acid and coated in sutures are described in U.S. Patent Application Publica with POLYCAPROLATETM, a copolymer of glycolide and tion Nos. 20020161168, 2004.0024169, and 20040116620. epsilon-caprolactone), DEXONTM S (synthetic sutures com [0804) Absorbable sutures may be used below the surface posed of the homopolymer of glycolic acid), MAXONTM CV of the skin to provide support to the skin closure. They may (polyglyconate synthetic sutures prepared from a copolymer also be used in areas where suture removal might jeopardize of glycolic acid and trimethylene carbonate), plain, mild the repair such as with small children who might not easily chromic, and chromic gut sutures composed of purified con cooperate with suture removal. nective tissue (mostly collagen) derived from the serosal layer [0805] In certain embodiments, sutures that may be used in of beef intestines, and non-absorbable sutures such as DER combination with anti-scarring agents are non-absorbable, MALONR (nylon), MONOSOFR (nylon), SURGILONR which may be of monofilament and braided types. Non-ab (nylon). SURGIDACTM (polyethylene terephthalate) sorbable sutures are permanent and include sutures made of TI-CRONTM (sutures prepared from fibers of high molecular polyamide (also known as nylon, such as nylon 6 and nylon weight, long chain and linear polyesters having recurrent 6.6), polyester (e.g., polyethylene terephthlate), polytet aromatic rings as an intergral component), SURGIPROTM rafluoroethylene (e.g., expanded polytetrafluoroethylene), (sutures composed of an isotactic crystalline stereoisomer of polyether-ester such as polybutester (block copolymer of polypropylene (a synthetic linear polyolefin) and polyethyl butylene terephthalate and polytetra methylene ether glycol), ene), SURGIPROTM II (sutures composed of an isotactic polyurethane, metal alloys, metal (e.g., stainless steel wire), crystalline stereoisomer of polypropylene (a synthetic linear polypropylene, polyethelene, silk, and cotton. Exemplary polyolefin) and polyethylene), NOVAFILTM (sutures com non-absorbable sutures include coated polyester sutres with a posed of polybutester, a copolymer of butylenesterephthalate trade name Procare (Dolphin Sutures, India), GORTEXTM and polytetramethylene ether glycol), VASCUFILTM (sutures (made of expanded polytetrafluoroethylene, sold by Gore), composed of a copolymer of butylenes terephthalate and NOVAFILTM (made of polybutester, Wyeth, Madison, N.J.), polytetramethylene ether glycol and coated with POLYTRI monofilament polyamide sutures with a trade name Linex BOLATETM, an absorbable polymer of e-caprolactone/gly (Dolphin Sutures, India), SUTURAE (black braided silk colidelpoloxamer 188), FLEXONTM (twisted multistrand sutures, Sutura Inc., Fountain Valley, Calif.), monofilament steel sutures coated with orange or white PTFE poly(tetraflo polypropylene sutures with a trade name Duracare (Dolphin roproethylene) or clear FEP poly(tetrafluoroethylene-co Sutures, India), MONOSOFOR (monofilament nylon suture, hexafluoropropylene), SOFSILKTM (sutures composed of United States Surgical Co., Norwalk, Conn.), DERMA natural proteinaceous silk fibers that are treated to remove the LONTM (monofilament nylon suture, Sherwood Services AG, naturally-occurring sericin gum), and stainless steel sutures. Switzerland), SURGILONTM (braided nylon suture coated In certain embodiments, sutures that may be used in combi with silicone, Sherwood Services AG, Switzerland), Ethilon nation with anti-scarring agents are used in various dental nylon suture (Ethicon, Inc., Somerville, N.J.), ETHIBOND procedures, i.e., oral and maxillofacial surgical procedures EXCELR) (braided polyester suture from Johnson & Johnson and thus may be referred to as “dental sutures.” The above Co., New Brunswick, N.J.), Pronova poly(hexafluoropropy mentioned procedures include, but are not limited to, oral lene-VDF) suture (Ethicon, Inc. Somerville, N.J.), surgery (e.g., removal of impacted or broken teeth), surgery to US 2009/0226500 A1 Sep. 10, 2009 66 provide bone augmentation, surgery to repair dentofacial 5,931,855, PCT Application Publication No. WO 98/52473, deformities, repair following trauma (e.g., facial bone frac barbed suture described in McKenzie et al., J Bone Joint Surg tures and injuries), surgical treatment of odontogenic and /Br/49(3): 440-7, 1967, and bi-directional suture described in non-odontogenic tumors, reconstructive surgeries, repair of U.S. Pat. Nos. 5,342,376, 6,241,747, US 2003/0074023, and cleft lip or cleft palate, congenital craniofacial deformities, Dattilo et al., 2003 Society For Biomaterials 29° Annual and esthetic facial surgery. Many of the various sutures Meeting Transactions. Page 101. Additional description of described above are used in such procedures and are available self-retaining sutures useful in the present invention may be from many of the same commercial sources. As above, dental found in U.S. Pat. Nos. 6,599,310, 6,773,450, 6,848,152, sutures may be degradable or non-degradable. Sutures used in published U.S. Application Nos. US 2004/0060410, US oral and maxillofacial surgical procedures may typically 2004/0060409, US 2004/0088003, and US 2004/0226427, range in size from USP 2-0 to USP 6-0. Dental sutures may and PCT Application Publication Nos. WO 03/001979, WO have a surgical needle attached. 