WO1987002583A1 - Traitement des maladies de demyelinisation - Google Patents

Traitement des maladies de demyelinisation Download PDF

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Publication number
WO1987002583A1
WO1987002583A1 PCT/US1986/002298 US8602298W WO8702583A1 WO 1987002583 A1 WO1987002583 A1 WO 1987002583A1 US 8602298 W US8602298 W US 8602298W WO 8702583 A1 WO8702583 A1 WO 8702583A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
colchicine
treatment
active ingredient
demyelinating diseases
Prior art date
Application number
PCT/US1986/002298
Other languages
English (en)
Inventor
Herman J. Weinreb
Original Assignee
The Rockefeller University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Rockefeller University filed Critical The Rockefeller University
Publication of WO1987002583A1 publication Critical patent/WO1987002583A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids

Definitions

  • This: invention relates to the treatment of demyelinating diseases f particularly multiple sclerosis (MS), with colchicine or_ colchiceine.
  • MS multiple sclerosis
  • Demyelinating diseases of central or peripheral origin are diseases which destroy myelin which is a substance compounded principally of fats and proteins. It is wrapped in numerous thin layers around nerve fibers where it acts as an insulator and speeds the transmission of messages along the nerve fibers. These afflictions include for example MS, Guillain-Barre syndrome and polymyositis. Of these, MS is by far the most prevalent. This invention will be described principally as it relates to MS.
  • MS is a disease of profound suffering and pervasive disability, the etiology of which remains unknown despite intensive investigation. It consists of patches or plagues of damaged myelin scattered throughout the central nervous system resulting from demyelination and subsequent scar formation.
  • multiple sclerosis describes the fact that in this disease there are many damaged areas filled with sclerotic (scar) .tissue. Over a long period, new scar tissue may develop or old ones enlarge. The result is progressive degeneration of the nervous system resulting in progressive debilitation of the afflicted individual.
  • SL'_ OSTITUTE SHEET MS significantly affects the most productive human age group (20-40 yrs). There are close to a million victims in the United States alone. The chief consequence of the disease is increasing deterioration of neurological function. Most victims are confined to wheelchairs or bed after 10 years. The prevalence ranges from 50/100,000 in the United States to 200/100,000 in Canada, Northern Great Britain, parts of France, Scandinavia and Russia.
  • ACTH has been of some benefit in promoting remission of acute attacks, but has not been shown to modify the overall course of the disease.
  • Combination therapy with ACTH and cyclophosphamide have shown some promise in temporarily halting the progression of severe MS.
  • the work is very recent, and no final conslusion has been possible.
  • Copolymer-I a synthetic polypeptide resembling myelin basic protein has shown some benefit, but these results are also too recent for proper evaluation.
  • Colchicine is (S)-N-(5,6,7,9-tetrahydro-9-oxabenzo [a] heptaten-7-yl) acetamide. It has long been known as a therapeutic agent for humans, particularly as a gout suppressant and in the treatment of Familial Mediterranean Fever. It may be safely administered both orally and parenterally. Its activity in the mammalian body is well known and understood. Colchiceine is the 10- demethylated homolog of colchicine. It has also been used for the same purposes. Colchicine is the preferred therapeutic agent for the known utilities. It is also the preferred agent for use in this invention because it is readily available at reasonable cost and is extremely effective in retarding the progression of MS.
  • colchicine and colchiceine may be administered to humans to treat demyelinating diseases, such as MS by retarding the process of demyelination. It is most convenient to administer the therapeutic agent orally, but parenteral administration including intravenous or intramuscular injection may also be employed.
  • An effective dose for treating the disease will vary with a number of factors well known and understood by the physician. These include, for example, age and weight of the patients and the status of the disease.
  • SHEET may vary from about .02 to .04 mg/kg of body weight per day.
  • the required dosage will be administered once a day in a sustained release doage unit which may contain 1.2 to 2.4 mg of active compound as the principal active ingredient.
  • a sustained release doage unit which may contain 1.2 to 2.4 mg of active compound as the principal active ingredient.
  • Another convenient dosage unit is a scored tablet, each tablet containing 0.2 to 0.4 mg of active agent per scored segment. Such tablets are particularly useful since they permit the physician to investigate a large number of dosage regimens and titrate the optimum effective dosage for an individual patient.
  • the oral and parenteral dosage units will be prepared in accordance with standard procedures and will contain the selected active compound as the only or principal active ingredient in the composition.
  • Any of a wide variety of known inert excipients may be employed to prepare compositions useful in the practice of this invention. These include, for example, dextrose, starch, talc, various types of clay, mineral oil, cottonseed or sesame oil, as well as water or various miscible and immiscible aqueous compositions in which the therapeutic agent is soluble or may be suspended with the aid of known surfactants.
  • the active ingredient can be formulated in tablet form with water soluble binding agents such as lactose or other palatable carbohydrates.
  • SUBSTITUTE SHEET For rectal administration suppositories or inserts containing the active ingredient dispersed in such reagents as cocoa butter, petroleum, or other natural lubricants or in a synthetic emmollient such as polyethylene glycol 1000 or polyethylene glycol 4000 may be used.
  • Transdermal administration will normally be from sustained release preparation which may be applied as a patch or. from a gauze applied to the skin.
  • the preferred method of administering the active agents of this invention is from sustained release dosage forms since this is most convenient for patients, and avoids the necessity of constant clock watching or interruption of normal daily activities.
  • a number of compositions suitable for such preparations are known and can be usefully employed.
  • One convenient procedure is to formulate the selected motility control agent in a time disintegrating tablet or pellet coated with various thicknesses of known materials such as carnauba wax, cellulose esters and ethers, fats, keratin, gluten or various natural or synthetic esters.
  • Tablets in which the motility control agent is ⁇ contained in a slowly dissolving core such as a core of stearic acid or castor oil are useful.
  • Mixed release granule tablets comprising mixtures of the drug itself and the drug in separate particles coated with materials which dissolve at different rates such as dehydrogenated castor oil or fatty acids can also be employed.
  • the active material can be bound to an ion exchange resin such as a sulfuric acid type cation exchange resin.
  • the active agents of this invention are useful in treating the diseases to which this disclosure applies by inhibiting demyelination, thereby abating the progression of neurological disability.
  • MS were treated orally using tablets containing 0.6 mg of colchicine three times per day.
  • Treatment failure was defined as a decline in either the DSS or the Al/UEI by one point or the FSS by two points for a period of one month after beginning colchicine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Méthode de traitement de maladies de démyélinisation telles que la sclérose en plaques par un traitement à base de colchicine ou colchicéine.
PCT/US1986/002298 1985-10-29 1986-10-27 Traitement des maladies de demyelinisation WO1987002583A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US79261085A 1985-10-29 1985-10-29
US792,610 1985-10-29

