US 20080287866A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0287866 A1 Heller (43) Pub. Date: Nov. 20, 2008

(54) METHODS AND COMPOSITIONS FOR THE Publication Classification TREATMENT OF PAN (51) Int. Cl. (76) Inventor: Adam Heller, Austin, TX (US) A6II 3/31 (2006.01) Correspondence Address: A6IP 25/00 (2006.01) CLARK & ELBNG LLP A6M 3L/00 (2006.01) 101 FEDERAL STREET BOSTON, MA 02110 (US) (21) Appl. No.: 12/012,115 (52) U.S. Cl...... 604/82: 514/612 (22) Filed: Jan. 31, 2008 Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 60/887,431, filed on Jan. 31, 2007, provisional application No. 60/930,261, The invention features methods, kits, and compositions for filed on May 15, 2007. the treatment of pain. US 2008/028786.6 A1 Nov. 20, 2008

METHODS AND COMPOSITIONS FOR THE 0006. It is an object of the invention to provide new meth TREATMENT OF PAN ods, kits, and compositions for the treatment of pain and itch.

CROSS-REFERENCE TO RELATED SUMMARY OF THE INVENTION APPLICATIONS 0007. Applicants have discovered that oxidizing amines, 0001. This application claims benefit of U.S. Provisional such as N-chloro amines and N-dichloro amines, are useful Ser. No. 60/887,431 filed on Jan. 31, 2007, and U.S. Provi for the treatment of pain and itch. sional Ser. No. 60/930.261, filed on May 15, 2007, each of 0008 Accordingly, in a first aspect the invention features a which is incorporated herein by reference. method of treating pain in a patient in need thereof by topi cally administering to the patient an agent selected from BACKGROUND OF THE INVENTION N-chloro amines and N-dichloro amines in an amount suffi cient to treat the pain. 0002 Chronic pain is one of the most important clinical 0009. The invention also features a method of treating pain problems in all of medicine. For example, it is estimated that at a site in a patient in need thereof by locally injecting at the over 5 million people in the United States are disabled by back site an agent selected from N-chloro amines and N-dichloro pain. The economic cost of chronic back pain is enormous, amines in an amount Sufficient to treat the pain. resulting in over 100 million lost work days annually at an 0010. The invention further features a method of treating estimated cost of S50-100 billion. It has been reported that pain in a patient in need thereof by administering to the approximately 8 million people in the U.S. report that they patient an agent selected from N-chloro amines and experience chronic neck or facial pain and spendan estimated N-dichloro amines in an amount Sufficient to treat the pain, S2 billion a year for treatment. The cost of managing pain for wherein the pain is nociceptive pain, Somatic pain, visceral oncology patients is thought to approach S12 billion. Chronic pain, procedural pain, or inflammatory pain caused by pain disables more people than cancer or heart disease and trauma, Surgery, or an autoimmune disease. In certain costs the American public more than both cancer and heart embodiments the pain is caused by trauma, Surgery, hernia disease combined. In addition to the physical consequences, tion of an intervertebral disk, spinal cord injury, shingles, chronic pain has numerous other costs including loss of HIV/AIDS, cancer related pain, amputation, neurodegenera employment, marital discord, depression and prescription tive disorders, carpal tunnel syndrome, diabetic neuropathy, drug addiction. It goes without saying, therefore, that reduc postherpetic neuralgia, fibromyalgia, a musculoskeletal dis ing the morbidity and costs associated with persistent pain order, or any other painful condition described herein. remains a significant challenge for the healthcare system. 0011. In a related aspect, the invention features a method 0003 Intractable severe pain resulting from injury, illness, of treating itchina patient in need thereof by topically admin scoliosis, spinal disc degeneration, spinal cord injury, malig istering to the patient an agent selected from N-chloroamines nancy, arachnoiditis, chronic disease, pain syndromes (e.g., and N-dichloro amines in an amount sufficient to treat the failed back syndrome, complex regional pain syndrome) and itch. other causes is a debilitating and common medical problem. 0012. In an embodiment of any of the above aspects, the In many patients, the continued use of analgesics, particularly agent is administered locally at the site of pain or itch. drugs like narcotics, are not a viable solution due to tolerance, 0013. In another related aspect, the invention features a kit loss of effectiveness, and addiction potential. including (i) a composition including an agent selected from 0004 Oxidizing agents are widely used as disinfectants. N-chloro amines and N-dichloro amines in an amount suffi Examples of oxidizing disinfectants include aqueous solu cient to treat pain when administered to a patient, and (ii) tions of chlorine, where hypochlorite and hypochlorous acid instructions for topically administering the composition to a co-exist near neutral pH; of iodine, often dissolved as potas patient for the treatment of pain. In certain embodiments, the sium tri-iodide in potassium iodide containing Solutions; of composition is formulated for topical administration (e.g., hydrogen peroxide; of N-chloro-compounds, like Chloram formulated as a cream, lotion, spray, Stick, iontophoresis ine-T, the sodium salt of N-chloro-p-toluenesulfonamide and Solution, or ointment). its salts with other cations or like Chloramine-B, the sodium 0014. The invention also features a kit including (i) a com salt of N-chloro-benzenesulfonamide and its salts with other position formulated for injection and including an agent cations; and of chloramine, NH2Cl, also known as selected from N-chloro amines and N-dichloro amines in an monochloramine; and of oZone. All are bactericidal and/or amount Sufficient to treat pain when administered to a patient, fungicidal, and some also deactivate viruses. Chlorine and the and (ii) instructions for locally injecting the composition at a product of its reaction with water hypochlorous acid, and site of a patient for the treatment of pain. chloramine, as well as oZone, are widely used to disinfect 0015 The invention further features a kit including (i) a municipal drinking water. Oxidizing agents are also applied composition including an agent selected from N-chloro in sterilization, for example of Surgical instruments. amines and N-dichloroamines in an amount Sufficient to treat 0005. Oxidizing agents are also used in treatment of pain when administered to a patient, and (ii) instructions for wounds and disease. Bactericidal oxidizing agents are used administering the composition to a patient for the treatment of also to disinfect wounds, to prevent and control pathogen nociceptive pain, Somatic pain, visceral pain, procedural pain, caused inflammation, to assist in the healing of skin and other or inflammatory pain caused by trauma, Surgery, or an wounds, and to treat pathogen-caused diseases. When used to autoimmune disease. In certain embodiments, the kit further disinfect wounds, they are optionally topically applied, for includes instructions for administering the composition to a example by Swabbing, brushing, spraying, or in a dressing. patient Suffering from pain caused by trauma, Surgery, her They are applied topically also in order to prevent infection niation of an intervertebral disk, spinal cord injury, shingles, before the skin is purposely pierced or cut, for example, prior HIV/AIDS, cancer related pain, amputation, neurodegenera to an injection, withdrawal of a blood sample, or Surgery. tive disorders, carpal tunnel syndrome, diabetic neuropathy, US 2008/028786.6 A1 Nov. 20, 2008 postherpetic neuralgia, fibromyalgia, a musculoskeletal dis N-chloro alpha-aminoisobutyric acid, N-chlorotaurine, order, or any other painful condition described herein. N-chlorotaurine ethyl ester, N-chlorotaurine sulfonamide, 0016. The invention also features a kit including (i) a com N-chloro-acetylglycine, N-chloroalanine, N-chlorobeta-ala position including an agent selected from N-chloro amines nine, N-chloro phenylalanine, N-chloro norvaline, N-chlo and N-dichloro amines in an amount sufficient to treat itch roleucine, N-chloro isoleucine, N-chloroproline, N-chloro when administered to a patient, and (ii) instructions for topi omega aminoundecanoic acid, N-chloroaspartic acid, cally administering the composition to a patient for the treat N-chloroglutamic acid, N-chloroasparagine, N-chlorovaline, ment of itch. N-chlorocystine, N-chloromethionine, N-chloroglutamine, 0017. In a related aspect, the invention features a kit N-chlorotryptophane, N-chlorohistidine, N-chloroarginine, including (i) an inorganic oxide, (ii) an ammonium salt, (iii) a N-chlorolysine. N-chloro alpha-aminobutyric acid, N-chloro hypochlorite salt, (iv) instructions for contacting the inor gamma-aminobutyric acid, N-chloro alpha, epsilon diamino ganic oxide, the ammonium salt, and the hypochlorite salt pimelic acid, N-chloro ornithine, N-chloroanthranilic acid, with water to form a solution, and (V) instructions for admin N-chloro p-aminobenzoic acid, N-chlorosulfanilic acid, istering the Solution to a patient for the treatment of pain or N-chloro orthanilic acid, N-chloro phenyl sulfamic acid, itch. In certain embodiments, the kit further includes a buffer. N-chloroaminopropanesulfonic acid, N-chloro ami In still other embodiments, the kit includes instructions for nomethane-Sulfonic, N-chloro glycylglycine, N-chloro gly topically administering the solution into a patient for the cylglycylglycine, N-chloro metanilic