2004/014236, WO 03/017850, WO 2004/030520, WO 2004/ [0807] In certain embodiments, sutures that may be used in 030704, WO 2004/030705, and WO 2007/005296. combination with anti-scarring agents are microsutures [0811] In one embodiment, a commercially available Microsutures are used in microsurgical procedures that are suture that may be used in combination with an anti-scarring performed under a surgical microscope. Such surgical proce agentis CONTOURTHREADSTM (Quill Medical, Research dures include, but are not limited to, reattachment and repair Triangle Park, N.C.). CONTOUR THREADSTM are non of peripheral nerves, spinal microsurgery, microsurgery of absorbable self-retaining suture product cleared by the FDA the hand, various plastic microsurgical procedures (e.g., for the elevation and fixation of midface, brow and neck areas. facial reconstruction), microsurgery of the male or female They are made from clear polypropylene. reproductive systems, and various types of reconstructive [0812] In another embodiment, the suture that may be used microsurgery. Microsurgical reconstruction is used for com in combination with a fibrosing agent is a suture with a similar plex reconstructive surgery problems when other options structure to the CONTOURTHREADSTM but is composed of such as primary closure, healing by secondary intention, skin a degradable polymer. These degradable polymers polyester grafting, local flap transfer, and distant flap transfer are not can comprise the residues of one or more of the monomers adequate. Microsutures are available from many of the com selected from lactide, lactic acid, glycolide, glycolic acid, mercial sources identified above and are made from the same e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, materials described above. As above, microsutures may be hydroxybutyric acid, beta-butyrolactone, gamma-butyrolac degradable or non-degradable. Microsutures have a very tone, gamma-valerolactone, y-decanolactone, Ö-decanolac small caliber, often as small as USP9-0 or USP 10-0, and may tone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-diox have an attached needle of corresponding size. epan-2One. Examples include polydioxanone, poly(lactide [0808] Additional exemplary sutures that may be used in co-trimethylene carbonate) polymers, poly(lactide-co combination with anti-scarring agents are described in U.S. glycolide) polymers and poly(lactide-co-glycolide-co Pat. Nos. 5,766,188, 4,441,496, 6,692,516, 4,550,730, 4,052, trimethylene carbonate) polymers. 988, and U.S. Patent Application Publication Nos. [0813] In other embodiments, the suture that may be used in 2005267532, 2005.240224, 2004111116, 2004088003, combination with an anti-scarring agent is Aptos Thread 2002095180. developed by Dr. Sulamandize of Moscow (available from [0809] In certain embodiments, the suture can further com I-LIFT TENSOR THREADS, Argentine). Description of prise a coating. The coating can comprise a degradable or a such suture may be found in European Published Patent non-degradable polymer. Coatings can include but are not Application No. 1,075,843A1 and WO 00/51658. The suture limited to polybutylene adipate (SURGIDACTM) to silicone has conical retainers arranged sequentially along the length of (TI-CRONTM), poly(glycolide-co-lactide) (e.g., polyglactin a thread and oriented in a direction opposite to that of the 370), copolymers of gylcolide, e-caprolactone, and polox thread tension, with the distance between retainers being no amer 188, copolymers of glycolide and, e-caprolactone (e.g., less than 1.5 times the thread diameter. polycaprolate), poloxamer 188, calcium stearate, and cal [0814] As indicated above, certain types of self-retaining cium stearoyl lactylate, as well as blends and mixtures sutures that may be used in combination with an anti-scarring thereof. Coatings can also include polymers that can com agent according to the present invention are commercially prise the residues of one or more of the monomers selected available. In certain other embodiments, self-retaining from lactide, lactic acid, glycolide, glycolic acid, e-caprolac sutures may be made using any suitable method, including tone, gamma-caprolactone, hydroxyvaleric acid, hydroxybu injection molding, stamping, cuffing, laser, extrusion, sepa tyric acid, beta-butyrolactone, gamma-butyrolactone, rate manufacture and subsequent attachment of retainers, and gamma-valerolactone, y-decanolactone, Ö-decanolactone, the like. With respect to cutting, polymeric thread or filaments trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan may be purchased, and the retainers are subsequently cut onto 2One. Exemplary coatings that can be used are described in the filament body. In certain embodiments, barbed sutures