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WO1999040907A1 - Procedes d'apport regule de disulfure de carbone dans le traitement d'etats inflammatoires - Google Patents

Procedes d'apport regule de disulfure de carbone dans le traitement d'etats inflammatoires Download PDF

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Publication number
WO1999040907A1
WO1999040907A1 PCT/US1999/002679 US9902679W WO9940907A1 WO 1999040907 A1 WO1999040907 A1 WO 1999040907A1 US 9902679 W US9902679 W US 9902679W WO 9940907 A1 WO9940907 A1 WO 9940907A1
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WIPO (PCT)
Prior art keywords
inhibitors
substituted
dithiocarbamate
antagonists
carbon disulfide
Prior art date
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PCT/US1999/002679
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English (en)
Inventor
Ching-San Lai
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Medinox, Inc.
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Publication date
Application filed by Medinox, Inc. filed Critical Medinox, Inc.
Priority to AU26628/99A priority Critical patent/AU2662899A/en
Publication of WO1999040907A1 publication Critical patent/WO1999040907A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods for the treatment of inflammatory conditions and compositions useful therefor.
  • methods are provided for simultaneously treating a pathological condition with a pharmacologically active agent and an adjuvant which prolongs the circulating lifetime thereof.
  • Carbon disulfide (CS 2 ) is a chemical component of dithiocarbamates.
  • dithiocarbamates a number of clinical applications of dithiocarbamates have been reported in the published literature.
  • diethyldithiocarbamate a metal chelator
  • Dithiocarb i.e., diethyldithiocarbamate
  • has also been used for the treatment of HIV patients see, for example, Reisinger, E. C.
  • the safe exposure levels of CS 2 permitted by regulation have been determined to be in the range of 10-20 ppm (about 4-8 ⁇ M in the air; see, for example, Price, B., et al., supra and Reinhardt, F., et al., supra).
  • the LD 50 values for CS 2 in 20-day-old rats and 1-day-old rats have been estimated to be 1.55 grams/kg and 0.58 grams/kg, respectively (see, for example, Green and Hunter, in Toxicol. Appl. Pharmacol., 78:130-8 (1985)).
  • CS 2 is known to react with amino- or sulfhydryl groups of protein molecules (see, for example, Valentine, W. M. et al., in Chem. Res. Toxicol., 8:96-102 (1995)) .
  • Conjugation of CS 2 and glutathione forms 2-thiothiazolidine carboxylic acid (TTCA) ; the latter product can be quantitated by chromatographic methods .
  • TTCA 2-thiothiazolidine carboxylic acid
  • the levels of TTCA detected in the urine seem to correlate with the in vivo level of CS 2 (see, for example, Simon and Nicot, in J. Chromatograpy, 620:47-53 (1993)).
  • Dithiocarbamates are known to be unstable in acidic media, especially when the pH falls below 7 (see, for example, Martens, T., et al . , in J. Pharmaceut Sciences 82:379-383 (1993)).
  • the decomposition of dithiocarbamates seems to proceed via a hydrogen ion-catalyzed reaction.
  • diethyldithiocarbamate is rapidly decomposed to ethylamine and carbon disulfide with no evidence of toxic hydrogen sulfide production (see, for example, Martens, T., et al . , supra) .
  • dithiocarbamate derivatives were found to be protective against carbon tetrachloride (CC1 4 ) -induced liver injury (see, for example, Sakaguchi, H. et al . , in Biochem. Pharmac . , 15:756 (1966)).
  • This protective action of dithiocarbamates was later attributed to CS 2 , especially in the case of oral administration of dithiocarbamate, wherein CS 2 is released upon acid hydrolysis in the stomach
  • NFKB nuclear factor kappaB
  • NSAID e.g., aspirin, ibuprofen and ketoprofen
  • CS 2 is capable of directly inhibiting the activity of NFKB, without the need for any other active agents to be present. It is assumed, therefor, that the inhibitory effect of, for example, pyrrolidine dithiocarbamate and other dithiocarbamates on NFKB may simply be attributed to CS 2 released upon in vivo hydrolysis of dithiocarbamates rather than as a result of the action of the parental compound per se. Dithiocarbamates may therefore be considered as pro-drugs for CS 2 for the treatment of inflammatory conditions mediated via NFKB pathways .
  • Figure 1 collectively presents uv-visible spectra of N-methyl-D-glucamine dithiocarbamate (MGD) under different pH conditions.
  • MGD N-methyl-D-glucamine dithiocarbamate
  • Figure 1A pH 7.4
  • Figure IB pH 4.0
  • Uv- visible spectra were recorded with a Hewlett-Packard Diode Array Spectrophotometer.
  • Both the 258 nm and 286 nm peaks of MGD which are prominent at pH 7.4, disappeared at pH 4.0, indicative of the cleavage of the amide bond of MGD at acidic pH.
  • the 196 nm peak is assigned to carbon disulfide.
  • Figure 2 presents a plot of uninjected footpad severity scores versus time for L-proline dithiocarbamate treatment of adjuvant-induced arthritic rats.
  • the rats were separated into two groups (18 animals in each group) .
  • One group received an oral administration of L-proline dithiocarbamate in drinking water at lib (10 mg/ml) and the other group drank distilled water at lib until day 14.
  • the degree of swelling in the uninjected footpad was estimated by the severity scoring system as follows: 0, no redness or inflammation; 1, one area of redness or inflammation less than 2 mm in diameter; 2, two areas of redness or inflammation, each less than 2 mm in diameter; 3, partial redness and/or inflammation of the footpad; 4, redness and/or inflammation of substantially the entire footpad; 5, criteria of 4 plus at least one toe red/inflamed; and 6, criteria of 4 plus toes inflamed and deformed (i.e., toes curl under) .
  • Asterisks indicate statistically significant differences (p ⁇ 0.05) in the severity scores between the treated animals and the controls.
  • inventions for the treatment of inflammatory conditions mediated by nuclear factor kappa-B (NFKB) .
  • invention methods comprise administering an effective amount of a therapeutic consisting essentially of carbon disulfide in a pharmaceutically acceptable carrier to a subject in need thereof.
  • the carbon disulfide is administered in a chemically protected form.
  • Those of skill in the art can readily identify suitable chemically protected forms of carbon disulfide for use herein.
  • a presently preferred source of carbon disulfide contemplated for use herein are dithiocarbamates which are readily hydrolyzable under selected physiological conditions .
  • selected physiological conditions refers to the physiological conditions typical of the site at which hydrolysis of dithiocarbamates is desired. For example, oral administration subjects the dithiocarbamate to the acidic conditions of the stomach, which induce hydrolysis of the administered dithiocarbamate .
  • each of R 1 and R 2 is independently a C, up to C 18 alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, substituted acyl, or R 1 and/or R 2 is a divalent or polyvalent moiety, wherein said divalent or polyvalent moiety serves as the same substituent for two or more dithiocarbamate structures, thereby linking said structures together so as to form a bis (dithiocarbamate) or poly (dithiocarbamate) species, x is 1 or 2, and
  • M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.
  • dithiocarbamate compounds having generic structure I are those wherein:
  • R,, and/or R 2 is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene and substituted aralkylene, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis (dithiocarbamate) species.
  • R 1 and/or R 2 is a polyvalent moiety, wherein said polyvalent moiety serves as the same substituent for a plurality of dithiocarbamate structures, thereby linking said structures together so as to form a poly (dithiocarbamate) species .
  • each of R 1 and R 2 a C, up to C 12 alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, wherein the substituents are selected from carboxyl, -C(0)H, oxyacyl, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, nitro or sulfuryl, and
  • M Fe +2 or Fe +3 .
  • Still further preferred dithiocarbamate compounds having generic structure I are those wherein:
  • Monovalent cations contemplated for incorporation into the above-described dithiocarbamate compounds include H + , Na + , NH 4 + , tetraalkyl ammonium, and the like.
  • Physiologically compatible divalent or trivalent transition metal cations contemplated for incorporation into the above-described dithiocarbamate compounds include charged forms of iron, cobalt, copper, manganese, ruthenium, or the like (e.g., Fe +2 , Fe +3 , Co +2 , Co +3 , Cu +2 , Mn +2 , Mn +3 or Ru +3 ) .