acid, N-chloro-N-octo treatment of pain or itch or instructions for infusing the solu decanyl glycine, dichloramine, N-dichloro methylamine, tion into a patient at a site of pain. N-dichloro ethylamine, N-dichloro isobutylamine, 0018. In a related aspect, the invention features an infusion N-dichloro-2-methylbutylamine, N-dichloro phenethy device including: (i) a first reservoir containing a first Solution lamine, N-dichloro agnatine, N-dichloro histamine, including an ammonium salt oran amine or a salt thereof; (ii) N-dichloro tryptamine, N-dichloro-3-methylthiopropan a second reservoir containing a second solution including amine, N-dichloro spermine, N-dichloro carnosine, hypochlorous acid or a salt thereof; (iii) a mixing chamber for N-dichloro carcinine, N-dichloroglycine, N-dichloro alpha combining the first solution and the second solution to form a aminoisobutyric acid, N-dichlorotaurine, N-dichlorotaurine chlorinated amine; and (iv) a cannula in fluid communication ethyl ester, N-dichlorotaurine sulfonamide, N-dichloroala with the mixer chamber for delivering the N-chloroamine to nine, N-dichloro beta-alanine, N-dichloro phenyl alanine, a subject. N-dichloro norvaline, N-dichloroleucine, N-dichloro isoleu 0019. The invention further features an infusion device cine, N-dichloroproline, N-dichloro omega aminounde including: (i) a reservoir containing a first solution including canoic acid, N-dichloroaspartic acid, N-dichloroglutamic an ammonium chloride Salt and/oran amine and chloride ion; acid, N-dichloroasparagine, N-dichlorovaline, N-dichlo (ii) a power source electrically connected to an electrode in romethionine, N-dichloroglutamine, N-dichlorotryptophane, contact with the solution and configured to produce N-chloro N-dichloroarginine, N-dichlorolysine, N-dichloro alpha amine via electrolysis; and (iii) a cannula in fluid communi aminobutyric acid, N-dichloro gamma-aminobutyric acid, cation with the solution for delivering the N-chloroamine to N-dichloro alpha, epsilon diamino pimelic acid, N-dichloro a subject. ornithine, and pharmaceutically acceptable salts, esters, and 0020. The invention also features an infusion device amides thereof. including: (i) a first reservoir containing a first Solution 0024. In certain embodiment of any of the above methods, including an amine or a salt thereof; (ii) a second reservoir kits, devices, or bandages, the agent is a chlorinated analge containing a second solution including a chloride ions; (iii) a sic, chlorinated tricyclic antidepressant, chlorinated Stimu power source electrically connected to an electrode in contact lant, or a polymer bearing N-chloroamine groups. with the second solution and configured to produce hypochlo 0025 Chlorinated analgesics which can be used in the rous acid or a salt thereof via electrolysis; (iv) a mixing methods, kits, devices, and bandages of the invention include, chamber for combining the first solution and the hypochlor without limitation, N-chloro lidocaine, desethyl-N-chloro ous acid or a salt thereof to form an N-chloroamine; and (v) lidocaine. N-chloroprilocalne, N-chlorotocainide, desethyl a cannula in fluid communication with the mixing chamber N-chloroetidocaine, desbutyl-N-chloro ropivacaine, desbu for delivering the N-chloroamine to a subject. tyl-N-chloro bupivacaine, desbutyl-N-chloro levobupiv 0021. In one embodiment of any of the above methods, acaine, desmethyl-N-chloro mepivacaine, desethyl-N-chloro kits, devices, or bandages the patient experiences some pain procaine, desethyl-N-chloro proparacaine, desethyl-N- relief or some itch relief within 5, 10, 15, 20, 30, or 45 minutes chloro allocain, desmethyl-N-chloro encainide, desethyl-N- of administering the chlorinated amine of the invention. chloro procainamide, desethyl-N-chloro metoclopramide, 0022. In another embodiment of any of the above meth desmethyl-N-chloro stovaine, desethyl-N-chloro pro ods, kits, devices, or bandages, the pain or itch does not result poxycaine, desethyl-N-chloro chloroprocaine. N-chloro from an infection in the patient. flecainide, desethyl-N-chloro tetracaine, N-chloro procaine, 0023. In yet another embodiment of any of the above N-chloro proparacaine, N-chloro procainamide, N-chloro methods, kits, devices, or bandages, the agentis selected from metoclopramide, N-chloro propoxycaine. N-chloro chlorop chloramine, chlorourea, N-chloro methylamine, N-chloro rocaine, N-chloro tetracaine, N-chlorobenzocaine, N-chloro ethylamine, N-chloro isobutylamine, N-chloro-2-methylbu butamben, and desethyl-N-chloro dibucaine. tylamine, N-chloro pyrrolidine, N-chloro phenethylamine, 0026 Chlorinated tricyclic antidepressants which can be N-chloro agnatine, N-chloro histamine, N-chloro used in the methods, kits, devices, and bandages of the inven tryptamine. N-chloro-3-methylthiopropanamine, N-chloro tion include, without limitation, N-chloro amoxapine, desm spermine, N-chloro carnosine, N-chloro carcinine, chloram ethyl-N-chloro trimipramine, desmethyl-N-chloro dothiepin, ine T. chloramine B, N-chloro glutathione sulfonamide, desmethyl-N-chloro doxepin, desmethyl-N-chloro amitrip N-chloroglycine, N-chlorosulfamic acid, N-chlorosarcosine, tyline, N-chloro protriptyline, N-chloro desipramine, desm US 2008/028786.6 A1 Nov. 20, 2008 ethyl-N-chloro clomipramine, desmethyl-N-chloro clozap 0037. The term “neuropathic pain' is used herein to refer ine, desmethyl-N-chloro loxapine, N-chloro nortriptyline, to pain originating from abnormal processing of sensory desmethyl-N-chloro cyclobenzaprine, desmethyl-N-chloro input by the peripheral or central nervous system consequent cyproheptadine, desmethyl-N-chloro olopatadine, desm on a lesion to these systems. ethyl-N-chloro promethazine, desmethyl-N-chloro trimepra 0038. The term “procedural pain” refers to pain arising zine, desmethyl-N-chloro chlorprothixene, desmethyl-N- from a medical, dental or Surgical procedure wherein the chloro chlorpromazine, desmethyl-N-chloro propiomazine, procedure is usually planned or associated with acute trauma. desmethyl-N-chloro prochlorperazine, desmethyl-N-chloro 0039. The term “itch' (also known as pruritus) is used thiethylperazine, desmethyl-N-chloro trifluoperazine, des herein in the broadest sense and refers to all types of itching ethyl-N-chloro ethacizine, and desmethyl-N-chloro imi and stinging sensations localized and generalized, acute inter pramine. mittent and persistent. The itch may be idiopathic, allergic, 0027 Chlorinated stimulants which can be used in the metabolic, drug-induced, due to liver, kidney disease, or can methods, kits, devices, and bandages of the invention include, C without limitation, N-chloro amphetamine, N-dichloro 0040. By “patient' is meant any animal. In one embodi amphetamine, and N-chloro methamphetamine. ment, the patient is a human. Other animals that can be treated 0028 Polymers bearing N-chloroamine groups which can using the methods and devices of the invention includebut are be used in the methods, kits, devices, and bandages of the not limited to non-human primates (e.g., monkeys, gorillas, invention include, without limitation, N-chlorinated chitosan, chimpanzees), domesticated animals (e.g., horses, pigs, N-chlorinated deacetylated hyaluronic acid, and N-chlori goats, rabbits, sheep, cattle, llamas), companion animals nated polylysine. (e.g., guinea pigs, rats, mice, lizards, Snakes, dogs, cats, fish, 0029. In certain embodiment of any of the above methods, hamsters, and birds), animals participating in races or con kits, devices, or bandages, the agent is selected from chloram tests (horses, camels, dogs, birds), and marine mammals. ine, dichloramine, N-chlorotaurine, N-dichloro taurine, 0041. The term “pharmaceutically acceptable salt' repre N-chloro desmethylchlorpromazine, N-chloro lidocaine, sents those salts which are, within the scope of sound medical N-chloro amphetamine, N-dichloro amphetamine, and judgment, Suitable for use in contact with the tissues of N-chloro methamphetamine. humans and lower animals without undue toxicity, irritation, 0030. When used for topical administration, the chlori allergic response and the like, and are commensurate with a nated amine of the invention desirably has a solubility at reasonable benefit/risk ratio. Pharmaceutically acceptable about 25°C. ofat least about 10M, 10M, 10 M, or 10 salts are well known in the art. The salts can be prepared in Mboth in water and in chloroform to allow for rapid diffusion situ during the final isolation and purification of the agents of to the nerve endings. the invention, or separately by reacting the free base function 0031. In certain embodiments the chlorinated amine of the with a suitable organic acid. Representative acid addition invention has a long life (i.e., is highly stable) in comparison salts include but are not limited to acetate, adipate, alginate, to chloramine, which has a half-life on the order of days. For ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, example, sulfonate salts of N-chloro taurine may be desirable borate, butyrate, camphorate, campherSulfonate, citrate, to use as Such salts can be stored for many months without cyclopentanepropionate, digluconate, dodecylsulfate, significant decomposition. ethanesulfonate, fumarate, glucoheptonate, glycerophos 0032. The term “pain' is used herein in the broadest sense phate, hemisulfate, heptonate, hexanoate, hydrobromide, and refers to all types of pain, including acute and chronic hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, pain, such as nociceptive pain, e.g. Somatic pain and visceral isethionate, lactobionate, lactate, laurate, lauryl Sulfate, pain; inflammatory