Publications (1)

Publication Number Publication Date
WO1987002583A1 true WO1987002583A1 (fr) 1987-05-07

Family

ID=25157487

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1986/002298 WO1987002583A1 (fr) 1985-10-29 1986-10-27 Traitement des maladies de demyelinisation

Country Status (3)

Country Link
EP (1) EP0245368A4 (fr)
JP (1) JPS63501154A (fr)
WO (1) WO1987002583A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256385A2 (fr) * 1986-08-02 1988-02-24 BEHRINGWERKE Aktiengesellschaft Utilisation de la 15-déoxyspergualine comme médicament
EP4338740A1 (fr) 2022-09-13 2024-03-20 Johannes Gutenberg-Universität Mainz Timbre transdermique pour favoriser ou accélérer la myélinisation et/ou la remyélinisation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
British Medical Journal, 20 January 1979, pages 199-200, HORROBIN et al, "Polyunsaturated fatty, Acids and Colchine in Multiple Sclerosis *
See also references of EP0245368A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0256385A2 (fr) * 1986-08-02 1988-02-24 BEHRINGWERKE Aktiengesellschaft Utilisation de la 15-déoxyspergualine comme médicament
EP0256385A3 (fr) * 1986-08-02 1992-04-01 BEHRINGWERKE Aktiengesellschaft Utilisation de la 15-déoxyspergualine comme médicament
EP4338740A1 (fr) 2022-09-13 2024-03-20 Johannes Gutenberg-Universität Mainz Timbre transdermique pour favoriser ou accélérer la myélinisation et/ou la remyélinisation

Also Published As

Publication number Publication date
EP0245368A4 (fr) 1988-01-25
EP0245368A1 (fr) 1987-11-19
JPS63501154A (ja) 1988-04-28

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