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
  • A61K31/33—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

Definitions

• This invention concerns application of the heterocyclic indole; compound melatonin, Formula I, in a drug, bioaffecting, and body treating process and particularly an encephalotherapeutic process useful in the control of the symptoms of epilepsy, Parkinsonism, and the psychotherapeutic management of certain mental diseases 011.0- onzonznno 0 on3 DESCRIPTION OF THE PRIOR ART
• Parkinsons disease is a motor incapacitating disease characterized by rigidity and tremor of the limbs. The disease, has been treated mainly with anticholinergic compounds. Response is variable and dosage must be carefully adjusted for each patient. At best control of the symptomshas been only moderately successful.
• L dopa L-dihydroxyphenylalanine
• Melatonin the substance which has now been found to .be useful in the management of the foregoing conditions, is a hormone secreted by the pineal gland. It is a known compound which has been associated with the pineal gland since its identification as the pineal hormone in 1959 (Lerner and Case, J. Am. Chem. Soc. 81, 60845 (1959)). Although substantial biochemical and physiological research on the pineal gland and melatonin has been conducted during the last years, noclinically useful method of therapy based upon the knowledge developed has yet been suggested. The acute pharmacology of the compound has been described by Barchas et al., Nature 214, 912-20 (1967).
• the present invention involves the systemic administration by the oral or parenteral routes of an effective nontoxic dose ofmelatonin where it is desired to control the symptoms of epilepsy, Parkinsons disease, and some mental diseases.
• Administration of the substance exerts a marked calming effect on patients and causes changes in the electroencephalogram.
• a period of sleep follows administration of the drug, but other desired effects are sustained for a considerable period after the subject awakens.
• the EEG reflects an increase in alpha rhythm and with epileptics the paroxysmal activity is substantially diminished or eliminated.
• Parkinsonism a prompt diminution of muscle tremor occurs and after daily administration for several days marked reduction in rigidity with a concomitant increase in motor ability takes place.
• melatonin is substantially without undesired side eifects.
• the substance is well absorbed, well tolerated, and substantially non-irritating to the tissues and gastrointestinal tract.
• Subjective comments by normal individuals to whom the drug has been administred suggest that a rather pleasant sensation is involved. Following a normal sleep the patient is easily awakened and reports a feeling of comfort and well being. No impairment of alertness or judgment results.
• the effects reported are desirable for the management of patients having behavioral disorders such as manic depressive psychosis, senile dementia, and presenile dementia which are manifested by either agitation or depression since the drug has a claming effect yet induces a feeling of elation.
• Dosage is in the range of 0.5 to 2.0 g. per day, preferably divided into two or three units.
• the preferred dose is -1 g. per day orally. Lower doses can be effectively used, particularly when administered intravenously.
• the lowest dose found effective was 0.25 mg./kg. of body weight intravenously.
• the applicable dosage range for the management of each of the conditions with which the invention is concerned is 0.25 to 30 mg./kg. of body weight per day.
• a solution in 1% aqueous, ethanol is employed.
• solutions or suspensions in other parenteral liquid vehicles such as peanut oil are applicable.
• flavored suspensions or solutions may be employed, but tablets and capsules are generally adequate and are preferred.
• the average reaction time for the 10 subjects before treatment was 233.771-103 msec., and 90 minutes after treatment, 272.4:118 msec. At the end of 2 hours the experiment was concluded. At this time the subjects reported that they felt a sensation of well-being, comfort, and elation.
• Example 2 Epilepsy treatment.A patient, age 24 years, female, suffering from grand mal and temporal lobe epilepsy of 21 years duration and under treatment with sodium hydantoinate 300 mg. per day, carbamazepine 600 mg. per day, and phenothiazine mg. per day, was treated with a single dose of 0.25 mg./kg. of melatonin intravenously as a solution in 1% aqueous ethanol. A second patient, age 26, male, suffering from grand mal, myoclonic seizures, temporal lobe seizures and dementia of 17 years duration, and under treatment with sodium hydantoinate 300 mg. per day was treated similarly with a single dose of 1 mg./kg. of body weight of melatonin intravenously.
• Example 3 Epilepsy treatment.A 27 year old female suffering from grand mal, petit mal, myoclonic seizures, focal temporal lobe seizures, mental deficiency and secondary schizophrenia-like psychosis of 13 years standing was under treatment with sodium hydantoinate 100 mg. per day and diazepam 10 mg. per day. This treatment was discontinued for a period of five 'days before treatment with melatonin was initiated. On the first day of treatment, 60 mg. of melatonin was administered intravenously as a solution in 1%v aqueous ethanol, and on each of the second and third days 30 mg. was administered intravenously. The following electroencephalographic activity was observed on the first day following the 60 mg. dose.
• Example 4 Treatment of Parkinsons disease-An adult male patient suffering from Parkinsons disease of 4 years duration who had been treated previously with anti-ch0 linergic agents was withdrawn from all therapy for 5 days. During this period a panel of three physicians individually evaluated the patient with respect to rigidity, tremor, and motor ability. Melatonin, mg., divided into 2 doses daily was administered intravenously as a solution in 1% aqueous ethanol for a period of 1 week. On the third day of treatment the patient was again evaluated by the three physicians. At this time only slight diminution in rigidity had occurred, but the tremor had been substantially abolished. Motor ability had not substantially improved. At the end of the first week intravenous treatment was terminated and oral treatment was commenced at the rate of see mg.
• Tremor was measured both at rest and when the subject was attempting to button his coat, the latter being referred to as maximum tremor.
• Maximum tremor was usually found to diminish within 18 min. after dosage with melatonin during the course of therapy. Within 38 to '67 min. after melatonin treatment tremor was practically abolished and a distinct alpha rhythm was seen in the EEG.
• a process which comprises administering orally or parenterally to a patient suffering from behavioral disorder or epilepsy or Parkinsons disease an effective non-toxic dose of melatonin.

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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)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Cited By (5)

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• 1970
  • 1970-05-25 US US40393A patent/US3642994A/en not_active Expired - Lifetime
• 1971
  • 1971-02-12 CA CA105,249A patent/CA960966A/en not_active Expired
  • 1971-05-19 ZA ZA713249A patent/ZA713249B/xx unknown
  • 1971-05-21 NL NL7106993A patent/NL7106993A/xx not_active Application Discontinuation
  • 1971-05-21 DE DE19712125427 patent/DE2125427A1/de active Pending
  • 1971-05-24 BE BE767566A patent/BE767566A/xx unknown
  • 1971-05-24 FR FR7118707A patent/FR2100679B1/fr not_active Expired
  • 1971-05-24 GB GB1659171A patent/GB1356965A/en not_active Expired

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