  • the ratio of dithiocarbamate-species to counter-ion M can vary widely.
  • substituted alkyl comprises alkyl groups further bearing one or more substituents selected from hydroxy, alkoxy (of a lower alkyl group) , mercapto (of a lower alkyl group) , cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, trifluoromethyl, cyano, nitro, nitrone, amino, amido, -C(0)H, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl, and the like.
  • cycloalkyl refers to cyclic ring-containing groups containing in the range of about 3 up to 8 carbon atoms
  • substituted cycloalkyl refers to cycloalkyl groups further bearing one or more substituents as set forth above.
  • cycloalkylene refers to divalent ring-containing groups containing in the range of about 3 up to 8 carbon atoms
  • substituted cycloalkylene refers to cycloalkylene groups further bearing one or more substituents as set forth above.
  • alkylene refers to saturated, divalent straight or branched chain hydrocarbyl groups typically having in the range of about 2 up to 12 carbon atoms
  • substituted alkylene refers to alkylene groups further bearing one or more substituents as set forth above .
  • alkenyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms
  • substituted alkenyl refers to alkenyl groups further bearing one or more substituents as set forth above.
  • alkenylene refers to divalent straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and typically having in the range of about 2 up to 12 carbon atoms
  • substituted alkenylene refers to alkenylene groups further bearing one or more substituents as set forth above .
  • alkynyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms
  • substituted alkynyl refers to alkynyl groups further bearing one or more substituents as set forth above.
  • aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted aryl” refers to aryl groups further bearing one or more substituents as set forth above.
  • alkylaryl refers to alkyl- substituted aryl groups and "substituted alkylaryl” refers to alkylaryl groups further bearing one or more substituents as set forth above.
  • arylalkyl refers to aryl- substituted alkyl groups and "substituted arylalkyl” refers to arylalkyl groups further bearing one or more substituents as set forth above.
  • arylalkenyl refers to aryl- substituted alkenyl groups and "substituted arylalkenyl” refers to arylalkenyl groups further bearing one or more substituents as set forth above.
  • arylalkynyl refers to aryl- substituted alkynyl groups and "substituted arylalkynyl” refers to arylalkynyl groups further bearing one or more substituents as set forth above.
  • arylene refers to divalent aromatic groups typically having in the range of 6 up to 14 carbon atoms and "substituted arylene” refers to arylene groups further bearing one or more substituents as set forth above .
  • alkarylene refers to alkyl- substituted divalent aryl groups typically having in the range of about 7 up to 16 carbon atoms and "substituted alkarylene” refers to alkarylene groups further bearing one or more substituents as set forth above.
  • aralkylene refers to aryl- substituted divalent alkyl groups typically having in the range of about 7 up to 16 carbon atoms and "substituted aralkylene” refers to aralkylene groups further bearing one or more substituents as set forth above.
  • aralkenylene refers to aryl-substituted divalent alkenyl groups typically having in the range of about 8 up to 16 carbon atoms and "substituted aralkenylene” refers to aralkenylene groups further bearing one or more substituents as set forth above .
  • aralkynylene refers to aryl-substituted divalent alkynyl groups typically having in the range of about 8 up to 16 carbon atoms and "substituted aralkynylene” refers to aralkynylene groups further bearing one or more substituents as set forth above.
  • heterocyclic refers to cyclic (i.e., ring-containing) groups containing one or more heteroatoms (e.g., N, 0, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and "substituted heterocyclic” refers to heterocyclic groups further bearing one or more substituents as set forth above.
  • heteroatoms e.g., N, 0, S, or the like
  • heterocycloalkylene refers to divalent cyclic (i.e., ring-containing) groups containing one or more heteroatoms (e.g., N, 0, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and "substituted heterocycloalkylene” refers to heterocycloalkylene groups further bearing one or more substituents as set forth above .
  • aroyl refers to aryl- carbonyl species such as benzoyl and "substituted aroyl” refers to aroyl groups further bearing one or more substituents as set forth above.
  • acyl refers to alkyl- carbonyl species .
  • halogen refers to fluoride, chloride, bromide or iodide atoms.
  • Diseases and conditions contemplated for treatment in accordance with the present invention include inflammatory conditions and infectious diseases, such as, for example, septic shock, hemorrhagic shock, anaphylactic shock, toxic shock syndrome, ischemia, cerebral ischemia, administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease), diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic chor iomeningi t i s , glomerulonephritis, uveitis, ileitis, inflammation (e.g., liver inflammation, renal inflammation, and the like) , burn, infection (including bacterial, viral, fungal and parasitic infections) , hemodialysis, chronic fatigue syndrome, stroke
  • improved methods for the treatment of pathological conditions employing a pharmacologically active agent therefor, the improvement comprising administering said pharmacologically active agent as part of a therapeutic consisting essentially of said pharmacologically active agent and carbon disulfide in a pharmaceutically acceptable carrier.
  • the therapeutic employed for carrying out the improved methods comprises said pharmacologically active agent, a physiologically compatible compound which is readily hydrolyzable under selected physiological conditions to release carbon disulfide, and a pharmaceutically acceptable carrier therefor.
  • physiologically compatible compounds which are readily hydrolyzable under selected physiological conditions to release carbon disulfide include dithiocarbamates as described in detail hereinabove.
  • Pharmacologically active agents contemplated for administration in accordance with the present invention i.e., in combination with carbon disulfide in a pharmaceutically acceptable carrier or a physiologically compatible compound which is readily hydrolyzable under selected physiological conditions to release carbon disulfide include:
  • NSAIDs such as acetaminophen (Tylenol, Datril, etc.), aspirin, ibuprofen (Motrin, Advil, Rufen, others) , choline magnesium salicylate (Triasate) , choline salicylate (Anthropan) , diclofenac