U.S. Pat. Nos. 4,047,533, 4,201,216, 4,470.416, 4,788,979, may be produced according to U.S. Pat. No. 6,848,152 and 4,857,602, 4,994,074, 5,037,950, 5,100,433, 5,102,420, U.S. Patent Application Publication Nos. US 2004/0226427 5,123,912, 5,522,842, 5,543,218, 6,703,035, and 6,703,035. and US 2004/0060409. In certain embodiments, the anti-scarring agent can be incor [0815] In certain embodiments, sutures that may be used in porated into or onto the suture coating polymers described combination with an anti-scarring agent according to the above. present invention are already attached to surgical needles. [0810] In certain embodiments, sutures that may be used in Attachment of sutures and surgical needles is described in combination with anti-scarring agents are self-retaining U.S. Pat. Nos. 3,981,307, 5,084,063, 5,102,418, 5,123,911, sutures. Such sutures include but are not limited to: one-way 5,500,991, 5,722,991, 6,012,216, and 6,163,948, and U.S. sutures disclosed in U.S. Pat. Nos. 3,123,077, 5,053,047, Patent Application Publication No. US 2004/0088003. A US 2009/0226500 A1 Sep. 10, 2009 67 method for the manufacture of surgical needles is described in certain embodiments including self-retaining sutures, the U.S. Pat. No. 5,533,982, and a method for the manufacture of sutures may be coated prior to the formation of retainers polymer-coated surgical needles is described in U.S. Pat. No. during the manufacturing process (thereby resulting in 5,258,013. sutures having selectively uncoated portions). In certain other [0816) In certain embodiments, the sutures that may be embodiments including self-retaining sutures, the sutures used in combination with an anti-scarring agent according to may be coated after or concurrent with the formation of the present invention are pointing at both ends (including retainers. suture connectors as described in U.S. Pat. No. 6,241,747) In [0824) i. Dip Coating certain other embodiments, the sutures may have one point [0825] Dip coating is one coating process that can be used ing end and an achor on the other end. The anchor may be to coat a suture In one embodiment, the anti-scarring agent is used to secure the implantation of the suture in soft tissue dissolved in a solvent for the anti-scarring agent and is then (e.g., those described in U.S. Patent Application Publication coated onto the suture. No. US2005/0267531) or the attachment of sutures to the [0826] Anti-Scarring Agent with an Inert-Solvent bone (e.g., those described in U.S. Pat. No. 6,773,450 and [0827. In one embodiment, the solvent is an inert solvent PCT Application Publication No. WO 2004/014236). for the suture such that the solvent does not dissolve the suture [0817] In certain other embodiments, the suture may be a to any significant extent and is not absorbed by the suture to relatively short suture with sharp pointing ends. Such a suture any significant extent. The suture can be immersed, either may function similar to a staple when used in connecting partially or completely, in the anti-scarring agent/solvent tissues and thus permits a surgeon to rapidly and securely solution for a specific period of time. The rate of immersion attach the edges of a wond in a boldly tissue or reconfigure the into the anti-scarring agent/solvent solution can be altered tissue without the necessity for threading and tying numerous (e.g., 0.001 cm per sec to 50 cm per sec). The suture can then individual stitches or for the use of a complicated tool to insert be removed from the solution. The rate at which the suture can the suture. This type of sutures may thus be referred to as be withdrawn from the solution can be altered (e.g., 0.001 cm “suture connector.” In certain embodiments, the suture con per sec to 50 cm per sec). The coated suture can be air-dried. nector may be a bi-directional self-retaining suture. In certain The dipping process can be repeated one or more times other embodiments, the suture connector may be found by depending on the specific application. The suture can be dried linking two relatively short uni-directional self-retaining under vacuum to reduce residual solvent levels. This process sutures together to form a bi-directional self-retaining suture will result in the anti-scarring agent being coated on the (see, U.S. Pat. No. 6,241,747). surface of the suture. D. Methods for Making Sutures that Comprise Anti-Scarring [0828] Anti-Scarring Agent with a Swelling Solvent Agents [0829. In one embodiment, the solvent is one that will not [0818] Various methods may be used to make sutures that dissolve the suture but will be absorbed by the suture. These comprise anti-scarring agents. For example, such methods solvents can thus swell the suture to some extent. The suture may comprise the step of coating (e.g., spraying or dipping) can be immersed, either partially or completely, in the anti all or part of the sutures. Additionally, sutures themselves scarring agent/solvent solution for a specific period of time may be comprised at least in part of materials that inhibit (seconds to days). The rate of immersion into the anti-scar fibrosis in or around the site where the sutures are implanted ring agent/solvent solution can be altered (e.g., 0.001 cm per or inserted. sec to 50 cm per sec). The suture can then be removed from [0819. In certain embodiments, only selected portions the solution. The rate at which the suture can be withdrawn (such as middle sections or the self-retaining sections) of from the solution can be altered (e.g., 0.001 cm per sec to 50 sutures may be coated or otherwise comprise anti-scarring cm per sec). The coated suture can be air-dried. The dipping agents or anti-scarring agent-containing compositions. In process can be repeated one or more times depending on the certain further embodiments, portions of the sutures may be specific application. The suture can be dried under vacuum to selectively left unassociated with anti-scarring agents oranti reduce residual solvent levels This process will result in the scarring agent-containing compositions, for example, the anti-scarring agent being adsorbed into the suture The anti suture surfaces between retainer and main suture body in scarring agent may also be present on the surface of the which tissue may be gripped may be so selectively unassoci suture. The amount of surface associated anti-scarring agent ated with anti-scarring agents or anti-scarring agent-contain may be reduced by dipping the coated suture into a solvent for ing compositions. In certain other embodiments, the suture the anti-scarring agent or by spraying the coated suture with surface may comprise one or more wells of anti-scarring a solvent for the anti-scarring agent. agents or anti-scarring agent-containing compositions. In [0830] Anti-Scarring Agent with a Solvent other embodiments, all sections of sutures may be coated or [0831] In one embodiment, the solvent is one that will be otherwise comprise anti-scarring agents or anti-scarring absorbed by a suture and that will dissolve the suture. The agent-containing compositions suture can be immersed, either partially or completely, in the [0820) 1. Exemplary Methods for Combining Anti-scarring anti-scarring agent/solvent solution for a specific period of Agents with Sutures time (seconds to hours). The rate of immersion into the anti [0821]. Various exemplary methods for combining anti scarring agent/solvent solution can be altered (e.g., 0.001 cm scarring agents with sutures to produce sutures that comprise per sec to 50 cm per sec). The suture can then be removed anti-scarring agents are described in more detail below from the solution. The rate at which the suture can be with [0822) a. Coating of Sutures with Anti-Scarring Agents drawn from the solution can be altered (e.g., 0.001 cm persec [0823] Anti-scarring agents or compositions comprising to 50 cm per sec). The coated suture can be air-dried. The anti-scarring agents may be coated onto or into a suture by dipping process can be repeated one or more times depending various methods known in the art such as by dipping, spray on the specific application. The suture can be dried under ing, electrospinning, painting or by vacuum deposition. In vacuum to reduce residual solvent levels. This process will US 2009/0226500 A1 Sep. 10, 2009

result in the anti-scarring agent being adsorbed into the suture time (seconds to hours). The rate of immersion into the anti as well as being surface associated. In the preferred embodi scarring agent/solvent solution can be altered (e.g., 0.001 cm ment, the exposure time of the suture to the solvent would be per sec to 50 cm per sec). The suture can then be removed such that the suture does not undergo significant permanent from the solution. The rate at which the suture can be with dimensional changes. The anti-scarring agent may also be drawn from the solution can be altered (e.g., 0.001 cm persec present on the surface of the suture. The amount of surface to 50 cm per sec). The coated suture can be air-dried. The associated anti-scarring agent may be reduced by dipping the dipping process can be repeated one or more times depending coated suture into a solvent for the anti-scarring agent or by on the specific application. The suture can be dried under spraying the coated suture with a solvent for the anti-scarring vacuum to reduce residual solvent levels. In the preferred agent. embodiment, the exposure time of the suture to the solvent [0832] In the above description, the suture can be a suture would be such that there is not significant permanent dimen that has not been modified as well as a suture that has been sional change to the suture (other than those associated with further modified by coating with a polymer (e.g., parylene), the coating itself). The anti-scarring agent may also be surface treated, surface etching, mechanical smoothing or present on the surface of the suture. The amount of surface roughening, or grafting prior to the coating process. associated anti-scarring agent may be reduced by dipping the [0833] In one embodiment, the anti-scarring agent