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United States Patent (19) 11 Patent Number: 4,485,088 Chvapil (45) Date of Patent: Nov

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United States Patent (19) 11 Patent Number: 4,485,088 Chvapil (45) Date of Patent: Nov United States Patent (19) 11 Patent Number: 4,485,088 Chvapil (45) Date of Patent: Nov. 27, 1984 54 METHOD OF TREATMENT OF FIBROTIC Primary Examiner-Stanley J. Friedman LESIONS BY TOPCAL ADMINISTRATION OF LATHYROGENC DRUGS 57. ABSTRACT The disclosure deals with a method of treating fibrotic 75 Inventor: Milos Chvapil, Tucson, Ariz. lesions related to abnormal collagen polymerization by 73 Assignee: Bio-Products, Inc., Tucson, Ariz. topical administration of lathyrogenic substances, such as 3-aminopropionitrile fumarate, aminoacetonitrile, 21 Appl. No.: 362,241 D-penicillamine, into the site of the injury. The lathyro 22 Filed: Mar. 26, 1982 genic drugs are administered by local injection or onto the skin and percutaneously transported into the site of 51) Int. Cl....................... A61K9/70; A61K 31/275 the lesion. Lathyrogens, administered locally as a single 52 U.S. C. ....................................... 424/28; 424/304 drug or in combination do not produce any local or 58 Field of Search .................................. 424/304, 28 systemic toxic effects and are improving the function of the pathological fibrosis based on the accumulation of 56 References Cited polymerized collagenous protein. PUBLICATIONS Code of Federal Regulations 37 (7-1-82), p. 38. 5 Claims, No Drawings 4,485,088 2 ble and acquiring mechanical strength. This process is METHOD OF TREATMENT OF FEBROTC also called maturation or polymerization of collagen LESIONS BY TOPCAL ADMINISTRATION OF and is the main target of this invention. LATHY ROGENC DRUGS Formation of a scar is the result of a fibroproliferative Y 5 inflammation. Scar is an imperfect method of repairing REFERENCES CITED tissue defects. Several steps could be identified in the E. E. Peacock, Jr. and Walton Van Winkle. Wound course of fibrotic reaction. The injury activates fibro Repair, Sanders Co. Philadelphia, USA, 1976. blasts to produce more collagen and glycosaminogly H. Keiser and A. Sjoerdsma. Clin. Pharmacol. Ther. - cans. Often part of the injury is bleeding by ruptured 8:593, 1967. 10 vessels. Blood is a known factor inducing fibrosis. In E. E. Peacock and J. W. Madden. Surgery 66: 215, ruptured or injured tendons, the presence of blood and 1969. blood proteins, mainly of fibrin, forms bridges between D. J. Prockop. German Pat. No. 2,228,187 (Dec. 14, the tendon and its sheath to form peritendineous adhe 1972). sions which immobilize the joint by impairing the glid In human medicine, there has always been an urgent 15 ing function of the tendon. Once collagen is formed and need for an efficient method of inhibiting abnormal accumulates at the site of the injury, it matures and only accumulation of collagen in the form of fibrotic, cir then do the abnormal functions of the tissue manifest rhotic or excessive scar lesions. Only in the last decade. themselves. have various aspects of collagen metabolism, and colla In the dynamics of the fibroproductive inflammation, gen regulating mechanisms made it possible to apply 20 basic knowledge to more integrated and complex sys various reactions reach their maximum and then decline tems as represented by various models of fibrosis in with time. Activity of lysyl oxidase, the enzyme which animals. The goal of various treatments aiming at the is involved in polymerization of collagen, is highest at inhibition of collagen metabolism was to inhibit selec much later stages after collagen has been accumulated tively the synthesis and deposition of this fibrous pro- 25 in the intercellular space. The maximal activity of lysyl tein specifically in the fibroticlesion, not in intact tis oxidase, coincides with formation of an insoluble colla sues. As will be shown below, so far, not an efficient gen within the injured tissue. Consequently, the optimal method was developed, in spite of the fact that every time of "pharmacological' interference with a certain aspect of collagen metabolism was taken into such a step of the inflammation, is at the time of maximum “therapeutic" consideration. It has been my experience 30 incidence and activity; of this specific process. We that inhibition of maturation (polymerization, stabiliza learned by our experiments that in skin incision wounds, tion of the structure) of collagen has so far been the the inhibition of lysyl-oxidase could be started five days most successful and powerful method of interfering after inflicting the injury, and continued the treatment with the physical properties of scar contractures and for 14-21 days to achieve an effective and permanent fibrotic structures. Apparently, it is not the total volume 35 prevention of collagen maturation. of collagenous structures