  • feldene sodium salicylate, sulindac (clinoril) , tolmetin (tolectin) , meloxicam, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like; analgesics/antipyretics (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine sulfate, oxycodone hydrochloride, codeine phosphate, dihydrocodeine bitartrate, pentazocine hydrochloride, hydrocodone bitartrate, levorphanol tartrate, diflunisal, trolamine salicy
  • anti-Fc receptor monoclonal antibodies e.g., hydroorotate dehydrogenase inhibitor, anti-IL2 monoclonal antibodies (e.g., CHI-621 and dacliximab) , buspirone, castanospermine, CD-59 (complement factor inhibitor) , 5-lipoxygenase inhibitor (e.g., CMI-392) , phosphatidic acid synthesis antagonists, ebselen, edelfosine, enlimomab, galaptin, platelet activating factor antagonists, selectin antagonists (e.g., ICAM-4) , interleukin-10 agonist, macrocylic lactone, methoxatone, mizoribine, OX-19, peptigen agents, PG-27, protein kinase C inhibitors, phosphodiesterase IV inhibitor, single chain antigen binding proteins, complement factor inhibitor, sialophorin, sirolimus, spirocyclic lactams
  • neuroprotective agents such as Q!-adrenoreceptor antagonist (i.e, o;-dihydroergocryptine) , NMDA antagonists (e.g., 5, 6, 7-tichloro-THQTQ, remacemide, 2-piperazinecarboxylic acid, N-indologlycinamide derivatives , spiro [benzo (b) thiophen-4 (5H) derivatives, CP-101606, eliprodil, dexanabinol, GV-150526, L-695902, L-701324, amantadine derivatives, dizocilpine, benzomorphan derivatives, aptiganel, (S) -ce-phenyl-2-pyridine ethanamide dihyrochloride
  • azulenesulfonic acid derivatives brain-derived neurotropic factor
  • adrenergic transmitter uptake inhibitor e.g., 1-butanamine
  • endothelin A receptor antagonists e.g., benzenesulfonamide derivatives, GABA A receptor antagonists (e.g., triazolopyrimidine derivatives and cyclohexaneacetic acid derivatives)
  • GPIIb Ilia receptor antagonists e.g., C68-22
  • platelet aggregation antagonist e.g., 2 ( IH) -quinolinone derivatives, lH-pyrrole-1-acetic acid derivatives and coumadin
  • Factor Xa inhibitor CPC-211
  • corticotropin releasing factor agonist e.g., cothrombins, fraxiparine, dermatan sulfate and heparinoid
  • dotarizine intracellular calcium chelators
  • nerve growth agonist e.g., lH-l,4-diazepine
  • nerve growth agonist e.g., lH-l,4-diazepine
  • lipid peroxidase inhibitor e.g., 2, 5-cyclohexadiene-l, 4-dione derivatives
  • sigma receptor agonist e.g., cyclopropanemethanamine derivatives and SA-4503
  • thyrotropin releasing hormone agonist e.g., JTP-2942, L-prolinamide and posatirelin
  • prolyl endopeptidase inhibitor monosialoganglioside GM1, proteolytic enzyme inhibitor (e.g., nafamostat) , neutrophil inhibitory factor, platelet activating factor antagonist (e.g., nupafant) , monoamine oxidase B inhibitor (e.g., parafluoroselegiline and benzonitrile derivative
  • T cell inhibitors such as synthetic leucocyte antigen derived peptides, interleukin-1 receptor antagonist, MG/AnergiX, anti-CD3 monoclonal antibodies, anti-CD23 monoclonal antibodies, anti-CD28 antibodies, anti-CD2 monoclonal antibodies, CD4 antagonists, anti-E selectin antibodies, MHC inhibitors, monogens, mycophenolate mofetil, LRA-1 inhibitors, selectin inhibitors, and the like; antimigraine agents, such as MK-462, 324C91, Phytomedicine, (S) -fluoxetine, calcium channel antagonists (e.g., nimodipine/Nimotop, flunarizine, dotarizine/FI-6026, iomerizine HCL/KB-2796, CPC-304, and CPC-317) , Q!-dihydroergocryptine,
  • synthetic leucocyte antigen derived peptides such as synthetic leucocyte antigen derived peptides, inter
  • 5-HT1 agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-85548, 311C, and GR-127607
  • 5-HT1D agonists e.g., Sumatriptan/Imitrex, Imigran, GR-8
  • 5-HT1D agents 2-thiophenecarboxamide, 3 -piperidinamine, diclofenac potassium, dihydroergotamine (e.g., DHE 45 ® ) , ergotamine tartrate, dolasetron mesilate, dotarizine, flupirtine, histamine-H3 receptor agonist, indobufen, 1-azulenesulfonic acid derivatives, cholinesterase inhibitors, (e.g., S-9977) , bradykinin antagonists, nitric oxide reductase inhibitors (e.g., BN-52296) , nitric oxide receptor antagonists, substance P antagonists (e.g., Capsaicin/Nasocap) , endopeptidase inhibitors (e.g., neutral endopeptidase, cloned) , piperazine derivatives, neurokinin 1 antagonists, metergoline, dopamine D2 antagonist (e.g.
  • antiarthritic agents such as anti-CD4 monoclonal antibodies, phospholipase Al inhibitor, loteprednol, tobramycin, combinations of loteprednol and tobramycin, salnacedin, amiprilose, anakinra, anergix, anti-B7 antibody, anti-CD3H, anti-gp39, anti-MHC MAbs, antirheumatic peptides, anti-Tac (Fv) -PE40, AP-1 inhibitors, AR-324, purine nucleotide phosphorylase inhibitors (e.g., BCX-5) , bindarit, CD2 antagonist (e.g., BTI-322) , campath-lH, CD4 antagonist (e.g., CE9.1 and
  • CD5 antagonist e.g., zolimomab
  • 5-lipoxygenase inhibitor e.g., zileuton, tenidap, and ABT-761
  • cyclooxygenase inhibitor e.g., cyclooxygenase inhibitor
  • metalloproteinase inhibitor e.g., XR-168, TNF convertase inhibitors, GI-155704A, AG-3340 and BB-2983
  • nitric oxide synthase inhibitors i.e, ARL-16556
  • phospholipase A2 inhibitor e.g., ARL-67974
  • selectin antagonist e.g., CAM inhibitors
  • leucotriene B4 antagonist e.g., CGS-25019C
  • collagenase inhibitor e.g., GR-129574A
  • cyclooxygenase 2 inhibitor e.g., cyclooxygenase 2 inhibitor
  • Hyalart nitric oxide antagonists (e.g., hydroxocobalamin) , stromelysin inhibitors (e.g., L-758354) , prostaglandin El agonist (e.g., misoprostol, and misoprostol+diclofenac) , dihydrofolate reductase inhibitor (e.g., trimetrexate, and MX-68) , opioid antagonist
  • nitric oxide antagonists e.g., hydroxocobalamin
  • stromelysin inhibitors e.g., L-758354
  • prostaglandin El agonist e.g., misoprostol, and misoprostol+diclofenac
  • dihydrofolate reductase inhibitor e.g., trimetrexate, and MX-68
  • opioid antagonists e.g., hydroxocobalamin
  • stromelysin inhibitors e.g., L
  • nalmefene e.g., nalmefene
  • corticotropin releasing factor antagonist e.g., NBI-103, and NBI-104
  • proteolytic enzyme inhibitor e.g., protease nexin-1, and NCY-2010
  • bradykinin antagonist e.g., bradykinin antagonist
  • tachykinin antagonists e.g., tachykinin antagonists, and NPC-17731
  • growth hormone antagonist e.g., octreotide
  • phosphodiesterase IV inhibitor e.g., PDEIV inhibitors
  • gelatinase inhibitor e.g., REGA-3G12
  • free radical scavengers e.g.,
  • prostaglandin synthase inhibitors e.g., sulfasalazine
  • phenylbutazone penicillamine, salsalate, azathioprine, indomethacin, meclofenamate sodium, gold sodium thiomalate, ketoprofen, auranofin, aurothioglucose, tolmetin sodium, and the like
  • antigout agents e.g., colchicine, allopurinol, and the like
  • anticoagulants e.g., heparin, heparin sodium, warfarin sodium, and the like
  • thrombolytic agents e.g., urokinase, streptokinase, altoplase, and the like
  • antifibrinolytic agents e.g., aminocaproic acid
  • hemorheologic agents e.g., pentoxifylline
  • antiplatelet agents e.g.