pain, dysfunctional pain, idiopathic pain, malate, maleate, malonate, mesylate, methanesulfonate, neuropathic pain, e.g., centrally generated pain and peripher 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, ally generated pain, migraine, and cancer pain. palmitate, pamoate, pectinate, persulfate, 3-phenylpropi 0033. The term “nociceptive pain' is used to include all onate, phosphate, picrate, pivalate, propionate, Stearate. Suc pain caused by noxious stimuli that threaten to or actually cinate, Sulfate, tartrate, thiocyanate, toluenesulfonate, unde injure body tissues, including, without limitation, by a cut, canoate, Valerate salts, and the like. Representative alkali or bruise, bone fracture, crush injury, and the like. Pain receptors alkaline earth metal salts include but are not limited to for tissue injury (nociceptors) are located mostly in the skin, Sodium, lithium, potassium, calcium, magnesium, and the musculoskeletal system, or internal organs. like, as well as nontoxic ammonium, quaternary ammonium, 0034. The term “somatic pain' is used to refer to pain and amine cations, including, but not limited to ammonium, arising from bone, joint, muscle, skin, or connective tissue. tetramethylammonium, tetraethylammonium, methylamine, This type of pain is typically well localized. dimethylamine, trimethylamine, triethylamine, ethylamine, 0035. The term “visceral pain” is used herein to refer to and the like. pain arising from visceral organs, such as the respiratory, 0042. As used herein, the terms “ester” and "amide' refer gastrointestinal tract and pancreas, the urinary tract and derivatives of the chlorinated amines described herein, reproductive organs. Visceral pain includes pain caused by including carboxylic acid esters and amides and Sulfonic acid tumor involvement of the organ capsule. Another type of esters and amides. Examples of Such derivatives include, visceral pain, which is typically caused by obstruction of without limitation the methyl, ethyl, isopropyl, propyl, butyl, hollow Viscus, is characterized by intermittent cramping and and hexyl sulfonic acid esters of N-chloro taurine and poorly localized pain. Visceral pain may be associated with N-dichloro taurine; sulfonamides of N-chloro taurine and inflammation as in cystitis or reflux esophagitis. N-dichloro taurine (e.g., formed from ammonia, secondary 0036. The term “inflammatory pain' includes pain asso amines, or primary amines); methyl, ethyl, isopropyl, propyl. ciated with active inflammation that may be caused by butyl, and hexylcarboxylic acid esters of amino acids, such as trauma, Surgery, infection and autoimmune diseases. gamma aminobutyric acid; and carboxylic acid amides (e.g., US 2008/028786.6 A1 Nov. 20, 2008 formed from ammonia, secondary amines, or primary syndrome, fibromyalgia, hallux Valgus, infectious arthritis, amines) of amino acids, such as gamma aminobutyric acid. joint diseases, Kabuki make-up syndrome, Legg-Perthes dis Methods for making such derivatives are well known in the ease, lupus, Lyme disease, Melas Syndrome, metabolic bone art. diseases, mitochondrial myopathies, mixed connective tissue 0043. By “treating pain' is meant preventing, reducing, or disease, muscular diseases, muscular dystrophies, muscu eliminating the sensation of pain in a subject. To treat pain, loskeletal abnormalities, musculoskeletal diseases, myositis, according to the methods of this invention, the treatment does myositis ossificans, necrotizing fasciitis, neurogenic arthr not necessarily provide therapy for the underlying pathology opathy, osteitis deformans, osteochondritis, osteomalacia, that is causing the painful sensation. Treatment of pain can be osteomyelitis, osteonecrosis, osteoporosis, Paget's disease, purely symptomatic. Pierre Robin syndrome, polymyalgia rheumatica, polymyo 0044. By “treating itch’ is meant preventing, reducing, or sitis, postpoliomyelitis syndrome, pseudogout, psoriatic eliminating the sensation of itch in a Subject. To treat itch, arthritis, reactive arthritis, Reiter disease, relapsing poly according to the methods of this invention, the treatment does chondritis, renal osteodystrophy, rhabdomyolysis, rheumatic not necessarily provide therapy for the underlying pathology diseases, rheumatic fever, Scleroderma, Sever's disease that is causing the itch. Treatment of itch can be purely symp (calceneal apophysitis), Sjögren's syndrome, spinal diseases, tomatic. spinal Stenosis, Still's disease, synovitis, temporomandibular 0045. By “an amount sufficient' is meant an amount of an joint disorders, tendinopathy, tennis elbow, tenosynovitis, agent administered in a method of the invention required to Tietze's syndrome, and Wegener's granulomatosis. prevent, reduce, or eliminate the sensation of pain (nocicep 0049. The term “administration' or “administering refers tion) or itch. The effective amount of agent used to practice to a method of giving a dosage of agent to a patient, where the the present invention for therapeutic treatment of pain or itch method is, e.g., topical, oral, nasal, ocular, Subcutaneous, varies depending upon the manner of administration, the age, intravenous, intraperitoneal, or intramuscular. The preferred and body weight, of the subject as well as the route of admin method of administration can vary depending on various fac istration and underlying pathology that is causing the pain or tors, e.g., the components of the composition being adminis itch. Ultimately, the attending physician or veterinarian will tered, site of the pain or itch, and its severity. decide the appropriate amount and dosage regimen. Such 0050. The term “injection” refers to bolus or infusion amount is referred to as a “sufficient” amount. delivery of an agent via needle or cannula, for example, 0046 By "chlorinated' is meant a material or compound Subcutaneously, intravenously, intraperitoneally, or intramus bearing one or more N H moieties which has been con cularly. verted to an N-Cl moiety. For compounds and materials in 0051. As used herein, “topical administration” refers to which more than one nitrogen center can be chlorinated, the application of an agent of the invention to the skin of a Subject. designation “N-chloro' refers to chlorination of at least one Topical administration includes transdermal administration, of the N H moities. In contrast, the designation Such as by iontophoresis. “N-dichloro” refers to a compound or material bearing at 0.052 A used herein, “local administration or administra least one —NC1 moiety. tion “locally refers to the delivery of an agent at, or adjacent 0047. As used herein, “N-chloro-GSA” or “N-chloro-glu to, the site of pain or itching, or near part of a nerve transmit tathione sulfonamide' refers specifically to chlorination of ting the pain or itching-signal. For example, local adminis the Sulfonamide nitrogen, as shown in the structure below. tration is typically within about 2 cm or less from the affected nerve ending, preferably within less than about 0.5 cm and most preferably withinless than about 2 mm from the ending. O 0053 Other features and advantages of the invention will O be apparent from the following detailed description and the O C Osln \ O claims. HN DETAILED DESCRIPTION O 0054 We have discovered that chlorinated amines, such as O NH chloramine, can be used to relieve pain and itch.

O Chlorinated Amines 0055. The methods, kits, and compositions of the inven 0048. By “musculoskeletal disorder is meant an immune tion can include one or more N-chloro amines. The term system-related disorder of the muscles, ligaments, bones, “N-chloroamine' is a generic term meaning N-monochloro joints, cartilage, or other connective tissue. Among the most compounds (e.g., Cl—NR, C1 NHR, chlorinated amine commonly-occurring musculoskeletal disorders are various bearing polymers, N-chloro amides, N-chloro ureas, and forms of arthritis, e.g., osteoarthritis, rheumatoid arthritis, N-chloro-sulfonamides). The term “N-dichloro amine' is a juvenile rheumatoid arthritis, and gout. Other musculoskel generic term meaning N-dichloro-compounds (e.g., Cl etal disorders include acquired hyperostosis syndrome, NR). The chlorinated amines of this disclosure are oxidants, acromegaly, ankylosing spondylitis, Behcet's disease, bone for example, of glutathione in vivo and are useful for the diseases, bursitis, cartilage diseases, chronic fatigue Syn treatment of pain and itch. The invention can be carried out drome, compartment syndromes, congenital hypothyroidism, using chlorinated simple amines, such as ammonia, methy congenital myopathies, dentigerous cyst, dermatomyositis, lamine, or ethylamine, oramines which in their unchlorinated diffuse idiopathic skeletal hyperostosis, Dupuytren’s con form have additional therapeutic utility. Such as an analgesic tracture, eosinophilia-myalgia syndrome, fasciitis, Felty's (e.g., N-chloro lidocaine, desethyl-N-chloro lidocaine, US 2008/028786.6 A1 Nov. 20, 2008