and a coated suture into a solvent for the anti-scarring agent or by polymer are dissolved in a solvent, for both the polymer and spraying the coated suture with a solvent for the anti-scarring the anti-scarring agent, and are then coated onto the suture agent. [0834] Anti-Scarring Agent/Polymer with an Inert-Solvent [0840] In the above description the suture can be a suture [0835] In one embodiment, the solvent is an inert solvent that has not been modified as well as a suture that has been for the suture such that the solvent does not dissolve the suture further modified by coating with a polymer (e.g., parylene), to any great extent and is not absorbed by the suture to any surface treated, surface etching, mechanical smoothing or great extent. The suture can be immersed, either partially or roughening, or grafting prior to the coating process. completely, in the anti-scarring agent/polymer/solvent solu [0841] In any one the above dip coating methods, the sur tion for a specific period of time. The rate of immersion into face of the suture can be treated with a plasma polymerization the anti-scarring agent/polymer/solvent solution can be method prior to coating of the anti-scarring agent or anti altered (e.g., 0.001 cm per sec to 50 cm per sec). The suture scarring agent containing composition, such that a thin poly can then be removed from the solution. The rate at which the meric layer is deposited onto the suture surface. Examples of suture can be withdrawn from the solution can be altered (e.g., such methods include parylene coating of sutures and the use 0.001 cm per sec to 50 cm per sec). The coated suture can be of various monomers such hydrocyclosiloxane monomers. air-dried. The dipping process can be repeated one or more Parylene coating may be especially advantageous if the times depending on the specific application. The suture can be suture, or portions of the suture, is composed of materials dried under vacuum to reduce residual solvent levels. This (e.g., stainless steel, mitinol) that do not allow incorporation of process will result in the anti-scarring agent/polymer being the therapeutic agent(s) into the surface layer using one of the coated on the surface of the suture. above methods. A parylene primer layer may be deposited [0836] Anti-Scarring Agent/Polymer with a Swelling Sol onto the electrical suture using a parylene coater (e.g., PDS Vent 2010 LABCOTER2 from Cookson Electronics, Inc., Foxbor [0837] In one embodiment, the solvent is one that will not ough, Mass.) and a suitable reagent (e.g., di-p-xylylene or dissolve a suture but will be absorbed by the suture. These dichloro-di-p-xylylene) as the coating feed material. solvents can thus swell the suture to some extent. The suture Parylene compounds are commercially available, for can be immersed, either partially or completely, in the anti example, from Specialty Coating Systems, Indianapolis, scarring agent/polymer/solvent solution for a specific period Ind.), including PARYLENEN (di-p-xylylene), PARYLENE of time (seconds to days). The rate of immersion into the C (a monchlorinated derivative of PARYLENE N, and anti-scarring agent/polymer/solvent solution can be altered PARYLENED, a dichlorinated derivative of PARYLENEN). (e.g., 0.001 cm per sec to 50 cm per sec). The suture can then [0842] In another embodiment, a suspension of the anti be removed from the solution. The rate at which the suture can scarring agent in a polymer solution can be prepared. The be withdrawn from the solution can be altered (e.g., 0.001 cm suspension can be prepared by choosing a solvent that can per sec to 50 cm per sec). The coated suture can be air-dried. dissolve the polymer but not the anti-scarring agent or a The dipping process can be repeated one or more times solvent that can dissolve the polymer and in which the anti depending on the specific application. The suture can be dried scarring agent is above its solubility limit. In similar pro under vacuum to reduce residual solvent levels. This process cesses described above, a suture can be dipped into the sus will result in the anti-scarring agent/polymer being coated pension of the anti-scarring agent and polymer solution such onto the surface of the suture as well as the potential for the that the suture is coated with the suspension. anti-scarring agent being adsorbed into the suture. The anti [0843) ii. Spray Coating scarring agent may also be present on the surface of the [0844] Spray coating is another coating process that can be suture. The amount of surface associated anti-scarring agent used. In the spray coating process, a solution or suspension of may be reduced by dipping the coated suture into a solvent for the anti-scarring agent, with or without a polymeric or non the anti-scarring agent or by spraying the coated suture with polymeric carrier, is nebulized and directed to the suture to be a solvent for the anti-scarring agent. coated by a stream of gas. One can use spray sutures such as [0838] Anti-Scarring Agent/Polymer with a Solvent an air-brush (for example models 2020, 360, 175, 100, 200, [0839] In one embodiment, the solvent is one that will be 150, 350, 250, 400, 3000, 4000, 5000, 6000 from Badger absorbed by a suture and that will dissolve the suture. The Air-brush Company, Franklin Park, Ill.), spray painting suture can be immersed, either partially or completely, in the equipment, TLC reagent sprayers (for example Part #14545 anti-scarring agent/solvent solution for a specific period of and 14654, Alltech Associates, Inc Deerfield, Ill., and ultra US 2009/0226500 A1 Sep. 10, 2009 69 sonic spray sutures (for example those available from Sono of surface associated anti-scarring agent may be reduced by Tek, Milton, N.Y.) One can also use powder sprayers and dipping the coated suture into a solvent for the anti-scarring electrostatic sprayers. agent or by spraying the coated suture with a solvent for the [0845] In one embodiment, the anti-scarring agent is dis anti-scarring agent. solved in a solvent for the anti-scarring agent and is then [0852] In the above description the suture can be a suture sprayed onto the suture. that has not been modified as well as a suture that has been [0846] Anti-Scarring Agent with an Inert-Solvent further modified by coating with a polymer (eg, parylene), [0847] In one embodiment, the solvent is an inert solvent surface treated, surface etching, mechanical smoothing or for a suture such that the solvent does not dissolve the suture roughening, or grafting prior to the coating process to any great extent and is not absorbed by the suture to any [0853] In one embodiment, the anti-scarring agent and a great extent. The suture can be held in place or the suture can polymer are dissolved in a solvent, for both the polymer and be mounted onto a mandrel or rod that has the ability to move the anti-scarring agent, and are then spray coated onto the in an X, Y or Z plane or a combination of these planes. Using Suture. one of the above described spray sutures, the suture can be [0854] Anti-Scarring Agent/Polymer with an Inert-Solvent spray coated such that the suture is either partially (for [0855] In one embodiment, the solvent is an inert solvent example, coating of the self-retaining region only) or com for a suture such that the solvent does not dissolve the suture pletely coated with the anti-scarring agent/solvent solution. to any great extent and is not absorbed by the suture to any The rate of spraying of the anti-scarring agent/solvent solu great extent. The suture can be spray coated, either partially tion can be altered (e.g., 0.001 ml per sec to 10 ml per sec) to (for example, coating of the self-retaining region only) or ensure that a good coating of the anti-scarring agent is completely, in the anti-scarring agent/polymer/solvent solu obtained. The coated suture can be air-dried. The spray coat tion for a specific period of time. The rate of spraying of the ing process can be repeated one or more times depending on anti-scarring agent/solvent solution can be altered (e.g., 0.001 the specific application. The suture can be dried under ml persec to 10 ml persec) to ensure that a good coating of the vacuum to reduce residual solvent levels. This process will anti-scarring agent is obtained. The coated suture can be result in the anti-scarring agent being coated on the surface of air-dried. The spray coating process can be repeated one or the suture. more times depending on the specific application. The suture [0848] Anti-Scarring Agent with a Swelling Solvent can be dried under vacuum to reduce residual solvent levels. [0849] In one embodiment, the solvent is one that will not This process will result in the anti-scarring agent/polymer dissolve a suture but will be absorbed by the suture. These being coated on the surface of the suture. solvents can thus swell the suture to some extent. The suture [0856] Anti-Scarring Agent/Polymer with a Swelling Sol can be spray coated, either partially (for example, coating of Vent the self-retaining region only) or completely, in the anti [0857] In one embodiment, the solvent is one that will not scarring agent/solvent solution. The rate of spraying of the dissolve a suture but will be absorbed by the suture. These anti-scarring agent/solvent solution can be altered (e.g., 0.001 solvents can thus swell the suture to some extent. The suture ml persec to 10 ml persec) to ensure that a good coating of the can be spray coated, either partially (for example, coating of anti-scarring agent is obtained. The coated suture can be the self-retaining region only) or completely, in the anti air-dried. The spray coating process can be repeated one or scarring agent/polymer/solvent solution. The rate of spraying more times depending on the specific application. The suture of the anti-scarring agent/solvent solution can be altered (e.g., can be dried under vacuum to reduce residual solvent levels. 