WO1998024449A1 - Utilisation d'oxandrolone dans le traitement d'un trouble d'ordre neurologique - Google Patents

Utilisation d'oxandrolone dans le traitement d'un trouble d'ordre neurologique Download PDF

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Publication number
WO1998024449A1
WO1998024449A1 PCT/US1997/022333 US9722333W WO9824449A1 WO 1998024449 A1 WO1998024449 A1 WO 1998024449A1 US 9722333 W US9722333 W US 9722333W WO 9824449 A1 WO9824449 A1 WO 9824449A1
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WIPO (PCT)
Prior art keywords
oxandrolone
muscular dystrophy
patient
muscle
administered
Prior art date
Application number
PCT/US1997/022333
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English (en)
Inventor
Gerald Fenichel
Original Assignee
Gerald Fenichel
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 Gerald Fenichel filed Critical Gerald Fenichel
Priority to AU76228/98A priority Critical patent/AU7622898A/en
Publication of WO1998024449A1 publication Critical patent/WO1998024449A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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

  • Oxandrolone (17-methyl-17-hydroxy-2-oxa-5-androstan-3-one) is a known compound which is commercially available. The preparation of oxandrolone is described, inter alia, in U.S. Patent No. 3,128,283.
  • Oxandrolone is an anabolic steroid synthetically derived from testosterone. Oxandrolone has a unique chemical structure compared with other testosterone analogs. Oxandrolone contains an oxygen rather than a carbon atom at the 2 -position within the phenanthrene nucleus (1) and lacks a 4-ene function in the A-ring. The anabolic activity of oxandrolone is approximately 6 times greater than its androgenic activity and has been found to be 6.3 times greater than that of methyltestosterone (1).
  • Anabolic activity refers to the ability to cause nitrogen retention, promoting weight gain and increasing muscle strength.
  • Androgenic activity refers to the ability to enhance male characteristics (i.e. secondary sex characteristics such as facial hairs and voice changes) . Because of the high ratio of anabolic to androgenic activity, oxandrolone is less likely to cause adverse cosmetic consequences in women than many testosterone analogs .
  • oxandrolone undergoes relatively little hepatic metabolism (2, 3) .
  • Oxandrolone has been administered to malnourished patients with alcoholic hepatitis (4, 5) . Oxandrolone has been shown to be safe even in dosages of up to 80 mg/day in patients with alcoholic hepatitis (4) .
  • the subject invention discloses the use of an oxandrolone in the treatment of a symptom associated with a neurological disorder.
  • the subject invention provides a method of treating a symptom associated with a neurologic disorder in a patient which comprises administering an oxandrolone to the patient.
  • Oxandrolone as used herein encompasses 17-methyl-17-hydroxy- 2-oxa-5-androstan-3-one (both racemic mixtures and optically active enantiomers) as well as pharmaceutically acceptable esters thereof.
  • an oxandrolone product which is commercially available is the Oxandrin ® tablet from BTG Pharmaceuticals Corp., Iselin, NJ 08830, which is 17OU- methyl-17/3-hydroxy-2-oxa-5 ⁇ :-androstan-3-one . This product was used throughout the studies described herein.
  • Oxandrolone may be administered orally, intravenously, intramuscularly, subcutaneously, topically, intratracheally, intrathecally, intraperitoneally, rectally, vaginally or intrapleurally.
  • oxandrolone is administered orally, it is administered in the form of a tablet, a pill, a liquid or a capsule.
  • a liquid may be administered in the form of a solution or a suspension.
  • compositions produced in accordance with the invention may comprise conventional pharmaceutically acceptable diluents or carriers.
  • Tablets, pills, liquids and capsules may include conventional excipients such as lactose, starch, cellulose derivatives, hydroxypropyl methylcellulose and magnesium stearate.
  • Suppositories may include excipients such as waxes and glycerol .
  • injectable solutions will comprise sterile pyrogen-free media such as saline and may include buffering agents, stabilizing agents, solubilizing agents or preservatives. Conventional enteric coatings may also be used.
  • Compositions for topical administration may be in the form of creams, ointments, lotions, solutions, transdermal delivery systems, transdermal patches or gels.
  • a neurologic disorder as used herein encompasses any neurologic disorder as defined and described in "The Merck Manual", sixteenth edition (1992). For example, muscular dystrophy, myasthenia gravis, multiple sclerosis, Alzheimer's disease, neuropathy, and amyotrophic lateral sclerosis (Lou Gehrig's disease) are neurologic disorders.
  • poliomyelitis is also a neurologic disorder.
  • Muscular dystrophy is a group of inherited, progressive muscle disorders of unknown etiology. Examples of muscular dystrophy are Duchenne/Becker Muscular Dystrophy (DMD) and Landouzy-Dejerine muscular dystrophy.
  • DMD is an inexorably progressive disease of muscle that results in severe disability by the age of 10 to 12 years and in death at about 20 years. It is inherited by X-linked inheritance and caused by disturbances at the Xp21 locus.
  • the abnormal gene product is dystrophin, a protein that links f-actin to a transsarcolemmal dystroglycan complex whose function may be to transmit the force of contraction to the extracellular matrix.