N-chloro prilocalne, N-chloro tocainide, desethyl-N-chloro and Chloramine-T. N-chloro-sulfonamides can be used in etidocaine, desbutyl-N-chloro ropivacaine, desbutyl-N- their un-ionized and anionic forms. When anionic, it can be chlorobupivacaine, desbutyl-N-chloro levobupivacaine, des the free anion, or a salt, such as a Li", Na', K", Ca", Mg", or methyl-N-chloro mepivacaine, desethyl-N-chloro procaine, Zn" salt. desethyl-N-chloro proparacaine, desethyl-N-chloro allocain, desmethyl-N-chloro encainide, desethyl-N-chloro procaina 0059 Chlorinated Amine Polymers mide, desethyl-N-chloro metoclopramide, desmethyl-N- 0060. The methods, kits, and compositions of the inven chloro stovaine, desethyl-N-chloro propoxycaine, desethyl tion can include one or more chlorinated amine-bearing poly N-chloro chloroprocaine, N-chloro flecainide, desethyl-N- mers. Exemplary chlorinated polymers which can be used in chloro tetracaine, N-chloro procaine, N-chloro proparacaine, the methods, kits, and compositions of the invention include, N-chloro procainamide, N-chlorometoclopramide, N-chloro without limitation, N-chlorinated chitosan, N-chlorinated propoxycaine. N-chloro chloroprocaine, N-chloro tetracaine, deacetylated hyaluronic acid, and N-chlorinated polylysine. N-chloro benzocaine. N-chloro butamben, and desethyl-N- N-chlorinated amine-bearing polymers can be prepared using chloro dibucaine); tricyclic antidepressant (e.g., N-chloro methods analogous to those described in U.S. Pat. No. 5,773, amoxapine, desmethyl-N-chloro trimipramine, desmethyl 608, incorporated herein by reference. N-chloro dothiepin, desmethyl-N-chloro doxepin, desm 0061 N-Dichloro Amines ethyl-N-chloro amitriptyline, N-chloro protriptyline, 0062. The methods, kits, and compositions of the inven N-chloro desipramine, desmethyl-N-chloro clomipramine, tion can include one or more N-dichloroamines. Exemplary desmethyl-N-chloro clozapine, desmethyl-N-chloro loxap N-chloro amines that can be used in the methods, kits, and ine, N-chloro nortriptyline, desmethyl-N-chloro cyclobenza compositions of the invention include, without limitation, prine, desmethyl-N-chloro cyproheptadine, desmethyl-N- dichloramine, N-dichloro methylamine, N-dichloro ethy chloro olopatadine, desmethyl-N-chloro promethazine, lamine, N-dichloro isobutylamine, N-dichloro-2-methylbu desmethyl-N-chloro trimeprazine, desmethyl-N-chloro chlo tylamine, N-dichlorophenethylamine, N-dichloro agnatine, rprothixene, desmethyl-N-chloro chlorpromazine, desm N-dichloro histamine, N-dichloro tryptamine, N-dichloro-3- ethyl-N-chloro propiomazine, desmethyl-N-chloro prochlo methylthiopropanamine, N-dichloro spermine, N-dichloro rperazine, desmethyl-N-chloro thiethylperazine, desmethyl carnosine, N-dichloro carcinine, N-dichloroglycine, N-chloro trifluoperazine, desethyl-N-chloro ethacizine, or N-dichloro alpha-aminoisobutyric acid, N-dichlorotaurine, desmethyl-N-chloro imipramine), or stimulant (e.g., N-dichlorotaurine ethyl ester, N-dichlorotaurine sulfona N-chloro amphetamine, N-dichloro amphetamine, or mide, N-dichloroalanine, N-dichloro beta-alanine, N-chloro methamphetamine). Other chlorinated amines that N-dichloro phenylalanine, N-dichloro norvaline, N-dichlo can be used in the methods, compositions, and kits of the roleucine, N-dichloro isoleucine, N-dichloroproline, invention are described below. N-dichloro omega aminoundecanoic acid, N-dichloroaspar 0056 N-Chloro Amines tic acid, N-dichloroglutamic acid, N-dichloroasparagine, 0057 Exemplary N-chloro amines that can be used in the N-dichlorovaline, N-dichloromethionine, N-dichloro methods, kits, and compositions of the invention include, glutamine, N-dichlorotryptophane, N-dichloroarginine, without limitation, chloramine, chlorourea, N-chloro methy N-dichlorolysine, N-dichloro alpha-aminobutyric acid, lamine, N-chloro ethylamine, N-chloro isobutylamine, N-dichloro gamma-aminobutyric acid, N-dichloro alpha, N-chloro-2-methylbutylamine, N-chloro pyrrolidine, epsilon diamino pimelic acid, and N-dichloro ornithine. N-chlorophenethylamine. N-chloro agnatine, N-chloro his 0063 Preparation of Chlorinated Amines tamine, N-chloro tryptamine, N-chloro-3-methylthiopropan 0064 Chlorinated amines can be prepared by the reaction amine, N-chlorospermine, N-chloro carnosine, N-chloro car of the amine with a chlorine source under reaction conditions cinine, chloramine T. chloramine B, N-chloro glutathione which lead to the replacement of one or two hydrogenatoms sulfonamide, N-chloroglycine, N-chlorosulfamic acid, at the amino nitrogen with chlorine atoms. Such reactions are N-chlorosarcosine, N-chloro alpha-aminoisobutyric acid, known to chemists skilled in the art. For example, the follow N-chlototaurine, N-chlorotaurine ethyl ester, N-chlorotau ing chlorine sources, without limitation, may be used to pro rine Sulfonamide, N-chloro-acetylglycine, N-chloroalanine, duce the N-dichloro amines: HOC1 or its salts (for example, N-chloro beta-alanine, N-chloro phenyl alanine, N-chloro NaOCl or KOCl). N-chloroarylsulfonamide salts (i.e., norvaline, N-chloroleucine, N-chloro isoleucine, N-chloro N-chloro-4-alkylbenzenesulfonamide); HClO3, N-chloro proline, N-chloro omega aminoundecanoic acid, N-chloroas Succinimide, Cl, thionylchloride, phosgene, PCls, PCls, and partic acid, N-chloroglutamic acid, N-chloroasparagine, related chlorinating agents. In a typical reaction, the amine is N-chlorovaline. N-chlorocystine, N-chloromethionine, dissolved in a lower alkanol (for example, methanol or etha N-chloroglutamine, N-chlorotryptophane, N-chlorohisti nol) and made acidic. To this solution an aqueous NaOCl dine, N-chloroarginine, N-chlorolysine. N-chloro alpha-ami solution is added. The reaction results in the chlorination of nobutyric acid, N-chloro gamma-aminobutyric acid, the amino group and the precipitation of sodium chloride. The N-chloro alpha, epsilon diamino pimelic acid, N-chloro orni Solvent is evaporated at low temperatures, for example, below thine, N-chloroanthranilic acid, N-chloro p-aminobenzoic 30° C. and a residue is obtained. The residue is taken up in a acid, N-chlorosulfanilic acid, N-chloro orthanilic acid, Solvent and the chlorinated amine isolated, for example, by N-chloro phenyl sulfamic acid, N-chloroaminopropane extraction with a solvent not miscible with the aqueous lower sulfonic acid, N-chloro aminomethane-sulfonic, N-chloro alkanol phase. The production of N-chloro versus N-dichloro glycylglycine, N-chloroglycylglycylglycine, N-chloro meta derivatives can be controlled by the relative stoichiometry the nilic acid, and N-chloro-N-Octodecanylglycine. amine and chlorinating agent. For additional experimental 0058 Exemplary N-chloro-sulfonamides that can be used protocols see, for example, Marcinkiewicz et al., J. of Inflam in the methods, kits, and compositions of the invention matory Research 49:280 (2000); Chinake et al., Phys. Chem. include, without limitation, N-chloro-GSA, Chloramine-B Chem. Phys. 3:4957 (2001); Martincigh et al., J. Phys. Chem. US 2008/028786.6 A1 Nov. 20, 2008

A. 102:9838 (1998), and U.S. Pat. No. 3,932,605, each of half-life, so that frequent dosing during a day is required in which is incorporated herein by reference. order to Sustain the plasma level at a therapeutic level. 0070. Many strategies can be pursued to obtain controlled Therapy and Formulation release in which the rate of release outweighs the rate of 0065. The agents of the invention, N-chloro amines and metabolism of the therapeutic compound. For example, con N-dichloroamines, may be administered by any appropriate trolled release can be obtained by the appropriate selection of route for treatment of pain or itch. These may be administered formulation parameters and ingredients, including, e.g., to humans, domestic pets, livestock, or other animals with a appropriate controlled release compositions and coatings. pharmaceutically acceptable diluent, carrier, or excipient, in Examples include single or multiple unit tablet or capsule unit dosage form. Administration may be topical, parenteral, compositions, oil solutions, Suspensions, emulsions, micro intravenous, intra-arterial, Subcutaneous, intramuscular, capsules, microspheres, nanoparticles, patches, and lipo intracranial, intraorbital, ophthalmic, intraventricular, intrac SOS. apsular, intraspinal, intracisternal, intraperitoneal, intranasal, 0071. Formulations for oral use include tablets containing aerosol, by Suppositories, or oral administration. the active ingredient(s) in a mixture with non-toxic pharma 0066. Therapeutic formulations may be in the form of ceutically acceptable excipients. These excipients may be, for liquid Solutions or Suspensions; for oral administration, for example, inert diluents or fillers (e.g., Sucrose and Sorbitol), mulations may be in the form of tablets or capsules; and for lubricating agents, glidants, and antiadhesives (e.g., magne intranasal formulations, in the form of powders, nasal drops, sium Stearate, Zinc Stearate, Stearic acid, silicas, hydrogenated ear drops, or aerosols. Vegetable oils, or talc). 0067 Methods well known in the art for making formula 0072. In accordance with the methods, kits, and composi tions are found, for example, in "Remington: The Science and tions of the invention, agents can be infused into a patient Practice of Pharmacy” (20th ed., ed. A. R. Gennaro, 2000, using an infusion pump system. For example, skin-adhered Lippincott Williams & Wilkins). Formulations for parenteral infusion delivery systems which can be used include, without administration may, for example, contain excipients, sterile limitation, the pump systems described in U.S. Pat. Nos. water, or saline, polyalkylene glycols such as polyethylene 7,303,549; 7,303,543; 7.300,419; 7,297,138; 7,144,384; glycol, oils of vegetable origin, or hydrogenated napthalenes. 