within a certain tissue, but The fibrotic, collagenous tissue is in a continuous rather the physical properties of the callogenous matrix increased metabolic turnover. Both synthesis and deg which represent the real danger to the function of the radation of collagen are increased and their relative tissue or organ. When collagen is cross-linked, possibly activities change with time of healing. It could be as by stable covalent cross-links involving the function of 40 sumed that by decreasing the structural stability in the lysyl oxidase, it is less degradable by mammalian colla scar (i.e., decreasing the degree of polymerization of genase and forms a compact rigid scar binding less collagen) by administration of lathyrogenic agent, the water. As will be demonstrated below, formation of a pool of “extractable" collagen is increased. These forms scar, which ultimately shrinks, contracts, forms defor would be more readily available to digestion by collage mities, strictures, represent the real danger for the pa- 45 nase system and by other proteolytic enzymes in the tient. It is the object of this disclosure to present a new later stage. This will result in a reduction of the size and method of topical interference with the formation of volume of the fibrotic mass. mature scars by a group of drugs, called lathyrogens. Pharmacology of Fibrosis . Lathrogens are defined as a group of chemical sub There exist several steps unique for collagen which stances inhibiting by any method the formation of inter-50 could be used as a target for so-called "specific interfer molecular and intramolecular covalent cross-links in ence” with collagen metabolism. These stages are: collagen or elastin structures. 1. Hydroxylation of prolyl and lysyl residues by ap propriate hydroxylases. BACKGROUND INFORMATION 2. Glycosylation of some e-NH2 hydroxylysyl groups In order to justify my reasons for administering cer- 55. and; . tain drugs called lathyrogens topically into the site of 3. subsequent secretion of the molecule out of the fibrotic lesion, it is necessary to outline several topics : cell. - related to this new therapeutical method. 4. In the extracellular space, the molecule further' - Dynamics of Scar Formation polymerizes or matures under the effect of lysyl Scar callagen is synthesized by fibroblasts. While still 60 oxidase which forms the basis for development of within the fibroblasts, the collagen polypeptides are stable covalent cross-links. hydroxylated, form a triple helix and undergo glycosy 5. At different stages of collagen synthesis the mole lation to the transport form, known as procollagen. cule is degradable but the "younger" the molecule Procollagen is then secreted from the fibroblasts into is, the faster the degradation by tissue collagenases. the extracellular wound environment, to form tropocol 65 Several sophisticated methods were developed and lagen. Tropocollagen then undergoes intramolecular studied with the aim to reduce collagen deposition or and intermolecular covalent cross-linking to form colla polymerization in the fibrotic lesion (D. J. Prockop gen fibers which are becoming progressively less solu German Pat. No. 2,228,187). In all these situations, the 4,485,088 3 4. medication was administered either perorally or paren densation of aldehydes or formation of Schiff bases as terally, in other words by systemic route, where the shown in Scheme I. Scheme I Suggested methods of the effect of lathyrogens on the covalent cross-links in the collagen structure. BAPN in-chi-Nil, Lysyl oxidase G -- 3-(CH-CHO Penicillamine Hydroxylysine CU C O2 8-Semialdehyde Lysine a-Amino adipic acid OH -thH >-R- CH2NH- R Hydroxylysine Labile Schiff Stable CH-(CH2)3-CHO base cross-link --OHC-R- >-R-C-ERCHO Aldol condensate Stable cross-link Since BAPN and D-penicillamine affect two different drug was distributed among all tissue and body fluids. sites in the formation of covalent cross-links, when used All various methods of interference with individual 30 together their effect is additive. The lathyritic proper steps of collagen synthesis have one major deficiency; ties of penicillamine derive from its ability to chelate they work very nicely in isolated, closed systems of aldehydes formed by the action of lysyl oxidase on the cells in tissue cultures and are minimally effective or epsilon amino group of tropocollagen lysine. In addi quite ineffective in vivo in the whole organism. In fact, tion, direct inhibition of of lysyl oxidase by D-penicilla after systemic administration of many of these drugs 35 mine was demonstrated. The overall effectiveness of (proline analogs, chelating agents, colchicine, etc.) their systemically-administered D-penicillamine in decreas toxic effect is close to the therapeutic effect. Thus, there ing the structural stability of collagen has been well is a permanent risk of general toxicity of the drug
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