Classifications

• • 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
  • A61K31/66—Phosphorus compounds
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes

Definitions

• This invention relates to a method for treating patients who have been exposed to toxic chemical agents .
• the method involves administering an effective amount of a disulfide or thiol-containing compound to a patient who has been exposed to a toxic chemical, or to prophylax persons who are regularly exposed to such agents.
• Toxic chemical agents may be grouped in any of a number of classifications.
• the most well known are the organophosphates, which include both pesticides and certain chemical agents classified as chemical warfare agents, and which include mustards and Lewisites.
• Sulfur and nitrogen mustards include many well-known chemical agents, for military purposes as well as for medicinal use.
• Lewisites which are chlorinated arsenic complexes, are particularly toxic agents.
• Atropine is a well-known natural product of the deadly nightshade plant family and may be administered topically to the skin or eyes, or parenterally in the event of a systematic exposure to cholinesterase inhibiting agents .
• Pralidoxime is a quaternary ammonium oxime that is classed as a cholinesterase re-activator, and is often administered to patients exposed to organophosphate based chemicals .
• Other treatment methods and agents for chemical exposure are also available.
• Mesna sodium 2-mercaptoethene sulfonate
• dimesna sodium 2, 2' -dithiobis ethane sulfonate
• mesna and dimesna have been shown to be effective protective agents against.-, certain specific types of toxicity associated with the administration of cytotoxic drugs used to treat patients for various types of cancer.
• mesna has been used with some success in mitigating the toxic effects of cytotoxic agents such as ifosfamide, oxazaphosphorine, melphalane, cyclophospha-mide, trofosfamide, sulfosfamide, chlorambucil, busulfan, triethylene thiophosphamide, triaziquone, and others, as disclosed in U.S. Patent 4,220,660, issued September 2, 1980.
• cytotoxic agents such as ifosfamide, oxazaphosphorine, melphalane, cyclophospha-mide, trofosfamide, sulfosfamide, chlorambucil, busulfan, triethylene thiophosphamide, triaziquone, and others, as disclosed in U.S. Patent 4,220,660, issued September 2, 1980.
• pharmacological profiles of each compound indicate that, if proper conditions are maintained, mesna and dimesna do not prematurely inactivate primary therapeutic drugs to a significant degree. Thus, neither compound will significantly reduce activity of the chemotherapeutic agent, and in many cases, act to potentiate the effect of the main drug on targeted cancer cells.
• dimesna is a di er of mesna, with the optimum conditions for oxidation occurring in the slightly basic (pH -7.3), oxygen rich environment found in blood plasma.
• a reducing agent such as glutathione reductase, conditions prevalent in the kidneys, the primary constituent is mesna.
• Mesna acts as a protective agent for a number of cytotoxic agents by substituting a nontoxic sulfhydryl moiety for a toxic hydroxy (or aquo) moiety.
• Dimesna as well as some analogues, have excellent toxicity profiles in mammalian species. In fact, dimesna has been administered intravenously to mice and dogs in doses higher than the accepted oral LD 5 o for common table salt (3750 g/kg) , with no adverse effects. Dimesna has also been administered to humans in doses exceeding 40 g/m 2 , with no adverse effects .
• Mesna, and other analogues with free thiol moieties constitute the more physiologically active form of the two types of compounds described in this specification. These compounds manifest their activity by providing free thiol moieties for terminal substitution at locations where a terminal leaving group of appropriate configuration, usually a hydroxy, aquo or superoxide is located. Mesna also tends to form conjugates with naturally occurring biochemicals that contain a free thiol moiety, such as cysteine, glutathione, homocysteine, and others.
• Dimesna and other disulfides can be activated intracellularly by glutathione reductase, a ubiquitous enzyme, thereby generating high concentrations of intracellular free thic ⁇ ls . These free thiols act to scavenge the free radicals and other nucleophilic compounds often responsible for causing cell damage.
• Ri is hydrogen, X-lower alkyl, or X-lower alkyl-R 3 ;
• R 2 is -lower alkyl-R 4 ;
• R 3 and R 4 are each individually S0 3 M or P0 3 M 2 ;
• X is absent or X is sulfur; and M is an alkali metal.
• the process essentially involves a two-step single pot synthetic process, which results in the conversion of an alkenyl sulfonate salt or acid to the desired formula I compound.
• the process in the case of mesna is a single step process that converts the alkenyl sulfonate salt to mesna or a mesna derivative by reacting with an alkali metal sulfide or with hydrogen sulfide .
• Step 1 is as described above.
• Step 2 of the process is performed in the same reaction vessel as Step 1 without the need to purify or isolate the mesna formed during that step.
• Step 2 includes the introduction of oxygen gas into the vessel, along with an increase in pressure and temperature above ambient values, at least 20 pounds per square inch (psi) and at least 60° C. Dimesna or a derivative thereof is formed in essentially quantitative yield.
• This invention involves the administration of an effective amount of a compound of formula I, below, for treating or mitigating the toxic adverse effects of toxic chemical exposure:
• Ri is hydrogen, lower alkyl or -(alkyl)m— R4 .
• R 2 and R 4 are each individually S0 3 ⁇ M + , P0 3 2 M 2 2+ , or P0 2 S ⁇
• R 3 and R 5 are each individually hydrogen, hydroxy, amino, nitro or sulfhydryl
• Each m is individually 1, 2, 3, 4, 5 or 6 with the proviso that if m is 1, then R 3 is hydrogen; and M is hydrogen or an alkali metal ion; or a pharmaceutically acceptable salt thereof.