7,070,580; 7,029.455; 7,018,360; 7,014,625; 6,960,192: Biocompatible, biodegradable lactide polymer, lactide/gly 6,830,558; 6,768,425; 6,749,587; 6,740,059; 6,702,779; collide copolymer, or polyoxyethylene-polyoxypropylene 6,699,218; 6,692.457; 6,669,669; 6,656,159; 6,656,158: copolymers may be used to control the release of the com 6,589,229; 6,520,938; 6,485,461; 6,475,196; 6,056,718 and pounds. Nanoparticulate formulations (e.g., biodegradable 5.997.501, each of which is incorporated herein by reference. nanoparticles, solid lipid nanoparticles, liposomes) may be Existing insulin infusion pumps can be used to deliver an used to control the biodistribution of the compounds. Other agent to a patient. Insulet Corporation of Bedford, Mass. potentially useful parenteral delivery systems include ethyl manufactures and sells OmniPod, a small, lightweight self ene-vinyl acetate copolymer particles, osmotic pumps, adhesive insulin pod that the user fills with insulin and wears implantable infusion systems, and liposomes. Formulations directly on the body for up to three days and then replaces. for inhalation may contain excipients, for example, lactose, or The OmniPod delivers precise, personalized doses of insulin may be acqueous solutions containing, for example, polyoxy into the body through a small subcutaneously inserted flex ethylene-9-lauryl ether, glycholate and deoxycholate, or may ible cannula. The company also sells a wireless, handheld be oily solutions for administration in the form of nasal drops, device that programs the OmniPod with the user's personal or as a gel. The concentration of the compound in the formu ized insulin delivery instructions, wirelessly monitors the lation will vary depending upon a number of factors, includ OmniPod's operation and incorporates a calibration device. ing the dosage of the drug to be administered, and the route of The insulin solution typically employed with these devices administration. can be replaced with an agent of the invention to deliver pain 0068. The agents may be optionally administered as a relief at the site of infusion. The dose-rate of agent is between pharmaceutically acceptable salt, Such as a non-toxic acid about 10 moles per hour and about 10 moles per hour, addition salts or metal complexes that are commonly used in preferably between about 10 moles per hour and about 10 the pharmaceutical industry. Examples of acid addition salts moles per hour. include organic acids such as acetic, lactic, pamoic, maleic, 0073. To relieve pain or itch a preferably aqueous solution citric, malic, ascorbic, succinic, benzoic, palmitic, Suberic, or a gel including an agent of the invention is applied topi salicylic, tartaric, methanesulfonic, toluenesulfonic, or trif cally, for example in a dressing. The concentration of the luoroacetic acids or the like; polymeric acids such as tannic agent in the Solution or gel of the dressing is generally higher acid, carboxymethyl cellulose, or the like; and inorganic acid than about 0.1 mMandless than about 0.1 M. Preferably, it is Such as hydrochloric acid, hydrobromic acid, Sulfuric acid higher than about 1 mM and is less than about 30 mM. Where phosphoric acid, or the like. Metal complexes include Zinc, the agent of the invention is gaseous, the dressing has a iron, and the like. flexible shell that reduces at least tenfold, preferably one 0069 Administration of compounds in controlled release hundred fold, the out diffusion of gases other than hydrogen, formulations is useful where the compound of formula I has for example of oxygen, chlorine, or chloramine. The shell can (i) a narrow therapeutic index (e.g., the difference between be adhered to the skin at its edges to form an adequately the plasma concentration leading to harmful side effects or gas-tight seal slowing the leakage of the Volatile agent. The toxic reactions and the plasma concentration leading to a shell can be made of a metallized, for example aluminized, therapeutic effect is Small; generally, the therapeutic index, plastic; or it can be made of a plastic through which gases TI, is defined as the ratio of median lethal dose (LDs) to permeate slowly, comprising, for example, polyvinylidene median effective dose (EDso)); (ii) a narrow absorption win chloride, used in SaranTM wrap to retard evaporation of water dow in the gastro-intestinal tract; or (iii) a short biological and other volatile components of food. US 2008/028786.6 A1 Nov. 20, 2008

0074. Where the agents of the invention have a short half sis, HIV, and polymyalgia rheumatica. The methods, compo life, the agent can be prepared just prior to administration. For sitions, and kits of the invention can be used to treat pain example, a dry powder including an ammonium salt, chlorate associated with any of a number of conditions, including back salt, and metal oxide can be mixed with water to produce an and neck pain, cancer pain, gynecological and labor pain, N-chloro amine just prior to use. fibromyalgia, arthritis and other rheumatological pains, 0075. In certain embodiments, the agents of the invention orthopedic pains, post herpetic neuralgia and other neuro are adsorbed onto dry carrier particles, such as particles of pathic pains, sickle cell crises, interstitial cystitis, urethritis talcum or Zinc oxide, for gradual release when applied topi and other urological pains, dental pain, headaches, postop cally. In general the weight percentage of the adsorbed agent erative pain, and procedural pain (i.e., pain associated with is at least about 0.01 wt % and is less than about 10 wt %; it is injections, draining an abcess, Surgery, dental procedures, preferably at least about 0.1 wt % and is less than about 2 wt opthalmic procedures, arthroscopies and use of other medical %. In general the weight percentage of the chemisorbed oxi instrumentation, cosmetic Surgical procedures, dermatologi dant is at least about 0.01 wt % and is less than about 10 wt %; cal procedures, setting fractures, biopsies, and the like). it is preferably at least about 0.1 wt % and is less than about 2 wt %. 0078 Pain and Function Indices 0076. The agents of the invention can also be delivered 0079. In order to measure the efficacy of any of the meth topically by iontophoresis. Iontophoresis is a needle-free, ods, compositions, or kits of the invention, a measurement non-invasive technology for delivering bioactive agents index may be used. Indices that are useful in the methods, through the skin using a small electric current to apply an compositions, and kits of the invention for the measurement electromotive force that transports ions through the stratum of pain associated with musculoskeletal, immunoinflamma corneum, the outermost layer of skin, and into the dermis, the tory and neuropathic disorders include a visual analog scale inner layer of skin that is comprised of connective tissue, (VAS), a Likert Scale, categorical pain scales, descriptors, the blood and lymph vessels, Sweat glands, hair follicles and an Lequesne index, the WOMAC index, and the AUSCAN elaborate sensory nerve network. index, each of which is well known in the art. Such indices may be used to measure pain, itch, function, stiffness, or other Indications variables. 0080 A visual analog scale (VAS) provides a measure of 0077. The methods, compositions, and kits of the inven a one-dimensional quantity. A VAS generally utilizes a rep tion are useful for treating pain, including clinical pain, resentation of distance. Such as a picture of a line with hash namely inflammatory pain, functional pain, nociceptive pain, marks drawn at regular distance intervals, e.g., ten 1-cm inter and neuropathic pain (e.g., peripheral neuropathic pain), vals. For example, a patient can be asked to rank a sensation whether acute or chronic (e.g., pain lasting for greater than of pain or itch by choosing the spot on the line that best one, two, three, four, or more months). Conditions that may corresponds to the sensation of pain or itch, where one end of be associated with pain include, for example, soft tissue, joint, the line corresponds to “no pain' (score of 0 cm) or “no itch' bone inflammation and/or damage (e.g., acute trauma, and the other end of the line corresponds to “unbearable pain' osteoarthritis, or rheumatoid arthritis), myofascial pain Syn or “unbearable itch' (score of 10 cm). This procedure pro dromes (fibromylagia), headaches (including cluster head vides a simple and rapid approach to obtaining quantitative ache, migraine and tension type headache), neurodegenera tive disorders (i.e., particularly those leading to nerve information about how the patient is experiencing pain or demyelination), Stump pain, myocardial infarction, angina, itch. VAS scales and their use are described, e.g., in U.S. Pat. ischemic cardiovascular disease, post-stroke pain, sickle cell Nos. 6,709,406 and 6,432,937. anemia, peripheral vascular occlusive disease, cancer, I0081. A Likert scale similarly provides a measure of a inflammatory conditions of the skin or joints, diabetic neur one-dimensional quantity. Generally, a Likert Scale has dis opathy, and acute tissue damage from Surgery or traumatic crete integer values ranging from a low value (e.g., 0, mean injury (e.g., lacerations or fractures). The present invention is ing no pain) to a high value (e.g., 7, meaning extreme pain). A also useful for the treatment, reduction, or prevention of mus patient experiencing pain is asked to choose a number culo-skeletal pain (after trauma or exercise), neuropathic pain between the low value and the high value to represent the caused by spinal cord injury, tumors, compression, inflam degree of pain experienced. Likert Scales and their use are mation, dental pain, episiotomy pain, deep and visceral pain described, e.g., in U.S. Pat. Nos. 6,623,040 and 6,766,319. (e.g., heart pain, bladder pain, or pelvic organ pain), muscle I0082. The Lequesne index and the Western Ontario and pain, eye pain, orofacial pain (e.g., odontalgia, trigeminal McMaster Universities (WOMAC) osteoarthritis index neuralgia, glossopharyngeal neuralgia), abdominal pain, assess pain, function, and stiffness in the knee and