0.001 ml persecto 10ml persec) to ensure that a good coating This process will result in the anti-scarring agent being of the anti-scarring agent is obtained. The coated suture can adsorbed into the suture. The anti-scarring agent may also be be air-dried. The spray coating process can be repeated one or present on the surface of the suture. The amount of surface more times depending on the specific application The suture associated anti-scarring agent may be reduced by dipping the can be dried under vacuum to reduce residual solvent levels coated suture into a solvent for the anti-scarring agent or by This process will result in the anti-scarring agent/polymer spraying the coated suture with a solvent for the anti-scarring being coated onto the surface of the suture as well as the agent. potential for the anti-scarring agent being adsorbed into the [0850] Anti-Scarring Agent with a Solvent suture. The anti-scarring agent may also be present on the [0851] In one embodiment, the solvent is one that will be surface of the suture. The amount of surface associated anti absorbed by a suture and that will dissolve the suture. The scarring agent may be reduced by dipping the coated suture suture can be spray coated, either partially (for example, Into a solvent for the anti-scarring agent or by spraying the coating of the self-retaining region only) or completely, in the coated suture with a solvent for the anti-scarring agent. anti-scarring agent/solvent solution. The rate of spraying of [0858] Anti-Scarring Agent/Polymer with a Solvent the anti-scarring agent/solvent solution can be altered (e.g., [0859] In one embodiment, the solvent is one that will be 0.001 ml persecto 10ml persec) to ensure that a good coating absorbed by a suture and that will dissolve the suture. The of the anti-scarring agent is obtained. The coated suture can suture can be spray coated, either partially (for example, be air-dried. The spray coating process can be repeated one or coating of the self-retaining region only) or completely, in the more times depending on the specific application. The suture anti-scarring agent/solvent solution. The rate of spraying of can be dried under vacuum to reduce residual solvent levels. the anti-scarring agent/solvent solution can be altered (e.g., This process will result in the anti-scarring agent being 0.001 ml persecto 10ml persec) to ensure that a good coating adsorbed into the suture as well as being surface associated. of the anti-scarring agent is obtained. The coated suture can In one embodiment, the exposure time of the suture to the be air-dried. The spray coating process can be repeated one or solvent would be such that the suture would incur no signifi more times depending on the specific application. The suture cant permanent dimensional changes. The anti-scarring agent can be dried under vacuum to reduce residual solvent levels. may also be present on the surface of the suture. The amount In the preferred embodiment, the exposure time of the suture US 2009/0226500 A1 Sep. 10, 2009 70 to the solvent would be such that there are not significant [0865] Within yet another embodiment, the outer layer of permanent dimensional changes to the suture (other than the coated suture, which is capable of inducing an in vivo those associated with the coating itself). The anti-scarring fibrotic response, is further treated to crosslink or functional agent may also be present on the surface of the suture. The ize the outer layer of the coating. Crosslinking of the coating amount of surface associated anti-scarring agent may be (and/or additional surface modification) can be accomplished reduced by dipping the coated suture into a solvent for the using a variety of methods, including, for example, subjecting anti-scarring agent or by spraying the coated suture with a the coated suture to a plasma treatment process. The degree of solvent for the anti-scarring agent. crosslinking and nature of the surface modification can be altered by changing the RF power setting, the location with [0860] In the above description the suture can be a suture respect to the plasma, the duration of treatment, as well as the that has not been modified as well as a suture that has been gas composition introduced into the plasma chamber. further modified by coating with a polymer (e.g., parylene), [0866] Protection of a biologically active surface can also surface treated by plasma treatment, flame treatment, corona beachieved by coating the surface with an inactive form of the treatment, surface oxidation or reduction, surface etching, anti-scarring agent, which is lateractivated. The anti-scarring mechanical smoothing or roughening, or grafting prior to the suture may be activated before, during, or after deployment coating process. (e.g., an inactive agent on the suture may be first activated to [0861) b. Other Exemplary Methods for Combining Anti one that induces or accelerates an in vivo fibrotic reaction). Scarring Agents with Sutures [0867] In one embodiment, the suture can be coated with an [0862] In certain embodiment, a particulate form of the inactive form of the anti-scarring agent, applied as described active agent (e.g., silk, wool, cyanoacrylate particles