  • interleukin 1 antagonists e.g., interleukin 1 receptors
  • interleukin 1 receptor antagonists e.g., anakinra
  • interleukin lb antagonists e.g., interleukin-l ⁇
  • interleukin lbeta converting enzyme inhibitors e.g., ICE-inhibitors
  • interleukin 8 antagonists e.g., IL-8 receptor
  • interleukin 13 agonists e.g., intereleukin-13
  • anti-TCR MAb e.g., NBI-114
  • CY-1503 clonazepam
  • CNS clonazepam
  • immune system function modulators e.g., NBI-106
  • cyclophosphamide cyclosporine A
  • cytokines e.g., IFN- ⁇ , alfaferone, IFN- ⁇ lb, betaseron, TGF- ⁇ 2, PEG-TGF- ⁇ 2, betakine, IFN- ⁇ /Rebif , frone, interferon- ⁇ , and IFN- ⁇
  • CD4+T cell inhibitors e.g., AnergiX
  • CD28 antagonists e.g., B7-1, B7-2, and CD28
  • directcytotoxicity therapies e.g., benzoporphyrin derivative (BPD)
  • FK-506, growth factors e.g., glial growth factor, GGF, nerve growth factors, TGF- ⁇ 2, PEG-TGF- ⁇ 2, and betakine
  • humanized MAb e.g., anti-IFN- ⁇ MAb, smart anti-IFN- ⁇ MAb, anti-Tac antibody, and smart anti-Ta
  • IFN-Q! IFN-Q!, IFN- ⁇ antagonist (e.g., anti-IFN- ⁇ MAb, and smart anti-IFN- ⁇ MAb) , IL-2 antagonists
  • IL-4 antagonists e.g., IL-4 fusion toxin, and DAB 389 IL-4
  • immune-mediated neuronal damage inhibitors e.g., NBI-114, NBI-115, and NBI-116
  • immunoglobins immunostimulants (e.g., poly-ICLC, edelfosine, ALP, ET-18-OCH3, ET-18-OME, NSC-24, and poly- IC+poly-L- lysine+carboxymethy1- cellulose)
  • immunosuppressants e.g., azathioprine, AI-100 animal protein, rDNA human protein AI-101, peptide, AI-102, castanospermine, tacrolimus, FK-506, FR-900506, Fujimycin,
  • Prograf anti-leukointegrin MAb, Hu23F2G, primatized anti-CD4 antibody, CE9.1, Galaptin 14-1, GL14-1, Lectin-1, recombinant IML-1, linomide, roquinimex, LS-2616, transcyclo-pentanyl purine analogs, MS-6044, spanidin, 15-deoxyspergualin, deoxyspurgiline, gusperimus HCL, NSC-356894, NKT-01, TCR, CD3/Ti, cyclosporine, OL-27-400, Sandlmmune, Human IL-10, onogens, anti-TCR MAbs, TCAR MAbs, Monogen TM19, Monogen TM27, Monogen TM29, Monogen TM31, peptigen TP12, anti-CD4 MAb, cantara, immunophilins, VX-10367, VX-10393, VX-10428, synthetic basic copolymer
  • interferon agonists e.g., poly-ICLC, and poly- IC+poly-L- lysine+carboxymethy1- cellulose
  • interferon- ⁇ -lb isoprinosine
  • IV methylprednisolone macrolides (e.g., tacrolimus, FK-506, FR-900506, Fujimycin, and Prograf), MAO
  • B inhibitors e.g., selegiline, and Parkinyl
  • methotrexate e.g., methotrexate
  • mitoxantrone e.g., muscle relaxants
  • muscarinic antagonists e.g., RGH-5002
  • muscarinic antagonists e.g., RGH-5002
  • RGH-5002 neurosteroids
  • neurosteroids e.g., NBI-106, and NBI-107
  • octapeptides e.g., peptide T
  • oxybutinin chloride e.g., oxygen free radical antagonists (e.g., tetrandrine, biobenzylisoquinoline alkaloid)
  • peptide agonists e.g., peptide agonists
  • peptide T e.g., peptide T
  • phenoxybenzamine e.g., phenoxybenzamine
  • phospholipase C inhibitors e.g., edelfosine
  • ALP ET-18-OCH3, ET-18-OME, NSC-24
  • photodynamic therapies e.g., benzoporphyrin derivative
  • BPD platelet activating factor antagonists
  • platelet activating factor antagonists e.g., ginkgolide B, and BN-52021
  • potassium channel antagonists e.g., aminodiaquine, and EL-970
  • propranolol e.g., aminodiaquine, and EL-970
  • prostaglandin synthase inhibitors e.g., sulfasalazine, salazosulfa-pyridine, PJ-306, SI-88, azulfidine, salazopyrin
  • protease antagonists e.g., ginkgolide B, and BN-52021
  • spergualin analogs e.g., spanidin, 15-deoxyspergualin, deoxyspurgiline, gusperimus HC1, NSC-356894, NKT-01
  • TCR peptide decoys e.g., NBI-114, NBI-115, and NBI
  • CD59 CD59
  • CTLA4Ig cyclosporines (e.g., CsA) , FK-506/rapamycin binding proteins (FKBP) , glucocorticoids, humanized version of OKT3 (e.g., huOKT3-185) , mycophenolate mofetil, hydroorotate dehydrogenase inhibitors (e.g., Brequinar) , orthoclone OKT3 (e.g., IgG2a anti-T cell murine monoclonal antibody, and muromonab-CD3) , rapamycins (e.g., AY-22989) , and streptomyces isolates (e.g., FR-900520, and FR-900523) , and the like; systemic lupus erythematosus (SLE) agents, such as androgen-derived steriods (e.g., Org-4094) , anti-CD4 humanized antibodies, anti-
  • CD2 complement inhibitors
  • complement inhibitors e.g., recombinant MCP-based complement inhibitors
  • cyclosporines e.g., Sandimmune, cyclosporine analog, OG-37325, cyclosporin-G, and NVal-CyA
  • cytokines e.g., IL-4 fusion toxin
  • cytokine receptor antagonists e.g., immunomodulatory cytokines
  • E-selectin 5 antagonists e.g., anti-ELAM, and CY-1787
  • FK506/tacrolimus e.g., Prograf
  • hypercalcemic agents e.g., KH-1060
  • IFN- ⁇ antagonists e.g., anti-IFN- ⁇ MAb, and smart anti-IFN- ⁇ MAb
  • ICE IL-l ⁇ converting enzyme inhibitors
  • E. coli e.g., celmoleukin, IL-2, TGP-3, and
  • Celeuk e.g., celeuk
  • immunoglobulins e.g., anti-ELAM, CY-1788, and humanized CY-1787
  • immunostimulants e.g., thymotrinan, RGH-0205, and TP3
  • immunosuppressants e.g., Rapamycin, AY-22989
  • immunotoxins e.g., Zolimomab aritox, xmmly-h65 - rta , xomazyme - lym/CD5 - Plus ,
  • intravenous immunoglobulins e.g., IVIG
  • integrin antagonists e.g., integrin blockers
  • MigisTM antibodies monoclonal antibody therapeutics
  • murine MAb e.g., anti-SLE vaccine
  • protease inhibitors e.g., matrix metalloprotease (MMP) inhibitors, and stromelysin
  • protein synthesis antagonists e.g., protein synthesis inhibitors
  • Spanidin 15 - deoxyspergualin, deoxyspurgiline, gusperimus hydrochloride
  • T cell inhibitors e.g., TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta-1, TGF-beta, T cell inhibitors, e.g.