  • Boys with DMD have no dystrophin at birth but are asymptomatic for several years. The absence of dystrophin does not cause weakness but rather increases the vulnerability of muscle fibers to necrosis from ordinary forces. Gene-replacement therapy would be the optimal treatment but is not expected to be available in the near future. Therefore, other means are being sought to decrease the rate of muscle breakdown and to increase strength in children with DMD.
  • Myasthenia gravis is a disorder of neuromuscular transmission and is characterized by episodic muscle weakness, mainly in muscles innervated by cranial nerves.
  • Poliomyelitis is an acute viral infection with a wide range of manifestations, including non-specific minor illness, aseptic meningitis (nonparalytic poliomyelitis) , and flaccid weakness of various muscle groups (paralytic poliomyelitis) .
  • Alzheimer's disease is a progressive degenerative condition with general atrophy of the brain with loss of neurons and reduced synaptic density in cerebral cortex.
  • Neuropathy is frequent among alcoholics and the malnourished. Neuropathy is also a neurocomplication in short-bowel syndromes, in diabetic patients and as a result of radiation injury. Neuropathy can also be hereditary.
  • Hereditary neuropathies are either hereditary sensory-motor neuropathies or hereditary sensory neuropathies. Examples of these neuropathies are peroneal muscular atrophy
  • CMT Charge-Marie-Tooth
  • ALS Amyotrophic Lateral Sclerosis
  • Interferon as used herein encompasses any interferon, preferably beta-interferon.
  • Corticosteroid as used herein encompasses inter alia glucocorticoids, mineralcorticoids and androgens .
  • glucocorticoids are hydrocortisone, cortisone, corticosterone and synthetic analogs of hydrocortisone and cortisone (such as cortisol, prednisolone and prednisone) .
  • mineralcorticoids are aldosterone and desoxycorticosterone.
  • Examples of androgens are DHEA, andros t enedione , testosterone and 11/3- hydroxyandrostenedione .
  • the subject invention provides a method to slow down the progression of weakness in a patient suffering from muscular dystrophy such as Duchenne Muscular Dystrophy which comprises administering an oxandrolone to the patient.
  • the subject invention provides a method to strengthen the muscles of a patient who suffers from muscle dystrophy which comprises administering an oxandrolone to the patient.
  • the subject invention provides a method of treating a symptom associated with a neurologic disorder in a patient which comprises administering a therapeutically effective amount of an oxandrolone to the patient.
  • the subject invention also provides a use of an oxandrolone in the preparation of a composition to treat a symptom associated with a neurologic disorder.
  • the subject invention also provides a use of an oxandrolone in the preparation of a composition to slow down the progression of weakness in a patient suffering from muscular dystrophy.
  • the subject invention also provides a use of an oxandrolone in the preparation of a composition to strengthen the muscles in a patient suffering from muscle dystrophy.
  • the oxandrolone may be administered in conjunction with a corticosteroid, an interferon or any known anti-inflammatory agent .
  • the oxandrolone may also be administered in conjunction with glutamine or human growth hormone.
  • the neurologic disorder is selected from the group consisting of muscular dystrophy, multiple sclerosis, poliomyelitis, or amyotrophic lateral sclerosis.
  • the muscular dystrophy is Duchenne muscular dystrophy.
  • the amount of oxandrolone administered is about 0.05-0.2 mg/kg/day.
  • the oxandrolone may be administered in a solid dosage form, in a liquid dosage form, in a sustained-release formulation or in a once a day formulation.
  • the liquid dosage form may inter alia be alcohol -based or formulated with a cyclodextrin such as hydroxypropyl-j ⁇ -cyclodextrin.
  • Oxandrolone was supplied by Bio - Technology General Corp . in tablets containing 2.5 mg of oxandrolone and the inactive ingredients: corn starch, lactose, magnesium stearate, and hydroxypropyl methylcellulose . After the initial evaluation each boy was given 0.1 mg/kg/day of oxandrolone. All study subjects took the medication daily throughout the course of the three month trial .
  • the average muscle score is used as the primary outcome measure because it remains linear throughout the course of disease (7) , and the reliability is high from visit-to-visit and between the two clinical evaluators (8) . Results are expressed as mean + standard error. The mean of the changes in the average muscle score for the ten boys measured at 1 and 3 months was calculated and compared to the mean of the changes in the average muscle score of the natural history controls (9) using a single group t-test.
  • prednisone has adverse effects that limit its long-term usefulness in many boys (13) .
  • Oxandrolone has not been used previously in children with neuromuscular disorders.
  • Stanozolol another anabolic steroid, increases muscle protein synthesis in boys with Duchenne muscular dystrophy (DMD) (14) , and supraphysiologic doses of testosterone, especially combined with exercise, increase fat-free mass and muscle size in normal men (15) .