hip of OA gynecological pain (e.g., dysmenorrhea and labor pain), pain patients using self-administered questionnaires. Both knee associated with nerve and root damage due to trauma, com and hip are encompassed by the WOMAC, whereas there is pression, inflammation, toxic chemicals, metabolic disor one Lequesne questionnaire for the knee and a separate one ders, hereditary conditions, Vasculitis and autoimmune dis for the hip. These questionnaires are useful because they eases, central nervous system pain, Such as pain due to spinal contain more information content in comparison with VAS or cord or brain stem damage, cerebrovascular accidents, Likert. Both the WOMAC index and the Lequesne index tumors, infections, demyelinating diseases including mul questionnaires have been extensively validated in OA, includ tiple Sclerosis, chronic lower back pain (e.g., ankylosing ing in Surgical settings (e.g., knee and hip arthroplasty). Their spondylitis, degenerative disk disease, radiculopathy, and metric characteristics do not differ significantly. radicular pain), Sciatica, chronic neck pain, and post-opera I0083. The AUSCAN (Australian-Canadian hand arthritis) tive pain (e.g., mastectomy, orthopedic and phantom limb index employs a valid, reliable, and responsive patient self pain). The present invention is also useful for treating pain reported questionnaire. In one instance, this questionnaire associated with post-herpetic neuralgia, cancer, cystic fibro contains 15 questions within three dimensions (Pain, 5 ques US 2008/028786.6 A1 Nov. 20, 2008

tions; Stiffness, 1 question; and Physical function, 9 ques wounds on the skin of the lower leg of an adult subject related tions). An AUSCAN index may utilize, e.g., a Likert or a VAS to the inventor. The itching was relieved for about 4 hours. scale. 0084 Indices that are useful in the methods, compositions, Example 5 and kits of the invention for the measurement of pain include the Pain Descriptor Scale (PDS), the Visual Analog Scale Reduced Heat Sensitivity (VAS), the Verbal Descriptor Scales (VDS), the Numeric Pain 0091 To assess heat sensitivity, boiling water was poured Intensity Scale (NPIS), the Neuropathic Pain Scale (NPS), into glasses and the inventor and an adult Subject related to the the Neuropathic Pain Symptom Inventory (NPSI), the Present inventor monitored the period for which they could tolerate Pain Inventory (PPI), the Geriatric Pain Measure (GPM), the pressing their chloramine-solution treated finger against the McGill Pain Questionnaire (MPQ), mean pain intensity (De cup. They immersed their left index finger in the chloramine scriptor Differential Scale), numeric pain scale (NPS) global Solution, prepared as described in Example 1, now at ambient evaluation score (GES) the Short-Form McGill Pain Ques temperature, and their right index fingers into a tap water tionnaire, the Minnesota Multiphasic Personality Inventory, Solution for 15 minutes then pressed their fingers against the the Pain Profile and Multidimensional Pain Inventory, the hot cups. They were able to press their chloramine-solution Child Heath Questionnaire, and the Child Assessment Ques treated fingers considerably longer, typically for periods tionnaire. between about 1.5 times and twice as long as they could press 0085 Itch can be measured by subjective measures (VAS, their tap-water treated fingers. Lickert, descriptors). Another approach is to measure scratch which is an objective correlate of itch using a vibration trans Example 6 ducer or movement-sensitive meters. Painful Blisters I0086. The following examples are intended to illustrate the invention, and is not intended to limit it. 0092 An adult subject presented with painful blisters of unknown origin on the little finger of her left hand. The EXAMPLES Subject had a history of diagnosed eczema on her face and undiagnosed but likely eczema on her hands. In previous Example 1 Suspected eczema episodes on her hands blisters have Preparation of a Chloramine Containing Solution formed, but more generally on the hands and never in a cluster such as this. Prior to treatment, the whole fingertip hurt and 0087. A solution of 0.15 Mammonium chloride was pre throbbed, and the joint was painful to bend due to pressure on pared and its pH was adjusted with concentrated ammonia the blisters. and with concentrated hydrochloric acid to about 7.4. The 0093. Fresh chloramine Solution was prepared as solution was chilled to 4°C. A second solution was prepared described in Example 1. by adjusting the pH of the 10-13 weight% sodium hypochlo 0094. In a first test, the subject dipped her finger into a cold rite solution (Sigma Aldrich, Milwaukee, Wis., Catalog chloramine solution for 10 minutes and reported immediate #425044) to about 7.4 with concentrated hydrochloric acid. pain relief, absence of throbbing and the ability to bend the 10 mL of the about 1.5 M hypochlorite-hypochlorous acid joint without pain. When she touched the blisters directly solution was added promptly after adjusting its pH to 100 mL there was a feeling of “pressure.” but not pain. The effect of the stirred and chilled first solution of 0.15 Mammonium lasted for about two hours and the pain had fully returned after chloride. The resulting solution was kept refrigerated until it three hours. was used. 0095. In a second test, very cold water was substituted for the chloramine solution. The subject dipped her finger into Example 2 the water for ten minutes and reported that the blisters were Relief of Pain by Topical Application still “quite painful' to the touch. 0096. In a third test, the original chloramine solution was I0088. About 20 mL of the solution of Example 1 were applied again and the Subject again reported pain relief. poured onto absorbent paper towel and the wet towel was held for 10 min at a pain-causing wound in the skin of a finger of Other Embodiments the inventor. The topical application of the wet paper towel 0097 All publications, patents, and patent applications caused mild, not unpleasant, local numbness and completely mentioned in this specification are herein incorporated by relieved the pain. After about 20 minutes there was neither reference to the same extent as if each independent publica numbness nor pain. tion or patent application was specifically and individually Example 3 indicated to be incorporated by reference. 0098. While the invention has been described in connec Relief of Pain by Topical Application tion with specific embodiments thereof, it will be understood that it is capable of further modifications and this application 0089. As in Example 2, except that the site of pain was is intended to cover any variations, uses, or adaptations of the near the fingernail of an adult subject related to the inventor. invention following, in general, the principles of the invention and including Such departures from the present disclosure Example 4 that come within known or customary practice within the art Relief of Itching by Topical Application to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the 0090. As in Example 1, except that the wet paper towel Scope of the claims. was held against a Zone of multiple, Small, red, itching, scab 0099. Other embodiments are within the claims. US 2008/028786.6 A1 Nov. 20, 2008

What is claimed is: N-dichloro norvaline, N-dichloroleucine, N-dichloro isoleu 1. A method of treating pain in a patient in need thereof, cine, N-dichloroproline, N-dichloro omega aminounde said method comprising topically administering to said canoic acid, N-dichloroaspartic acid, N-dichloroglutamic patient an agent selected from N-chloro amines and acid, N-dichloroasparagine, N-dichlorovaline, N-dichlo N-dichloroamines in an amount Sufficient to treat said pain. romethionine, N-dichloroglutamine, N-dichlorotryptophane, 2. A method of treating pain at a site in a patient in need N-dichloroarginine, N-dichlorolysine, N-dichloro alpha thereof, said method comprising locally injecting at said site aminobutyric acid, N-dichloro gamma-aminobutyric acid, an agent selected from N-chloro amines and N-dichloro N-dichloro alpha, epsilon diamino pimelic acid, N-dichloro amines in an amount Sufficient to treat said pain. ornithine, and pharmaceutically acceptable salts, esters, and 3. A method of treating pain in a patient in need thereof, amides thereof. said method comprising administering to said patient an 8. The method of any of claims 1, 3, or 5, wherein said agent selected from N-chloroamines and N-dichloro amines agent is a chlorinated analgesic, chlorinated tricyclic antide in an amount Sufficient to treat said pain, wherein said pain is pressant, chlorinated Stimulant, or a polymer bearing nociceptive pain, Somatic pain, visceral pain, procedural pain, N-chloroamine groups. or inflammatory pain caused by trauma, Surgery, or an 9. The method of claim 8, wherein said agent is a chlori autoimmune disease. nated analgesic selected from N-chloro lidocaine, desethyl 4. The method of claim 3, wherein said pain is caused by N-chloro lidocaine, N-chloroprilocaine, N-chlorotocainide, trauma, Surgery, herniation of an intervertebral disk, spinal desethyl-N-chloro etidocaine, desbutyl-N-chloro ropiv cord injury, shingles, HIV/AIDS, cancer related pain, ampu acaine, desbutyl-N-chloro bupivacaine, desbutyl-N-chloro tation, neurodegenerative disorders, carpal tunnel syndrome, levobupivacaine, desmethyl-N-chloro mepivacaine, des diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or ethyl-N-chloro procaine, desethyl-N-chloro proparacaine, a musculoskeletal disorder. desethyl-N-chloro allocain, desmethyl-N-chloro encainide, 5. A method of treating