  • TNF tumor necrosis factor
  • Alzheimer's disease agents such as ACh release enhancers (e.g., T-588 (benzothiophene derivative)), acetylcholine release stimulants (e.g., DUP-996 and analogues), AMPA agonists (e.g., AMAlex, and Isoxazole compound series) , AMPA GluR agonist
  • ACh release enhancers e.g., T-588 (benzothiophene derivative)
  • acetylcholine release stimulants e.g., DUP-996 and analogues
  • AMPA agonists e.g., AMAlex, and Isoxazole compound series
  • AMPA GluR agonists e.g., AMAlex, and Isoxazole compound series
  • AMPA GluR antagonists e.g., S-18986, and related quinolone derivatives
  • anticholinesterases e.g., E-2020
  • Ca-antagonists e.g., NS-649, spider venom-derived ICM peptides and analogues, and substituted 2-aminoindanes compound series
  • combined anticholinesterase and muscarinic AChR antagonists e.g., PD142676
  • K-channel blockers e.g., Trans-R-4- ( 4 -methoxyphenyl -methyl) cyclohexylanine and analogues, and margatoxin-based functional and/or structural analogues
  • MI muscarinic receptor agonists e.g., IDRA-21 [7-chloro-3-methyl-3,4-dihydro- 2H-1, 2, 4-benzothiadiazinine]
  • AMPA GluR antagonists e.g., S-18986,
  • NMDA antagonists e.g., certain indole derivatives, and (R- (R 1 , S 1 ) ) -a- (4- hydroxyphenyl) -beta-methyl-4- (phenylmenthyl) -1- piperidinepropanol and analogues
  • nicotinic AChR agonists e.g., ABT-418 [isoxazole, 3-meth-5- (1-meth-2-pyrrolidinyl) ]
  • antiparkinson agents e.g., ethosuximide, and the like
  • psoriasis agents such as 5-LO inhibitors (e.g., Wy-50295, Wy-49232, Lonapalene, RS-43179, MK-886, L-663536, ETH-615, DUP-654, Zileuton, epocarbazolin-A, and A-640
  • dihydrofolate reductase inhibitors e.g., G-301, dichlorobenzoprim, methotrexate, and methotrexate in microsponge delivery system
  • E-selectin inhibitors e.g.,
  • fibroblast growth factor antagonists e.g., Saporin mitotoxin, and Steno-Stat
  • fumagillin analogues e.g., AGM-1470, and TNP-470
  • G-proteins and signal transduction compounds e.g., CPC-A
  • gel formulations for acne e.g., nicotinamide, N-547, and Papulex
  • growth hormone antagonists e.g.,
  • hydroorotate dehydrogenase inhibitors e.g., Brequinar sodium, bipenquinate, and DuP-785
  • IL-1 and other cytokine inhibitors e.g., Septanil
  • IL-1 converting ezyme inhibitors IL-1 receptor antagonists
  • IL-2 antagonists e.g.,
  • IL-2 receptor- argeted fusion toxins DAB389IL-22
  • IL-8 receptors DAB389IL-2
  • immunostimulants e.g., Thymopentin, and Timunox
  • immunosuppressants e.g., XomaZyme-CD5 Plus, cyclosporine
  • leukotriene antagonists e.g., Sch-40120, Wy-50295, and
  • leukotriene B4 antagonists e.g.,
  • lipase clearing factor inhibitors e.g., 1-docosanol, and lidakol
  • lipid encapsulated reducing agent e.g., Dithranol
  • liposomal gel e.g., Dithranol
  • LO inhibitors e.g., CD581, CD554, Masoprocol
  • lithium succinate ointments e.g., lithium salts, and Efalith
  • LO/CO inhibitors e.g., LO/CO
  • membrane integrity agonists e.g., lithium salts, and Efalith
  • microtubule inhibitors e.g., Posophyliotoxin-containing compound, and Psorex
  • octapeptide somatostatin analogues e.g., Lanreotide, angiopeptin, BIM-23014, and Somatuline
  • oligonucleotides e.g., ISIS 4730, ISIS 3801, ISIS 1939, and IL-1 inhibitors
  • peptide agonists e.g., octapeptide, and peptide
  • PKC inhibitors phospholipase A2 compounds, pospholipase D compounds, photodynamic anticancer agents (e.g., 5-aminolevulinic acid, and 5-ALA) , photodynamic therapies (e.g., benzoporphyrin derivative, synthetic chlorins, synthetic porphyrins, and EF-9) , photosensitizer (e.g., Porfirmer sodium), PKC inhibitors (e.g., Safingol, and Kynac) , platelet activating factor antagonists (e.g., TCV-309) , platelet aggregation inhibitors (e.g., CPC-A), prodrug NSAIDs (e.g.,
  • prostaglandin agonist e.g., eicosapentaenoic acid + gamma-linolenic acid combination, and Efamol Marine
  • protein inhibitors e.g., SPC-103600, and SPC-1012
  • PLC protein kinase C
  • Ro-31-7549, Ro-31-8161, and Ro-31-8220 protein synthesis antagonists (e.g., Calcitriol, Du-026325, LG-1069, LG-1064, AGN-190168, Namirotene, and CBS-211A) , purine nucleoside phosphorylase inhibitors (e.g., BCX-34) , radical formation agonists (e.g., benzoporphyrin derivative) , recombinant antileukoproteinases (e.g., ALP-242) , retinoids (e.g., BMY-30123, LG-1069, and LG-1064) , retinoid derivatives (e.g., AGN-190168), rapamycin binding proteins
  • protein synthesis antagonists e.g., Calcitriol, Du-026325, LG-1069, LG-1064, AGN-190168, Namirotene, and CBS-211A
  • FKBP immunophilins
  • VX-10367 immunophilins
  • VX-104248 second generation monoaromatic retinoids (e.g., Acitretin, and Neotigason) , soluble IL-1, IL-4 and IL-7 receptors, somatostatin and somatostatin analogues (e.g.,
  • Octreotide, and Sandostatin steroids, (e.g., AGN-191743) , streptomyces anulatus isolates (e.g., epocarbazolin-A), superoxide dismutase
  • VCAM-1 inhibitors e.g., ISIS 3801
  • vitamin D analogues e.g., Ro-23-6474, KH-1060
  • vitamin D 3 analogues e.g., Tacalcitol, Bonealfa, TV-02 ointment
  • vitamin D 3 derivatives e.g., 1, 2-diOH-vitamin D 3
  • diabetes agents such as ACE inhibitors (e.g., captopril) , amylin, amylin agonists and antagonists (e.g., NormylinTM, AC137, GC747, AC253, and AC625) , autoimmune compounds (e.g., AI-401) , capsaicins (e.g., Zostrix-HP) , cell regulators (e.g., protein kinase C inhibitors, and Balanol) , domperidones (e.g., Motilium ® ) , fluvastatins
  • ACE inhibitors e.g., captopril
  • amylin, amylin agonists and antagonists e.g., Normy
  • DAB 389 IL-2, and DAB 486 IL-2) gene therapies (e.g., Transkaryotic Therapies), glucagons (e.g., recombinant yeast glucagon) , IL-10 compounds, iloprost, immunosuppressives (e.g., tacrolimus, Prograf, and FK-506) , proinsulin, insulin and insulin analogs (e.g., AI-401, Nu-Insulin compounds, Humulin, Iletin, HumalogTM, LYs-Pro, and Amaryl) , insulin-like growth factors (e.g., Chiron/Ciba-Geigy compounds, Fujisawa compounds, and Genetech compounds), insulinotropins (e.g., Pfizer/Scios Nova compounds) , nerve growth factors (e.g., Genentech compounds), oral hypoglycemics (e.g., AS-6, glimepiride, Amaryl, CL 316,243, acarb
  • 5-HT 4 antagonists e.g., SR-57746A, and SR-57746
  • 5-lipoxygenase inhibitors e.g., low MW dual 5-lipoxygenase and PAF inhibitor CMI-392
  • ACh agonists e.g., Pramiracetam, Choline-L- alfoscerate, L-alpha-glycerylphosphoryl-choline, and Delecit
  • adenosine agonists e.g.,
  • adenosine Al receptor agonists e.g., Azaisotere, 2-chloro-N- [4 (phenylthio) -1-piperidinyl] adenosine, and 2120136
  • adenosine reuptake inhibitors e.g., Diphenyloxazole derivatives
  • adrenergic transmitter re-uptake inhibitors e.g., Bifemelane, E-0687, MCI-2016, Alnert, and Celeport
  • aldose reductase inhibitors e.g., Spiro-3' pyrroline derivatives
  • alpha antagonists e.g., Drotaverine acephyllinate, and
  • alpha 2 agonists e.g., SNAP-5083, SNAP-5608, and SNAP-5682
  • AMPA receptor agonists e.g., heterocyclic compound SYM-1207, and heterocyclic compound SYM-1252
  • AMPA receptor antagonists e.g., LY-293558, and LY-215490
  • C5a release inhibitors e.g., protein derivative CMI-46000
  • calcium antagonists e.g., Lemildipine, NB-818, NPK-1886, Trimetazidine derivative, Iomerizine KP-2796, Diltiazem analog clentiazem maleate, and TA-3090
  • calcium channel antagonists e.g., nitrendipine-like compound diperdipine, YS-201, U-92032, Diltiazem derivative, 1058, SM-6586, KP-840, F-0401, D-31-D, Tetrahydronaphthalene derivatives, fasudil, AT-877, H-7, HA-1044, HA-1077, Eril, darodipine, dazodipine, PY-108-068, Plimo, Dihydropy-ridine, AE 0047, GJ-0956, Lacidipine, GR-43659