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé de traitement d'un patient souffrant d'un symptôme associé à un trouble d'ordre neurologique, ce procédé consistant à administrer à ce patient une oxandrolone.
PCT/US1997/022333 1996-12-05 1997-12-05 Utilisation d'oxandrolone dans le traitement d'un trouble d'ordre neurologique WO1998024449A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76228/98A AU7622898A (en) 1996-12-05 1997-12-05 The use of oxandrolone in the treatment of a neurological disorder

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3210596P 1996-12-05 1996-12-05
US60/032,105 1996-12-05

Publications (1)

Publication Number Publication Date
WO1998024449A1 true WO1998024449A1 (fr) 1998-06-11

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PCT/US1997/022333 WO1998024449A1 (fr) 1996-12-05 1997-12-05 Utilisation d'oxandrolone dans le traitement d'un trouble d'ordre neurologique

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AU (1) AU7622898A (fr)
WO (1) WO1998024449A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1618881A1 (fr) * 2004-07-20 2006-01-25 Santhera Pharmaceuticals (Schweiz) GmbH Utilisation de stéroides sans activité glucocorticoide pour le traitment de la dystrophie musculaire

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4617299A (en) * 1983-12-19 1986-10-14 Knepper Paul A Method for the prevention of ocular hypertension, treatment of glaucoma and treatment of ocular hypertension
US5026692A (en) * 1985-11-13 1991-06-25 Research Development Corporation Of Japan Use of sex hormone
US5183815A (en) * 1991-01-22 1993-02-02 Merck & Co., Inc. Bone acting agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4617299A (en) * 1983-12-19 1986-10-14 Knepper Paul A Method for the prevention of ocular hypertension, treatment of glaucoma and treatment of ocular hypertension
US5026692A (en) * 1985-11-13 1991-06-25 Research Development Corporation Of Japan Use of sex hormone
US5183815A (en) * 1991-01-22 1993-02-02 Merck & Co., Inc. Bone acting agents

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1618881A1 (fr) * 2004-07-20 2006-01-25 Santhera Pharmaceuticals (Schweiz) GmbH Utilisation de stéroides sans activité glucocorticoide pour le traitment de la dystrophie musculaire
WO2006007910A1 (fr) * 2004-07-20 2006-01-26 Santhera Pharmaceuticals (Schweiz) Ag Utilisation de steroides non-glucocorticoides pour le traitement d'une dystrophie musculaire
AU2005263369B2 (en) * 2004-07-20 2009-02-05 Santhera Pharmaceuticals (Schweiz) Ag Use of non-glucocorticoid steroids for the treatment of muscular dystrophy
AU2005263369B9 (en) * 2004-07-20 2009-06-04 Santhera Pharmaceuticals (Schweiz) Ag Use of non-glucocorticoid steroids for the treatment of muscular dystrophy

Also Published As

Publication number Publication date
AU7622898A (en) 1998-06-29

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