itch inapatient in need thereof, said desethyl-N-chloro procainamide, desethyl-N-chloro meto method comprising topically administering to said patient an clopramide, desmethyl-N-chloro stovaine, desethyl-N- agent selected from N-chloroamines and N-dichloro amines chloro propoxycaine, desethyl-N-chloro chloroprocaine, in an amount Sufficient to treat said itch. N-chloro flecainide, desethyl-N-chloro tetracaine, N-chloro 6. The method of any of claims 1, 3, or 5, wherein said procaine, N-chloro proparacaine, N-chloro procainamide, agent is administered locally at the site of pain or itch. N-chlorometoclopramide, N-chloro propoxycaine, N-chloro 7. The method of any of claims 1, 3, or 5, wherein said chloroprocaine, N-chloro tetracaine. N-chloro benzocaine, agent is selected from chloramine, chlorourea, N-chloro N-chlorobutamben, and desethyl-N-chloro dibucaine. methylamine, N-chloroethylamine, N-chloro isobutylamine, 10. The method of claim 8, wherein said agent is a chlori N-chloro-2-methylbutylamine, N-chloro pyrrolidine, nated tricyclic antidepressant selected from N-chloro amox N-chlorophenethylamine. N-chloro agnatine, N-chloro his apine, desmethyl-N-chloro trimipramine, desmethyl-N- tamine, N-chloro tryptamine, N-chloro-3-methylthiopropan chloro dothiepin, desmethyl-N-chloro doxepin, desmethyl amine, N-chlorospermine, N-chloro carnosine, N-chloro car N-chloro amitriptyline, N-chloro protriptyline. N-chloro cinine, chloramine T. chloramine B, N-chloro glutathione desipramine, desmethyl-N-chloro clomipramine, desmethyl sulfonamide, N-chloroglycine, N-chlorosulfamic acid, N-chloro clozapine, desmethyl-N-chloroloxapine, N-chloro N-chlorosarcosine, N-chloro alpha-aminoisobutyric acid, nortriptyline, desmethyl-N-chloro cyclobenzaprine, desm N-chlorotaurine, N-chlorotaurine ethyl ester, N-chlorotau ethyl-N-chloro cyproheptadine, desmethyl-N-chloro olo rine Sulfonamide, N-chloro-acetylglycine, N-chloroalanine, patadine, desmethyl-N-chloro promethazine, desmethyl-N- N-chloro beta-alanine, N-chloro phenyl alanine, N-chloro chloro trimeprazine, desmethyl-N-chloro chlorprothixene, norvaline, N-chloroleucine, N-chloro isoleucine, N-chloro desmethyl-N-chloro chlorpromazine, desmethyl-N-chloro proline, N-chloro omega aminoundecanoic acid, N-chloroas propiomazine, desmethyl-N-chloro prochlorperazine, desm partic acid, N-chloroglutamic acid, N-chloroasparagine, ethyl-N-chloro thiethylperazine, desmethyl-N-chloro triflu N-chlorovaline. N-chlorocystine, N-chloromethionine, operazine, desethyl-N-chloro ethacizine, and desmethyl-N- N-chloroglutamine, N-chlorotryptophane, N-chlorohisti chloro imipramine. dine, N-chloroarginine, N-chlorolysine. N-chloro alpha-ami 11. The method of claim 8, wherein said agent is a chlori nobutyric acid, N-chloro gamma-aminobutyric acid, nated Stimulant selected from N-chloro amphetamine, N-chloro alpha, epsilon diamino pimelic acid, N-chloro orni N-dichloro amphetamine, and N-chloro methamphetamine. thine, N-chloroanthranilic acid, N-chloro p-aminobenzoic 12. The method of claim 8, wherein said agent is a polymer acid, N-chlorosulfanilic acid, N-chloro orthanilic acid, selected from N-chlorinated chitosan, N-chlorinated deacety N-chloro phenyl sulfamic acid, N-chloroaminopropane lated hyaluronic acid, and N-chlorinated polylysine. sulfonic acid, N-chloro aminomethane-sulfonic, N-chloro glycylglycine, N-chloroglycylglycylglycine, N-chloro meta 13. The method of any of claims 1, 3, or 5, wherein said nilic acid, N-chloro-N-Octodecanyl glycine, dichloramine, agent is selected from chloramine, dichloramine, N-chloro N-dichloro methylamine, N-dichloroethylamine, N-dichloro taurine, N-dichloro taurine, N-chloro desmethylchlorprom isobutylamine, N-dichloro-2-methylbutylamine, N-dichloro azine, N-chloro lidocaine, N-chloro amphetamine, phenethylamine, N-dichloro agnatine, N-dichloro hista N-dichloro amphetamine, and N-chloro methamphetamine. mine, N-dichloro tryptamine, N-dichloro-3-methylthiopro 14. The method of claim 1 or 3, wherein said patient expe panamine, N-dichloro spermine, N-dichloro carnosine, riences some pain relief within 20 minutes of administering N-dichloro carcinine, N-dichloroglycine, N-dichloro alpha said agent. aminoisobutyric acid, N-dichlorotaurine, N-dichlorotaurine 15. The method of claim 5, wherein said patient experi ethyl ester, N-dichlorotaurine sulfonamide, N-dichloroala ences some relief from itch within 20 minutes of administer nine, N-dichloro beta-alanine, N-dichloro phenyl alanine, ing said agent. US 2008/028786.6 A1 Nov. 20, 2008

16. The method of claim 1 or 3, with the proviso that said N-dichloro methylamine, N-dichloroethylamine, N-dichloro pain does not result from an infection in said patient. isobutylamine, N-dichloro-2-methylbutylamine, N-dichloro 17. A kit comprising (i) a composition comprising an agent phenethylamine, N-dichloro agnatine, N-dichloro hista selected from N-chloro amines and N-dichloro amines in an mine, N-dichloro tryptamine, N-dichloro-3-methylthiopro amount Sufficient to treat pain when administered to a patient, panamine, N-dichloro spermine, N-dichloro carnosine, and (ii) instructions for topically administering said compo N-dichloro carcinine, N-dichloroglycine, N-dichloro alpha sition to a patient for the treatment of pain. aminoisobutyric acid, N-dichlorotaurine, N-dichlorotaurine 18. The kit of claim 17, wherein said composition is for ethyl ester, N-dichlorotaurine sulfonamide, N-dichloroala mulated for topical administration. nine, N-dichloro beta-alanine, N-dichloro phenyl alanine, 19. The kit of claim 18, wherein said composition is for N-dichloro norvaline, N-dichloroleucine, N-dichloro isoleu mulated as a cream, lotion, spray, Stick, iontophoresis Solu cine, N-dichloroproline, N-dichloro omega aminounde tion, or ointment. canoic acid, N-dichloroaspartic acid, N-dichloroglutamic 20. Akit comprising (i) a composition formulated for injec acid, N-dichloroasparagine, N-dichlorovaline, N-dichlo tion and comprising an agent selected from N-chloroamines romethionine, N-dichloroglutamine, N-dichlorotryptophane, and N-dichloro amines in an amount Sufficient to treat pain N-dichloroarginine, N-dichlorolysine, N-dichloro alpha when administered to a patient, and (ii) instructions for aminobutyric acid, N-dichloro gamma-aminobutyric acid, locally injecting said composition at a site of a patient for the N-dichloro alpha, epsilon diamino pimelic acid, N-dichloro treatment of pain. ornithine, and pharmaceutically acceptable salts, esters, and 21. A kit comprising (i) a composition comprising an agent amides thereof. selected from N-chloro amines and N-dichloro amines in an 25. The kit of any of claims 17, 20, 21, or 23, wherein said amount Sufficient to treat pain when administered to a patient, agent is a chlorinated analgesic, chlorinated tricyclic antide and (ii) instructions for administering said composition to a pressant, chlorinated Stimulant, or a polymer bearing patient for the treatment of nociceptive pain, Somatic pain, N-chloroamine groups. visceral pain, procedural pain, or inflammatory pain caused 26. The kit of claim 25, wherein said agent is a chlorinated by trauma, Surgery, or an autoimmune disease. analgesic selected from N-chloro lidocaine, desethyl-N- 22. The kit of claim 21, further comprising instructions for chloro lidocaine, N-chloro prilocalne, N-chloro tocainide, administering said composition to a patient Suffering from desethyl-N-chloro etidocaine, desbutyl-N-chloro ropiv pain caused by trauma, Surgery, herniation of an interverte acaine, desbutyl-N-chloro bupivacaine, desbutyl-N-chloro bral disk, spinal cord injury, shingles, HIV/AIDS, cancer levobupivacaine, desmethyl-N-chloro mepivacaine, des related pain, amputation, neurodegenerative disorders, carpal ethyl-N-chloro procaine, desethyl-N-chloro proparacaine, tunnel syndrome, diabetic neuropathy, postherpetic neural desethyl-N-chloro allocain, desmethyl-N-chloro encainide, gia, fibromyalgia, or a musculoskeletal disorder. desethyl-N-chloro procainamide, desethyl-N-chloro meto 23. Akit comprising (i) a composition comprising an agent clopramide, desmethyl-N-chloro stovaine, desethyl-N- selected from N-chloro amines and N-dichloro amines in an chloro propoxycaine, desethyl-N-chloro chloroprocaine, amount Sufficient to treat itch when administered to a patient, N-chloro flecainide, desethyl-N-chloro tetracaine, N-chloro and (ii) instructions for topically administering said compo procaine, N-chloro proparacaine, N-chloro procainamide, sition to a patient for the treatment of itch. N-chlorometoclopramide, N-chloro propoxycaine, N-chloro 24. The kit of any of claims 17, 20, 21, or 23, wherein said chloroprocaine, N-chloro tetracaine. N-chloro benzocaine, agent is selected from chloramine, chlorourea, N-chloro N-chlorobutamben, and desethyl-N-chloro dibucaine. methylamine, N-chloroethylamine, N-chloro isobutylamine, 27. The kit of claim 25, wherein said agent is a chlorinated N-chloro-2-methylbutylamine, N-chloro pyrrolidine, tricyclic antidepressant selected from N-chloro amoxapine, N-chlorophenethylamine. N-chloro agnatine, N-chloro his desmethyl-N-chloro trimipramine, desmethyl-N-chloro tamine, N-chloro tryptamine, N-chloro-3-methylthiopropan dothiepin, desmethyl-N-chloro doxepin, desmethyl-N- amine, N-chlorospermine, N-chloro carnosine, N-chloro car chloro amitriptyline, N-chloro protriptyline, N-chloro cinine, chloramine T. chloramine B, N-chloro glutathione desipramine, desmethyl-N-chloro clomipramine, desmethyl sulfonamide, N-chloroglycine, N-chlorosulfamic acid, N-chloro clozapine, desmethyl-N-chloroloxapine, N-chloro N-chlorosarcosine, N-chloro alpha-aminoisobutyric