  • calcium antagonists e
  • endothelin receptor antagonists include endothelin receptor antagonists, excitatory amino acid agonists (e.g., acylated polyamine analogs, and N- (4-hydroxyphenylpropa- nonyl) -spermine analog) , excitatory amino acid antagonists (e.g., Tryptophan, 4, 6-disubstituted stroke & kynurenine derivatives, NPC-17742, 5 CPC-701, and CPC-702) , glutamate antagonists
  • excitatory amino acid agonists e.g., acylated polyamine analogs, and N- (4-hydroxyphenylpropa- nonyl) -spermine analog
  • excitatory amino acid antagonists e.g., Tryptophan, 4, 6-disubstituted stroke & kynurenine derivatives, NPC-17742, 5 CPC-701, and CPC-702
  • glutamate antagonists e.g., glutamate antagonists
  • glycine antagonists e.g., 3-hydroxy-2, 5-dioxo- lH-benz [b] azepines
  • glycine NMDA associated antagonists e.g., 5 , 6-dihydro-lH-pyrrolo
  • GPIIb/IIIa antagonists e.g., Peptide C68-22
  • hemorheological agents e.g., Drotaverine acephyllinate, and Depogen
  • heparin e.g., hydroxyl radical formation inhibitors
  • hypocalcemic agents e.g., calcitonin peptide, related to hCGRP peptide
  • hypothermic agents/BMY-20862 e.g., ICAM-1 compounds
  • immunosuppressants e.g., small molecule
  • integrin general antagonists e.g., monoclonal antibody AN-100225, and monoclonal antibody AN-100226)
  • Interleukin-1 antagonists e.g., cyclic nitrones
  • lactic acid accumulation/inhibitors e.g., small molecule CPC-211
  • Leukotriene B4 antagonists e.g., Ebselen, DR-3305, PZ-25, PZ-51, RP 60931, and RP 61605
  • lipid peroxidase inhibitors e.g., Idebenone, and Avan
  • low molecular weight small molecules e.g., methyltransferase stimulants (e.g., 4-methyl benzenesulfonate, ademetionine sulfate tosilate, FO-156, and Ceritan)
  • monoamine oxidase B inhibitors e.g., MD-280040, MD-200243, MD-280080, Lazabemide, and Ro-19-6327
  • MS-153, MS-424, /Na + /H + Na + /Li + exchange inhibitors e.g., 2- (amino-methyl) chromans
  • Fraxiparin nafronyl/naftidrofuryl (e.g., Praxilene)
  • nerve growth factor agonists e.g., small molecule compounds, CNTF, BDNF, 2.5S NGF, onosialoganglioside GM1, and Sigen/Sygen
  • neuronal calcium channel blockers e.g., CPC-304, and CPC-317
  • neuronal differentiation compounds e.g., CPC-304, and CPC-317
  • neuropeptide agonists e.g., F-spondin
  • Neurotrophic Peptide Trofexin e.g., neutrophil inhibitory factors (e.g., small molecule compounds), nitric oxide agonists (e.g., hydroxy derivative N-3393, hydroxy derivative N-3398, nicorandil, and Therapicon) , nitric oxide antagonists, NMDA antagonists (e.g., Spiroisoindoles/dizocilpine derivatives, Oxindole compound, CP-112116, LY-104658, LY-235959,
  • FR-115427 Sialic acid derivative, N-palmitoyl-Betaethylglycoside neuraminic acid, ND-37, Ro-01-6794, 706, Dextrorphan, Ifenprodil analogue eliprodil, SL-82.0715, Lipophilic molecules, HU-211, Remacemide, 934-423, 12495,
  • NMDA antagonist-partial agonists e.g., Conantokin G peptide SYM-1010
  • NMDA channel blockers e.g., Aptiganel, CERESTAT, and CNS
  • NMDA receptor antagonists e.g., Kainate quisqua-late NNC-07-9202) , non-competitive NMDA antagonists (e.g., FPL-15896) , non-ionic copolymer RheothRx, nootropic/acetylcholine agonists (e.g., Oxiracetam, CT-848, and Neuractiv) , norepinephrine inhibitors (e.g., Midalci-pran) ,
  • NMDA receptor antagonists e.g., Kainate quisqua-late NNC-07-9202
  • non-competitive NMDA antagonists e.g., FPL-15896
  • non-ionic copolymer RheothRx e.g., nootropic/acetylcholine agonists (e.g., Oxiracetam, CT-848, and Neuractiv)
  • norepinephrine inhibitors e.g., Midalc
  • N-type calcium channel antagonists e.g., NS-626, and NS-638
  • opioid antagonists e.g., Nalmefene, nalmetrene, JF-1, ORF-11676, Cervene, and Incystene
  • opioid kappa receptor agonists e.g., acrylacetamide enadoline, and CI-997
  • organoselenims e.g., Ebselen, DR-3305, PZ-25, PZ-51, RP 60931, and RP 61605
  • oxygen scavengers e.g., Tirilazad mesylate, Lazaroids, and Freedox
  • PA2 inhibitors e.g., phospholipase A2 inhibitor
  • PAF antagonists e.g., nupafant, and
  • BB-2113 partial glycine NMDA agonists (e.g., ACPC), peptide/ GPIIb/IIIa antagonists (e.g., Integrelin) , peptidic neuron-specific calcium channel antagonists (e.g., SNX-111), phosphodiesterase inhibitors (e.g., Xanthine derivatives, propentofylline, Hoe-285, and
  • Hextol Hextol
  • phospholipase A2 inhibitors e.g., small organic molecule CEP-217
  • plasminogen activators e.g., plasminogen activators
  • r-ProUK recombinant pro-urokinase
  • platelet-activating factor antagonists e.g., r-ProUK (recombinant pro-urokinase)
  • platelet adhesion inhibitors e.g., Peptide
  • platelet aggregation antagonists e.g., cilostazol, peptide agents, GPHb-IIIA inhibitor, and TP-9201
  • platelet aggregation inhibitors e.g., Diaminoalkanioic acid derivatives
  • potassium channel agonists e.g., Nicorandil, RP-46417, SG-75, and Adancor
  • prolyl endopeptidase (PEP) inhibitors e.g., JTP-4819
  • protein kinase C inhibitors e.g., monosialoganglioside derivative Liga-20
  • proteolytic enzyme inhibitors e.g., Protease nexin-1, Incyte, PN-1, PN-2, Nafa ostat, FUT-175, Duthan, and Futhan
  • pyrimidine derivatives Quinolizine derivatives (e.g., Protease nex
  • Schwann cell derived molecules/promoters e.g., Sigma ligand
  • sigma antagonists e.g., Sigma ligand
  • sigma receptor antagonists e.g., tetrahyropyridinyl- isoxazolines and isoxazoles PD-144418
  • sodium/calcium channel modulators e.g.,
  • streptokinase e.g., Streptase
  • substituted guanadine e.g., small molecule CNS-1237
  • superoxide dismutase stimulants e.g., PEG conjugated enzyme superoxide dismutase/Dismutec, and PEG-SOD
  • thrombin inhibitors e.g., non-peptide
  • thromboxane synthase inhibitors e.g., Linotroban, and HN-11500
  • thyrotropin-releasing hormone agonists e.g., TRH agonists, Protirelin analogthymoliberin, and RX-77368,
  • ticlopidine e.g., Ticlid
  • TJ-8007 ticlopidine
  • TRH agonists e.g., Thyrotropin releasing hormones, and JTP-2942
  • agents useful for the treatment of carcinomas e.g., adriamycin, taxol, interleukin-1, interleukin-2
  • LHRH analogs such as nafarelin acetate
  • prostatic carcinoma agents useful for the treatment of prostatic carcinoma
  • agents useful for the treatment of endometriosis e.g., LHRH analogs
  • agents useful for the treatment of uterine contraction e.g. , oxytocin
  • agents useful for the treatment of diuresis e.g., vasopressin
  • agents useful for the treatment of cystic fibrosis e.g.,
  • Dnase i.e., deoxyribonuclease
  • SLPI SLPI
  • agents useful for the treatment of neutropenia e.g.
  • GCSF GCSF
  • agents useful for the treatment of lung cancer e.g., beta
  • agents useful for the treatment of ischemia/reperfusion injury e.g., selectin inhibitors, Irfl, and the like
  • nitric oxide synthase inhibitors e.g., Irfl, and the like
  • pharmacologically active agent s
  • said method comprising administering said pharmacologically active agent as part of a therapeutic consisting essentially of said pharmacologically active agent and carbon disulfide in a pharmaceutically acceptable carrier.
  • the carbon disulfide can be delivered in protected form as a physiologically compatible compound which is readily hydrolyzable under selected physiological conditions to release carbon disulfide (e.g., a dithiocarbamate).
  • pharmacologically active agent comprising administering said pharmacologically active agent as part of a therapeutic consisting essentially of said pharmacologically active agent and carbon disulfide in a pharmaceutically acceptable carrier.