or chi herein, which is then activated once the suture is deployed. tosan) may be coated onto the suture. In one embodiment, the Activation can be achieved by injecting an activating agent particulate form may be incorporated into a polymeric carrier (e.g., an enzyme) or a composition that includes an activating (e.g., PLG, PLA, polyurethane, suture coatings as described agent into the tissue or area surrounding the suture after above) Alternatively, or in addition, particles of the active deployment of the suture or after the anti-scarring agent has agent can be applied onto a polymer-coated suture. For been administered to the tissue (via drug delivery catheters or example, a suture can be coated with a polymer (e.g., a poly balloons). urethane) and then allowed to partially dry such that the [0868] In one embodiment, a suture includes a first coating surface is still tacky. A particulate form of the anti-scarring layer that includes a biologically active anti-scarring agent agent or an anti-scarring agent and secondary carrier, such as and a first reactive component. In one embodiment, the first described above, can then be applied to all or a portion of the reactive component is capable of reaction with a polyethylene tacky coating after which the suture is dried. glycol The coated suture can be further coated with a second [0863] In certain embodiments, a suture having a polymeric composition that includes a second reactive component (e.g., coating with or without an anti-scarring agent can be sub polyethylene glycol) that is capable of reaction with the first jected to athermal treatment process to soften the coating. An reactive component in the first coating layer. The reactive anti-scarring agent or an anti-scarring agent and secondary components of the first and second coating layers can be carrier then is applied to all or a portion of the softened bonded via a condensation reaction through formation of coating. ester bonds. Prior to the deployment of the intra-arterial seg [0864] Coated sutures may be further coated with an addi ment of the suture, an esterase is injected into the treatment tional composition and/or be treated to alter the release char site around the outside of the suture, which can cleave the acteristics of the coating composition and/or anti-scarring ester linkages, thus allowing the agent to become available to agent. For example, a suture having an anti-scarring agent or inhibit fibrosis anti-scarring composition incorporated into or coated onto [0869] 2. Anti-Scarring Agent Releasing Profiles the suture may be further coated with a composition or com [0870] In certain embodiments, anti-scarring agents may pound which delays the onset of activity of the anti-scarring be released from sutures that comprise anti-scarring agents. agent for a period of time after implantation. Protection of a In other embodiments, the anti-scarring agents may be biologically active surface can be achieved by coating the released from carriers that are applied to the surrounding suture surface with an inert molecule that prevents access to tissue as liquids, gels, pastes, suspensions, microspheres, the active site through steric hindrance. Representative nanoparticles or other such delivery vehicles. In certain other examples of such compositions or compounds include bio embodiments, such agents become part of sutures perma logically inert materials such as gelatin, PLGA/MePEG film, nently and no anti-scarring agents are released from the PLA, polyurethanes, suture coatings as described above, sili Suture. cone rubbers, surfactants, lipids, or polyethylene glycol, as [0871] The sutures or compositions of the present invention well as biologically active materials such as heparin (e.g., to may release the anti-scarring agent at one or more phases, the induce coagulation). In one embodiment, the active agent one or more phases having similar or different performance (e.g., poly-L-lysine, fibronectin, chitosan, silk, wool, bleo (e.g., release) profiles. The therapeutic agent may be made mycin, cyclosporine A, or CTGF) on the suture is top-coated available to the tissue at amounts which may be sustainable, with a physical barrier that does not contain an anti-scarring intermittent, or continuous; in one or more phases; and/or agent. The barrier layer can include non-degradable materials rates of delivery; effective to reduce orinhibit any one or more or biodegradable materials such as, e.g., gelatin PLGA/Me components offibrosis (or scarring), including: formation of PEG film, PLA, PLG, or polyethylene glycol. The barrier new blood vessels (angiogenesis), migration and prolifera layer (e.g., dissolves slowly or degrades once implanted into tion of connective tissue cells (such as fibroblasts or smooth the host As the top layer dissolves or degrades, the active muscle cells), deposition of extracellular matrix (ECM), and agent becomes exposed to the surrounding tissue and/or can remodeling (maturation and organization of the fibrous tis be released from the coating sue).