acid, nortriptyline, desmethyl-N-chloro cyclobenzaprine, desm N-chlorotaurine, N-chlorotaurine ethyl ester, N-chlorotau ethyl-N-chloro cyproheptadine, desmethyl-N-chloro olo rine Sulfonamide, N-chloro-acetylglycine, N-chloroalanine, patadine, desmethyl-N-chloro promethazine, desmethyl-N- N-chloro beta-alanine, N-chloro phenyl alanine, N-chloro chloro trimeprazine, desmethyl-N-chloro chlorprothixene, norvaline, N-chloroleucine, N-chloro isoleucine, N-chloro desmethyl-N-chloro chlorpromazine, desmethyl-N-chloro proline, N-chloro omega aminoundecanoic acid, N-chloroas propiomazine, desmethyl-N-chloro prochlorperazine, desm partic acid, N-chloroglutamic acid, N-chloroasparagine, ethyl-N-chloro thiethylperazine, desmethyl-N-chloro triflu N-chlorovaline. N-chlorocystine, N-chloromethionine, operazine, desethyl-N-chloro ethacizine, and desmethyl-N- N-chloroglutamine, N-chlorotryptophane, N-chlorohisti chloro imipramine. dine, N-chloroarginine, N-chlorolysine. N-chloro alpha-ami 28. The kit of claim 25, wherein said agent is a chlorinated nobutyric acid, N-chloro gamma-aminobutyric acid, stimulant selected from N-chloro amphetamine, N-dichloro N-chloro alpha, epsilon diamino pimelic acid, N-chloro orni amphetamine, and N-chloro methamphetamine. thine, N-chloroanthranilic acid, N-chloro p-aminobenzoic 29. The kit of claim 25, wherein said agent is a polymer acid, N-chlorosulfanilic acid, N-chloro orthanilic acid, selected from N-chlorinated chitosan, N-chlorinated deacety N-chloro phenyl sulfamic acid, N-chloroaminopropane lated hyaluronic acid, and N-chlorinated polylysine. sulfonic acid, N-chloro aminomethane-sulfonic, N-chloro 30. The kit of any of claims 17, 20, 21, or 23, wherein said glycylglycine, N-chloroglycylglycylglycine, N-chloro meta agent is selected from chloramine, dichloramine, N-chloro nilic acid, N-chloro-N-Octodecanyl glycine, dichloramine, taurine, N-dichloro taurine, N-chloro desmethylchlorprom US 2008/028786.6 A1 Nov. 20, 2008

azine, N-chloro lidocaine, N-chloro amphetamine, 37. The bandage of claim 35, wherein said agent is a N-dichloro amphetamine, and N-chloro methamphetamine. chlorinated analgesic, chlorinated tricyclic antidepressant, 31. A kit comprising (i) an inorganic oxide, (ii) an ammo chlorinated Stimulant, or a polymer bearing N-chloro amine nium salt, (iii) a hypochlorite salt, (iv) instructions for con groups. 38. The bandage of claim 37, wherein said agent is a tacting said inorganic oxide, said ammonium salt, and said chlorinated analgesic selected from N-chloro lidocaine, des hypochlorite salt with water to form a solution, and (v) ethyl-N-chloro lidocaine, N-chloro prilocalne, N-chloro instructions for administering said solution to a patient for the tocainide, desethyl-N-chloroetidocaine, desbutyl-N-chloro treatment of pain or itch. ropivacaine, desbutyl-N-chloro bupivacaine, desbutyl-N- 32. The kit of claim 31, further comprising a buffer. chloro levobupivacaine, desmethyl-N-chloro mepivacaine, 33. The kit of claim 31, further comprising instructions for desethyl-N-chloro procaine, desethyl-N-chloro propara topically administering said solution into a patient for the caine, desethyl-N-chloro allocain, desmethyl-N-chloro treatment of pain or itch. encainide, desethyl-N-chloro procainamide, desethyl-N- 34. The kit of claim 31, further comprising instructions for chloro metoclopramide, desmethyl-N-chloro stovaine, des infusing said solution into a patient at a site of pain. ethyl-N-chloro propoxycaine, desethyl-N-chloro chlorop rocaine, N-chloro flecainide, desethyl-N-chloro tetracaine, 35. Abandage comprising an agent selected from N-chloro N-chloro procaine, N-chloro proparacaine, N-chloro amines and N-dichloro amines in an amount Sufficient to treat procainamide, N-chloro metoclopramide, N-chloro pro pain or itch when applied to the skin of a patient. poxycaine, N-chloro chloroprocaine, N-chloro tetracaine, 36. The bandage of claim35, wherein said agent is selected N-chloro benzocaine, N-chloro butamben, and desethyl-N- from chloramine, chlorourea, N-chloro methylamine, chloro dibucaine. N-chloro ethylamine, N-chloro isobutylamine, N-chloro-2- 39. The bandage of claim 37, wherein said agent is a methylbutylamine, N-chloropyrrolidine, N-chlorophenethy chlorinated tricyclic antidepressant selected from N-chloro lamine, N-chloro agnatine, N-chloro histamine, N-chloro amoxapine, desmethyl-N-chloro trimipramine, desmethyl tryptamine. N-chloro-3-methylthiopropanamine, N-chloro N-chloro dothiepin, desmethyl-N-chloro doxepin, desm spermine, N-chloro carnosine, N-chloro carcinine, chloram ethyl-N-chloro amitriptyline, N-chloro protriptyline, ine T. chloramine B, N-chloro glutathione sulfonamide, N-chloro desipramine, desmethyl-N-chloro clomipramine, N-chloroglycine, N-chlorosulfamic acid, N-chlorosarcosine, desmethyl-N-chloro clozapine, desmethyl-N-chloro loxap N-chloro alpha-aminoisobutyric acid, N-chlorotaurine, ine, N-chloro nortriptyline, desmethyl-N-chloro cyclobenza N-chlorotaurine ethyl ester, N-chlorotaurine sulfonamide, prine, desmethyl-N-chloro cyproheptadine, desmethyl-N- N-chloro-acetylglycine, N-chloroalanine, N-chlorobeta-ala chloro olopatadine, desmethyl-N-chloro promethazine, nine, N-chloro phenylalanine, N-chloro norvaline, N-chlo desmethyl-N-chloro trimeprazine, desmethyl-N-chloro chlo roleucine, N-chloro isoleucine, N-chloroproline, N-chloro rprothixene, desmethyl-N-chloro chlorpromazine, desm omega aminoundecanoic acid, N-chloroaspartic acid, ethyl-N-chloro propiomazine, desmethyl-N-chloro prochlo N-chloroglutamic acid, N-chloroasparagine, N-chlorovaline, rperazine, desmethyl-N-chloro thiethylperazine, desmethyl N-chlorocystine, N-chloromethionine, N-chloroglutamine, N-chloro trifluoperazine, desethyl-N-chloro ethacizine, and N-chlorotryptophane, N-chlorohistidine, N-chloroarginine, desmethyl-N-chloro imipramine. N-chlorolysine, N-chloro alpha-aminobutyric acid, N-chloro gamma-aminobutyric acid, N-chloro alpha, epsilon diamino 40. The bandage of claim 37, wherein said agent is a pimelic acid, N-chloro ornithine, N-chloroanthranilic acid, chlorinated stimulant selected from N-chloro amphetamine, N-chloro p-aminobenzoic acid, N-chlorosulfanilic acid, N-dichloro amphetamine, and N-chloro methamphetamine. N-chloro orthanilic acid, N-chloro phenyl sulfamic acid, 41. The bandage of claim 37, wherein said agent is a N-chloroaminopropanesulfonic acid, N-chloro ami polymer selected from N-chlorinated chitosan, N-chlorinated nomethane-Sulfonic, N-chloro glycylglycine, N-chloro gly deacetylated hyaluronic acid, and N-chlorinated polylysine. cylglycylglycine, N-chloro metanilic acid, N-chloro-N-octo 42. The bandage of claim35, wherein said agent is selected decanyl glycine, dichloramine, N-dichloro methylamine, from chloramine, dichloramine, N-chlorotaurine, N-dichloro N-dichloro ethylamine, N-dichloro isobutylamine, taurine, N-chloro desmethylchlorpromazine, N-chloro N-dichloro-2-methylbutylamine, N-dichloro phenethy lidocaine, N-chloro amphetamine, N-dichloro amphetamine, lamine, N-dichloro agnatine, N-dichloro histamine, and N-chloro methamphetamine. N-dichloro tryptamine, N-dichloro-3-methylthiopropan 43. The bandage of claim 35, wherein a patient experiences amine, N-dichloro spermine, N-dichloro carnosine, some relief from pain or itch within 20 minutes of applying N-dichloro carcinine, N-dichloroglycine, N-dichloro alpha said bandage to the skin of said patient. aminoisobutyric acid, N-dichlorotaurine, N-dichlorotaurine 44. An infusion device comprising: ethyl ester, N-dichlorotaurine sulfonamide, N-dichloroala (i) a first reservoir containing a first solution comprising an nine, N-dichloro beta-alanine, N-dichloro phenyl alanine, ammonium salt or an amine or a salt thereof; N-dichloro norvaline, N-dichloroleucine, N-dichloro isoleu (ii) a second reservoir containing a second solution com cine, N-dichloroproline, N-dichloro omega aminounde prising hypochlorous acid or a salt thereof; canoic acid, N-dichloroaspartic acid, N-dichloroglutamic (iii) a mixing chamber for combining said first solution and acid, N-dichloroasparagine, N-dichlorovaline, N-dichlo said second solution to form a chlorinated amine; and romethionine, N-dichloroglutamine, N-dichlorotryptophane, (iv) a cannula in fluid communication with said mixer N-dichloroarginine, N-dichlorolysine, N-dichloro alpha chamber for delivering said N-chloroamine to a subject. aminobutyric acid, N-dichloro gamma-aminobutyric acid, 45. An infusion device comprising: N-dichloro alpha, epsilon diamino pimelic acid, N-dichloro (i) a reservoir containing a first solution comprising an ornithine, and pharmaceutically acceptable salts, esters, and ammonium chloride Salt and/or an amine and chloride amides thereof. 1On; US 2008/028786.6 A1 Nov. 20, 2008 12

(ii) a power source electrically connected to an electrode in (iii) a power source electrically connected to an electrode contact with said solution and configured to produce in contact with said second solution and configured to N-chloro amine via electrolysis; and produce hypochlorous acid or a salt thereof via elec (iii) a cannula in fluid communication with said solution trolysis; for delivering said N-chloro amine to a subject. (iv) a mixing chamber for combining said first solution and said hypochlorous acid or a salt thereof to form an 46. An infusion device comprising: N-chloro amine; and (i) a first reservoir containing a first solution comprising an (v) a cannula in fluid communication with said mixing amine or a salt thereof. chamber for delivering said N-chloroamine to a subject. (ii) a second reservoir containing a second solution com prising a chloride ions; c c c c c