  • the carbon disulfide can be delivered as a physiologically compatible compound which is readily hydrolyzable under selected physiological conditions to release carbon disulfide.
  • the therapeutic described herein can be delivered in a variety of ways, such as, for example, orally, intravenously, subcutaneously, parenterally, rectally, by inhalation, and the like.
  • the therapeutic contemplated for use herein can be delivered in a variety of pharmaceutically acceptable forms.
  • the therapeutic can be delivered in the form of a solid, solution, emulsion, dispersion, micelle, liposome, and the like.
  • physiologically active composition consisting essentially of a physiologically compatible compound which is readily hydrolyzable under selected physiological conditions to release carbon disulfide in a suitable vehicle rendering said compound (s) amenable to oral delivery, transdermal delivery, intravenous delivery, intramuscular delivery, topical delivery, nasal delivery, and the like.
  • compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use .
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active compound(s) is (are) included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos . 4,256,108; 4,160,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.
  • formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions may be in the form of a sterile injectable suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid) , naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • compositions contemplated for use in the practice of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • suppositories for rectal administration of the drug.
  • These compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • the dosage of carbon disulfide or physiologically compatible compound which is readily hydrolyzable under selected physiological conditions to release carbon disulfide falls in the range of about 0.01 mmoles/kg body weight of the subject/hour up to about 0.5 mmoles/kg/hr .
  • Typical daily doses lie within the range of from about 1 ⁇ g up to about 100 mg per kg body weight, and, preferably within the range of from 10 ⁇ g to 10 mg per kg body weight and can be administered up to four times daily.
  • the daily IV dose lies within the range of from about 1 ⁇ g to about 100 mg per kg body weight, and, preferably, within the range of from 10 ⁇ g to 10 mg per kg body weight .
  • Jurkat T cells are grown in RPMI 1640 medium supplemented with 10% fetal calf serum and penicillin-streptomycin. The cells are treated with 1 or 5 mM carbon disulfide dissolved in DMSO and the controls are treated with the same amount of DMSO alone for one hour. Both groups of cells are then incubated with either 10 ng/ml tumor necrosis factor or 10 ng/ml IL-1 for one hour. Cells are fractionated and nuclear extracts are prepared as described previously (see, for example, Stylianou, E et al . , in J. Biol. Chem. , 267:15836-15841 (1992)). The protein in this crude nuclear extract is determined using the method of Bradford. The amount of NFKB expressed is determined by Western blotting using anti-NF ⁇ B antibodies. The results show that CS 2 at either 1 or 5 mM levels inhibits the amount of NFKB induced either by TNF or IL-1.
  • Lewis rats male, 180-220 g were injected intradermally into the right hind footpad with M. tuberculosis (5 mg/ml in light mineral oil) . The rats were weighed daily and observed for tarsal joint and footpad swelling. A scoring system of 1-6 to estimate the degree of inflammatory lesions on the uninjected footpad was established to estimate the degree of swelling and deformation of the foot resulting from arthritic conditions. On day 7, the rats were separated into two groups, one received L-proline dithiocarbamate in drinking water (5-10 mg/ml, p.o.) and the other received distilled water alone for 14 days . The results in Figure 2 show that oral administration of L-proline dithiocarbamate significantly reduces the swelling in the uninjected footpad compared to the controls .
  • Lew and WF rats represent complete genetic disparity at both the major and minor histocompatibility loci.
  • Lew rats underwent either isogeneic (Lew-Lew) or allogeneic (WF-Lew) heterotopic cardiac transplantation to the abdominal aorta and vena cava by standard microvascular surgical techniques . All cardiac transplants were noted to have good initial contractile function. Graft function was monitored by palpation through the abdominal wall twice daily. Allograft rejection was defined by loss of palpable contractile activity and was confirmed by direct inspection at laparatomy.
  • NFKB myocardial nuclear factor kappa B
  • Combination therapy reduced nitrate/nitrite production better than monotherapy.
  • the stable end products of nitric oxide generation, plasma nitrite and nitrate were assayed by chemiluminescence on posttransplant day 5.
  • Plasma levels of nitrite/nitrate in WF-Lew were elevated six times over isograft controls (Table 2) .
  • Daily treatment with MGD reduced nitrate/nitrite levels 40%.
  • Daily treatment with CsA reduced nitrite/nitrate levels 65%.
  • the combination therapy of MGD and low dose CsA resulted in a 79% reduction in measured nitrite/nitrate levels.
  • NFKB Combination therapy reduced NFKB expression better than MGD or CsA alone.
  • Allograft rejection stimulates a response that has many inflammation-like characteristics.
  • the transcription factor NFKB a key initiator of the inflammation cascade, stimulates the expression of many inflammation-related genes including adhesion receptors and iNOS.
  • NFKB levels were examined in electrophoretic mobility gel shift assays from tissue samples collected on posttransplant day 4.
  • Table 3 shows that the amount of radioactivity shifted into the NFKB binding site is increased in the presence of the allograft (Group 2) .
  • MGD therapy alone reduced NFKB expression by about 50% (Group 3) .
  • CsA monotherapy reduced NFKB by 64%.
  • the combination of MGD and CsA reduces NFKB by 72% (Group 5) .
  • Table 3 Combination Therapy Reduces NFKB Expression Better Than
  • MGD was evaluated for its ability to prevent rejection after long-term, oral administration via the drinking water (Table 4) .
  • Monotherapy with low dose CsA until rejection permitted allograft survival for 23 days.
  • combination therapy employing low dose of CsA (2.5 mg/kg im/day until rejection) and MGD (5 mg/ml in the drinking water) daily for 100 days resulted in remarkably long term graft survival.
  • CsA 2.5 mg/kg im/day until rejection
  • MGD 5 mg/ml in the drinking water
  • dithiocarbamates such as N-methyl-D-glucamine dithiocarbamate (MGD) or L-proline dithiocarbamate can readily be decomposed to release carbon disulfide in the stomach (Masuda and Nakayama, supra) .
  • CS 2 released from these compounds may account for the observed effects in both arthritic model and allograft model in rats mediated via the inhibition of NFKB in vivo.
  • Wistar rats 200-250 grams, male are fasted overnight but allowed free access to water. Ten rats in each group are given ibuprofen alone or ibuprofen plus dithiocarbamate orally at doses of 10, 20 or 50 mg/kg. The rats are sacrificed five hours later and visible gastric damage is assessed by examining under microscope and histological evaluation.
  • Example 7
  • White New Zealand rabbits male, about 1 kg are given subcutaneously ibuprofen alone or ibuprofen plus dithiocarbamate at a dose of 30 mg/kg for every 12 hours. The animals are sacrificed on day 4 (after the 7th dose) and the visible ulcers in the stomach are examined and measured with calipers. The tissue samples are fixed in neutral buffered formalin and processed for histological evaluation.
  • Wistar rats male, 200-250 g are fasted overnight but allowed to free access to drinking water. Ibuprofen alone or ibuprofen plus dithiocarbamate is given orally at a dose of 1, 10, or 30 mg/kg (6 animals each group) . After one hour, the rats are anesthetized and 0.1 ml of lambda carrageenan (0.1% solution) is injected into the right hind foot pad. The volume of the pad is measured by hydroplethysmometry every hour for the next five hours .
  • Wistar rats male, 200-250 g are fasted overnight but allowed free access to drinking water. The rats are anesthetized and their backs are shaved. After an incision to the back, a sponge (2.5 x 1 x 0.5 cm) soaked with 2 ml of 0.5% carrageenan is implanted. Five hours later, the rats (6 animals in each group) are given orally either ibuprofen alone or ibuprofen plus dithiocarbamate at a dose of 30 mg/kg or vehicle control. One hour later, the rat is sacrificed and the sponge is carefully removed. The exudate is recovered from the sponge and the prostaglandin E2 level in the exudate is measured by enzyme-linked immunosorbent assay.
  • mice Male, 20-25 g are fed a standard diet and allowed free access to drinking water.
