| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 09.99 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 14.09.99 |
| PATENT TITLE |
Treating diseases of the anterior horn cells |
| PATENT ABSTRACT |
Administration of aminopyridine, preferably 3,4-diaminopyridine, increases motor strength and Functional Independence Measure in humans afflicted with diseases of the anterior horn cells, e.g., amyotrophic lateral sclerosis. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 23.12.93 |
| PATENT REFERENCES CITED |
Schmutzler et al., Anaesthesist 33(6), 1984, pp. 294-295. Bever, C.T., et al, Ann. Neurol, 27, 421-427 (1990). Bostock, H., et al, J. Physiol., 313, 301-315 (1981). Kaji, R., et al, Neurology, 38, 1884-1887 (1988). Lemeignan, M., et al, Brain Res., 304, 166-169 (1984). Lundh, H., et al, Journal of the Neurol. Sciences, 32, 29-43 (1977). Lundh, H., Brain Res. 153, 307-318 (1978). Matsumoto, M., et al, J. Pharmacol. Exp. Ther., 228, 573-578 (1984). McEvoy, K.M., et al, The New England Journ. of Med., 321, 1567-1571 (1989). Murray, N.B., et al, Neurology, 31: 265-271 (1981). Sherratt, R.M., et al, Nature, London, 283, 570-572 (1980). |
| PATENT CLAIMS |
What is claimed is: 1. A method of treating a human having a disease of the anterior horn cells, said method comprising administering an aminopyridine having the formula ##STR2## wherein x is 1 or 2, to said human in a therapeutically effective amount, thereby to increase motor strength in said human. 2. The method of treating a human having a disease of the anterior horn cells as recited in claim 1 wherein the aminopyridine is 3,4-diaminopyridine. 3. The method of treating a human having a disease of the anterior horn cells as recited in claim 1 wherein the disease is amyotrophic lateral sclerosis. 4. The method of claim 3 wherein the aminopyridine is 3,4-diaminopyridine. 5. The method of treating a human having a disease of the anterior horn cells as recited in claim 1 wherein the therapeutically effective amount ranges from about 5 to 100 mg per day. 6. The method of treating a human having a disease of the anterior horn cells as recited in claim 5 wherein the therapeutically effective amount ranges from about 30 to 100 mg per day. 7. The method of treating a human having a disease of the anterior horn cells as recited in claim 5 wherein said human is also treated with rehabilitation therapy. 8. The method of claim 1 wherein the aminopyridine has the depicted formula wherein x is 2. 9. The method of claim 8 wherein said disease is amyotrophic lateral sclerosis. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD This invention is directed to treating a human with a disease of the anterior horn cells, to increase motor strength in said human. BACKGROUND OF THE INVENTION Diseases of the anterior horn cells are characterized by death of motor neurons resulting in prolonged and sometimes permanent and progressive motor weakness. The conventional therapy for the motor weakness is rehabilitation therapy, i.e., physical and/or occupational therapy. SUMMARY OF THE INVENTION It has been discovered herein that administration of aminopyridine compound, preferably 3,4-diaminopyridine, to a human affected with a disease of the anterior horn cells causes increased motor strength in the affected human. In short, the present invention is directed to a method for treating a human with a disease of the anterior horn cells, said method comprising the step of administering aminopyridine having the formula ##STR1## wherein x is 1 or 2 (hereinafter sometimes referred to as "an aminopyridine compound herein" or as "the aminopyridine compounds herein"), to said human in a therapeutically effective amount, thereby to increase motor strength in said human. It is preferably used as an adjunct to rehabilitative therapy, i.e., physical and/or occupational therapy, to enhance the therapeutic benefit (i.e., the motor strength improving benefit) thereof. The experimental work herein was carried out on those with amyotrophic lateral sclerosis; however, the invention has application to all diseases of the anterior horn cells. Preferred dosages range from 30 to 100 mg per day. The phrase "cause increased motor strength" is used herein to mean increased motor strength within one hour of administration of an aminopyridine compound herein compared to motor strength prior to administration of said aminopyridine compound. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts graphs of plasma concentration of 3,4-diaminopyridine versus time after dose for 7 patients and shows results of Example I. FIG. 2 depicts graphs of motor score versus time of motor test performance, for 7 patients, and for mean values, and shows results of Example I. FIG. 3 depicts graphs of Functional Independence Measure (FIM) score versus time of FIM test performance, for 7 patients, and for mean values, and shows results of Example I. DETAILED DESCRIPTION The invention herein applies to all diseases of the anterior horn cells. These include infectious diseases, e.g., acute infectious poliomyelitis (illness characterized by viral invasion of the central nervous system, resulting in disseminated death of motor neurons, producing motor weakness and paralysis, caused, for example by infection by any of three types of poliovirus, other enteroviruses such as Coxsackieviruses A and B and echo picorna viruses), post polio syndrome (a chronic condition that occurs in polio survivors after a substantial time has elapsed since the acute phase of the illness, characterized by progressive weakness and functional disability developing in an individual with previously static deficits, and Creutzfeld-Jacob Syndrome; nutritional and toxic disorders, e.g., Combined System Disease (a syndrome which includes damage to upper and lower motor neurons, caused by vitamin B.sub.12 deficiency), and degeneration of motor neurons after exposure to aluminum, vincristine or acetyl ethyl tetramethyl tetralin; structural disorders, e.g., mass occupying lesions of the spinal cord indirectly impinging on motor neurons, causing dysfunction and cell death, including, e.g., syringomyelia (cyst), malignant metastatic tumors, primary spinal cord tumors (ependymoma, glioma), and vascular malformations; traumatic injuries, e.g., acute cervical spinal cord injury associated with delayed progressive "drop-out" of post-synaptic anterior horn cells in thoracic and lumbar cord; and degenerative diseases, e.g., amyotrophic lateral sclerosis (also referred to as ALS), progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, presenile dementia with motor neuron disease, spinal muscular atrophies, olivopontocerebellar atrophy, Joseph disease, Parkinson's disease, Huntington's chorea and Pick's disease. Aminopyridine compounds having the above structural formula wherein x is 1 are 2-aminopyridine, 3-aminopyridine and 4-aminopyridine. Aminopyridine compounds having the above structural formula wherein x is 2 are 2,3-diaminopyridine; 2,5-diaminopyridine; 2,6-diaminopyridine; 3,4-diaminopyridine; 4,5-diaminopyridine and 4,6-diaminopyridine. Citations to the preparation of 2-aminopyridine and 3-aminopyridine are found in the Merck Index, 11th edition at page 488. The compound 4-aminopyridine is a known compound. See for example, Booth et al U.S. Pat. No. 4,508,715; Bostock, H., et al, J. Physiol., 313:301-315 (1981); and Lundh, H., Brain Res., 153:307-318 (1978). The compound 3,4-diaminopyridine is commercially available, e.g., from Regis Chemical Corporation, Morton Grove, Ill. The syntheses of the others of the aminopyridine compounds herein are considered obvious. The aminopyridine compounds herein are readily formulated for administration in solid dosage form together with conventional carriers and excipients, e.g., starch, lactose, cellulose derivatives, magnesium stearate, stearic acid, and the like or in liquid dosage form, e.g., together with injectable liquid, e.g., water or isotonic saline. The aminopyridine compounds herein are readily administered orally or parenterally (e.g., intravenously). A therapeutically effective amount of aminopyridine compound herein, i.e., an amount which increases motor strength, generally ranges from 5 mg to 100 mg per day. Maximum tolerated dosage within this range can be readily established by starting with a low amount in said range and increasing dosage daily until 100 mg is reached or a lesser limit is determined by development of laboratory abnormalities or level of side effect(s) unacceptable to the patient. For example, a maximum tolerated dosage for 3,4-diaminopyridine can be established by starting with 20 mg for the first day and increasing by 10 mg per day to obtain a maximum tolerated dosage as determined by complaint by the patient of a level of abdominal cramping unacceptable to the patient, of no more than 100 mg per day. Typically, a maximum tolerated dosage of aminopyridine compound herein ranges from 30 mg to 100 mg per day. The therapeutically effective amount is preferably the maximum tolerated dosage administered either as a single dose, or for extended effect, divided into multiple doses administered no more often than at intervals of 1-3 hours, e.g. divided into four doses administered at intervals of three hours during waking hours. Serum level monitoring is appropriately utilized to develop dosages and dosage intervals after a first administration of the maximum tolerated dosage consistent with not exceeding the peak serum level obtained after administration of the maximum tolerated dosage. Preferably, the treatment with aminopyridine compound herein is carried out as an adjunct to rehabilitation therapy on motor weakness, i.e., physical and/or occupational therapy, e.g., carried out on a daily basis, e.g., five days a week. The two treatments (aminopyridine administration and rehabilitation therapy) are considered to reinforce each other, i.e., the treatment with the aminopyridine causes the rehabilitation therapy to be more successful. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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