• Effective amounts of the formula I compound to be administered according to the method of this invention are variable, and depend upon the severity of exposure and on the patient's response. Due to the excellent toxicity profile of the formula I compounds, large amounts of drug may be administered without risk of untoward side effects commonly associated with other drugs used to treat this condition.
• the formula I compound may be administered by oral route, allowing the patient to self-administer the agent, adding to convenience of use.
• the method also contemplates the possible administration of the formula I compound in combination with other agents to provide effective and safe treatment for toxic chemical exposure .
• Another object is to provide a method of treating a patient for toxic chemical exposure by administration of a thiol or reducible disulfide to the patient desirous of treatment.
• Another object is to provide for a safe and effective method of providing prophylaxis to a person at risk for toxic chemical exposure.
• the method of this invention involves the administration of an effective amount of a formula I compound to a patient suffering from complications of toxic chemical exposure.
• the effective amount of the formula I compound will depend upon the severity of the exposure and on the individual patient' s response to treatment. Since the formula I compounds are essentially nontoxic, large amounts can be safely administered.
• the preferred initial dosage to treat toxic chemical exposure will depend upon the level of exposure of each individual patient. Dosage may initially be as low as 0.1 mg/kg up to 3,000 mg/kg.
• the formula I compounds may be used to treat exposure to one or more of the toxic chemicals listed below in Tables 1 and 2.
• the formula I compound is dissolved in a suitable solvent, most preferably water, to produce a solution.
• a suitable solvent most preferably water
• One or more pharmaceutically acceptable excipients may also be added to provide for an elegant formulation.
• the formulation may also be incorporated into a continuous delivery device, such as an implanted parenteral infusional pump or similar device.
• the formula I compound may also be administered as a prophylactic measure to persons at risk for exposure to toxic chemicals.
• a person at risk is generally defined as one likely to come into contact with toxic chemicals in the near future, more specifically soldiers fighting an enemy known to possess chemical weapons, sportsmen and women, during periods immediately following application of pesticides, even civilians against whom a terrorist attack has been imminently threatened.
• Prophylactic administration according to this invention would preferably be through oral, topical or subdermal routes, most preferably in some form of time-release medicament.
• the formula I compound may be delivered subdermally, as by a skin patch. Skin patches and pumps have the advantage of continuous drug delivery without the need to take a pill every so often. Another means of administration is by aerosol spray, which can be sprayed on potential areas of skin exposure.
• the formula I compound is preferably combined with one or more pharmaceutically acceptable excipients, fillers and/or diluents.
• Oral dosage forms may include pills, caplets, tablets, a pleasantly flavored liquid solution or suspension, and others.
• the formula I compound may be contained in a deglutable container such as a gelatin capsule or the like. Since the half-life of the formula I compound is usually short, slow-release oral dosage forms are most preferred.
• the formula I compounds are believed to alleviate toxic chemical exposure by binding to the active, toxic species of the molecule and/or to its toxic metabolites. In so binding, the resultant compound is rendered relatively nontoxic and highly water soluble, which aids in its rapid elimination from the body.
• Administration of the formula I compound should preferably be started as soon as possible based on the clinical suspicion that a patient has been exposed to a toxic chemical, and may be administered to a patient who risks exposure, such as farmers, gardeners, pet groomers, veterinarians, soldiers or anyone else who risks exposure to such chemicals.
• the preferred initial dose is between 10 mg/kg and 1000 mg/kg. High doses may be repeated ad libitum until positive results are achieved.
• Dose rate may be altered depending upon the patient's response. if any adverse effects appear, the dose may be lowered or the timing changed. Dose alteration is well within the purview of one skilled in the medical arts. Slow release formulations of oral dosage forms are preferred in prophylaxis to provide for longer protection. In cases of continual exposure to pesticides, long-term affects may be controlled through administration of periodic amounts of the formula I compoun s . Also, due to the excellent safety profile, additional doses of the formula I compound may be administered safely if the initial dose does not produce a positive response. Treatment may be repeated as often as necessary.

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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Toxicology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2002
  • 2002-12-21 JP JP2004563152A patent/JP2006513190A/ja active Pending
  • 2002-12-21 MX MXPA05006721A patent/MXPA05006721A/es not_active Application Discontinuation
  • 2002-12-21 WO PCT/US2002/041238 patent/WO2004058274A1/en not_active Application Discontinuation
  • 2002-12-21 CA CA002511778A patent/CA2511778A1/en not_active Abandoned
  • 2002-12-21 CN CNA028301714A patent/CN1735417A/zh active Pending
  • 2002-12-21 EP EP02796029A patent/EP1583540A4/de not_active Withdrawn
  • 2002-12-21 AU AU2002360747A patent/AU2002360747B2/en not_active Ceased

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