  • the mice are anesthetized and the telemetry system consisting of implantable transmitters, a telemetry receiver and analog ECG adapter is implanted in the peritoneal cavity of each mouse. After surgery, the mice are allowed to recover for two weeks .
  • the mice are given intravenously either adriamycin alone or adriamycin plus dithiocarbamate at a dose of 4 mg/kg through the tail vein.
  • the treated mice are observed for two weeks.
  • the body weight, ECG and heart rate are recorded daily. At the end of the study, the animals are sacrificed and the hearts are processed for histological evaluation.

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Abstract

Selon la présente invention, on décrit pour la première fois que du disulfure de carbone CS2 peut inhiber directement l'activité de NFλB (facteur nucléaire kappa B) sans que la présence d'autres agents ne soit nécessaire. On en a déduit, par conséquent, que l'on pouvait attribuer l'effet inhibiteur sur le facteur NFλB, par exemple du dithiocarbamate de pyrrolidine et d'autres dithiocarbamates, plutôt au CS2, libéré lors d'une hydrolyse in vivo de dithiocarbamates, qu'au résultat de l'action du composé parentéral en lui-même. On peut donc considérer des dithiocarbamates comme des promédicaments de CS2, dans le traitement d'états inflammatoires induits par des mécanismes d'action du facteur NFλB. Ainsi, selon l'invention, on décrit des procédés de traitement d'états inflammatoires induits par des mécanismes d'action du facteur NFλB, de même que des nouvelles compositions utiles dans de tels procédés.
PCT/US1999/002679 1998-02-13 1999-02-08 Procedes d'apport regule de disulfure de carbone dans le traitement d'etats inflammatoires WO1999040907A1 (fr)

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WO2001021206A1 (fr) * 1999-09-17 2001-03-29 Suntory Limited MOYENS DE PREVENTION OU REMEDES CONTRE LA MYOCARDITE, LA CARDIOMYOPATHIE DILATEE ET L'INSUFFISANCE CARDIAQUE CONTENANT DES INHIBITEURS NF-λB EN TANT QU'INGREDIENT ACTIF
DE10252772A1 (de) * 2002-11-13 2004-05-27 Beiersdorf Ag Verwendung von einem oder mehreren Diethyldithiocarbamaten zur Herstellung von kosmetischen oder dermatologischen Zubereitungen zur Prophylaxe und Behandlung von entzündlichen Hautzuständen und/oder zum Hautschutz bei empfindlich determinierter und trockener Haut
EP1510207A1 (fr) * 2002-06-05 2005-03-02 Institute of Medicinal Molecular Design, Inc. Medicaments therapeutiques destines au diabete
EP1512397A1 (fr) * 2002-06-06 2005-03-09 Institute of Medicinal Molecular Design, Inc. Derives hydroxyaryle o-substitues
EP1512396A1 (fr) * 2002-06-05 2005-03-09 Institute of Medicinal Molecular Design, Inc. Inhibiteurs de l'activation de ap-1 et de nfat
EP1514544A1 (fr) * 2002-06-06 2005-03-16 Institute of Medicinal Molecular Design, Inc. Anti-allergique
EP1535610A1 (fr) * 2002-06-10 2005-06-01 Institute of Medicinal Molecular Design, Inc. Agent therapeutique pour soigner le cancer
EP1535609A1 (fr) * 2002-06-10 2005-06-01 Institute of Medicinal Molecular Design, Inc. Inhibiteur de l'activation de nf-kb
EP1555018A1 (fr) * 2002-06-11 2005-07-20 Institute of Medicinal Molecular Design, Inc. Traitements des maladies neurodegeneratives
US7671058B2 (en) 2006-06-21 2010-03-02 Institute Of Medicinal Molecular Design, Inc. N-(3,4-disubstituted phenyl) salicylamide derivatives
WO2013050426A1 (fr) * 2011-10-04 2013-04-11 Universitetet I Oslo Inhibiteurs d'anhydrase carbonique
CN111041014A (zh) * 2019-12-31 2020-04-21 浙江工业大学 一种磁性固定化脂肪酶及其在拆分1-甲基-3-苯丙胺中的应用

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US6703421B1 (en) 1999-09-17 2004-03-09 Daiichi Suntory Pharma Co., Ltd. Methods of using phenylmethylbenzoquinone and hydroquinone compounds for treatment of myocarditis, dilated cardiomyopathy and heart failure
JP4660045B2 (ja) * 1999-09-17 2011-03-30 松森　　昭 ＮＦ−κＢ阻害剤を有効成分とする心筋炎、拡張型心筋症および心不全の予防または治療薬
WO2001021206A1 (fr) * 1999-09-17 2001-03-29 Suntory Limited MOYENS DE PREVENTION OU REMEDES CONTRE LA MYOCARDITE, LA CARDIOMYOPATHIE DILATEE ET L'INSUFFISANCE CARDIAQUE CONTENANT DES INHIBITEURS NF-λB EN TANT QU'INGREDIENT ACTIF
EP1510207A4 (fr) * 2002-06-05 2008-12-31 Inst Med Molecular Design Inc Medicaments therapeutiques destines au diabete
EP1510207A1 (fr) * 2002-06-05 2005-03-02 Institute of Medicinal Molecular Design, Inc. Medicaments therapeutiques destines au diabete
EP1512396A1 (fr) * 2002-06-05 2005-03-09 Institute of Medicinal Molecular Design, Inc. Inhibiteurs de l'activation de ap-1 et de nfat
EP1512396A4 (fr) * 2002-06-05 2008-12-31 Inst Med Molecular Design Inc Inhibiteurs de l'activation de ap-1 et de nfat
EP1514544A4 (fr) * 2002-06-06 2009-01-07 Inst Med Molecular Design Inc Anti-allergique
US7626042B2 (en) 2002-06-06 2009-12-01 Institute Of Medicinal Molecular Design, Inc. O-substituted hydroxyaryl derivatives
EP1512397A1 (fr) * 2002-06-06 2005-03-09 Institute of Medicinal Molecular Design, Inc. Derives hydroxyaryle o-substitues
EP1512397A4 (fr) * 2002-06-06 2009-01-07 Inst Med Molecular Design Inc Derives hydroxyaryle o-substitues
EP1514544A1 (fr) * 2002-06-06 2005-03-16 Institute of Medicinal Molecular Design, Inc. Anti-allergique
EP1535610A1 (fr) * 2002-06-10 2005-06-01 Institute of Medicinal Molecular Design, Inc. Agent therapeutique pour soigner le cancer
EP1535609A4 (fr) * 2002-06-10 2009-01-07 Inst Med Molecular Design Inc Inhibiteur de l'activation de nf-kb
EP1535610A4 (fr) * 2002-06-10 2008-12-31 Inst Med Molecular Design Inc Agent therapeutique pour soigner le cancer
EP1535609A1 (fr) * 2002-06-10 2005-06-01 Institute of Medicinal Molecular Design, Inc. Inhibiteur de l'activation de nf-kb
EP1555018A1 (fr) * 2002-06-11 2005-07-20 Institute of Medicinal Molecular Design, Inc. Traitements des maladies neurodegeneratives
EP1555018A4 (fr) * 2002-06-11 2009-01-07 Inst Med Molecular Design Inc Traitements des maladies neurodegeneratives
DE10252772A1 (de) * 2002-11-13 2004-05-27 Beiersdorf Ag Verwendung von einem oder mehreren Diethyldithiocarbamaten zur Herstellung von kosmetischen oder dermatologischen Zubereitungen zur Prophylaxe und Behandlung von entzündlichen Hautzuständen und/oder zum Hautschutz bei empfindlich determinierter und trockener Haut
US7671058B2 (en) 2006-06-21 2010-03-02 Institute Of Medicinal Molecular Design, Inc. N-(3,4-disubstituted phenyl) salicylamide derivatives
WO2013050426A1 (fr) * 2011-10-04 2013-04-11 Universitetet I Oslo Inhibiteurs d'anhydrase carbonique
CN111041014A (zh) * 2019-12-31 2020-04-21 浙江工业大学 一种磁性固定化脂肪酶及其在拆分1-甲基-3-苯丙胺中的应用

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