US3642994A

US3642994A - Therapeutic process using melatonin

Info

Publication number: US3642994A
Application number: US40393A
Authority: US
Inventors: Fernando Anton-Tay
Original assignee: FERNANDO ANTON T
Current assignee: FERNANDO ANTON T
Priority date: 1970-05-25
Filing date: 1970-05-25
Publication date: 1972-02-15
Anticipated expiration: 1989-02-15
Also published as: FR2100679B1; BE767566A; FR2100679A1; DE2125427A1; GB1356965A; ZA713249B; NL7106993A; CA960966A

Abstract

THE SYMPTONS FO EPILEPSY AND PARKINSONISM ARE RELIEVED BY THE ORAL OR PARENTERAL ADMINISTRATION OF MELATONIN, AND A PSYCHOTROPIC EFFECT IS EXERTED.

Description

United States Patent ABSTRACT OF THE DISCLOSURE Thesymptoms of epilepsy and Parkinsonism are relieved by the oral or parenteral administration of melatonin, and a psychotropic effect is exerted.

FIELD OF THE INVENTION 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. More recently experimental use has been made of L-dihydroxyphenylalanine (L dopa) which promises to offer a substantial improvement over the anti-cholinergic agents in management of the disease. The dose required with L- dopa' is quite high, however, and many undesirable side effects accompany treatment. Accordingly, further therapeutic improvement is desirable.

Similarly 'with epilepsy, management of the symptoms has depended mainly upon the use of anti-convulsant drugs and sedatives such as diphenylhydantoin and phenobarbital. 'Response is quite variable and dosage with several drugs in combination is frequentlyy necessary to achieve any improvement.

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). Pharmacological studies with it were previously reported by Gessner et al., Nature 190, 179-80 (1961), particularly with respect to the actions on. smooth muscle, blood pressure, and behavioral activity in the rat. The compound has been reported to have hypnotic action on rats, but otherwise to be quite inert pharmacologically and to be non-toxic. In a study of the toxicity of melatonin in mice, the compound failed to produce death at doses up to 800 mg./kg. The-LD on injection Formula I ice could not be determined since sufliciently concentrated solutions could not be prepared to permit injection of a toxic dose. The most prominent biological action of melatonin previously known is its ability to lighten the color of the frogs skin (melanophore contractor).

SUMMARY OF THE INVENTION 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. Generally a period of sleep follows administration of the drug, but other desired effects are sustained for a considerable period after the subject awakens. In normal as well as patients suffering from epilepsy and Parkinsonism the EEG reflects an increase in alpha rhythm and with epileptics the paroxysmal activity is substantially diminished or eliminated. In 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.

Administration of 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. Stated generally 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. It is preferred to administer the substance by the oral route, but in emergency situations where quick action is needed, intravenous administration is used. The latter is also preferred for patients who cannot or refuse to accept oral medication. Other parenteral routes may be used.

For intravenous administration, a solution in 1% aqueous, ethanol is employed. For other parenteral routes solutions or suspensions in other parenteral liquid vehicles such as peanut oil are applicable. For oral use, flavored suspensions or solutions may be employed, but tablets and capsules are generally adequate and are preferred.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 Psychotropic action-Graded doses of melatonin ranging from 0.25 mg./kg. of body weight to 1.25 mg./ log. of body weight were administered by intravenous injection of solutions in 1% aqueous ethanol to five healthy volunteers in consecutive fashion. All subjects were studied by poligraphic records of parieto occipital electroencephalogram (EEG), respiration, and electrocardiogram (EKG). After the effects of the dose on one subject were evaluated, the next higher dose was administered to the next subject. At all doses practically the same effects were found although they become more apparent with the largest dose. In no case were undesirable etfects observed. Five additional volunteers were then treated with an intravenous dose of 1.25 mg./kg. of melatonin. Poligraphic records were prepared as before. Shortly after administration of this dose the EEG activity was characterized by slight deactivation. Fifteen to 20 minutes later the subjects fell asleep. They are easily awakened 45 minutes later. Most of them related that they had had vivid oniric episodes while asleep. In the following hour EEG activity was continuously monitored. During this time the EEG showed an increase in percentage and amplitude of alpha rhythms. As an objective measure of the subjects mental alertness and capacity they were required to estimate the duration of a 10 second interval 1 hour after treatment and the results were compared with those obtained in a similar test administered to them before treatment. Their average estimate was 1122:025 seconds before treatment and 11.10* 0.34 seconds 1 hour after treatment. In a similar test when the volunteers were permitted to listen to their own heart rhythm as a reference, the average 10 sec. time estimates were 1034:022 seconds before treatment and 10.441-033 seconds 90 minutes after treatment. The data is arranged in Tables I and II. As a further objective measure of the effect of the drug on mental activity reaction times were measured before, and 90 minutes after treatment with melatonin as above. Reaction time was measured electronically as the elapsed time between lighting a light in front of the patient and his pressing a button after seeing the signal. No substantial change in reaction time resulted from the treatment. 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.

TABLE I.EFFECT OF MELATONIN ADMINISTRATION OF 10 SECOND TIME ESTIMATE [No reference signal] Volunteer dose N0. MgJkg. Control Melatonin P TABLE IL-EFFECT OF MELATONIN ADMINISTRATION ON 10 SECOND ESTIMATE [Pulse as reference signal] Volunteer dose MgJkg. Control Melatonin P X 10. 34i0. 2O 10. 44:1;0. 33

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. In each of these patients changes similar to those observed in the healthy volunteers described in Example 1 occurred. In addition EEG changes indicating a depression of the paroxysmal activity during the first 4 hours after melatonin treatment were observed. One of these patients who was normally reactive to hyperventilation enjoyed a blockage of this reactivity as a result of the melatonin treatment.

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.

(A) Control record-The activity was characterized by the presence of spikes and sharp waves. The spike activity appeared in the amygdaloid nuclei and was projected to both hippocampus and temporal cortices.

(=B) Eleven minutes after melatonin administration the spike activity was replaced by slow theta trains in both cortices. The patient became somnolent and fell asleep 7 min. later. i

(C) Manifestation of rapid eye movement occurred during sleep and a decrease of the amplitude and frequency of the theta trains was observed. p

(D) The patient awoke after 50 minutes and the theta hippocampal trains reappeared. The background activity had a lower amplitude. These conditions continued for 220 minutes. 1

(E) At this point, trains of 15 to 25 c.p.s. appeared intercalated.

(:F) Three hundred minutes after melatonin administration, the record showed a regulation of the activity with complete disappearance of the paroxysmal graphoelements.

During the second and third days, when the patient received 30 mg. of melatonin per day, the EEG showed a diminution of the paroxysmal grapholements.

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. per day divided into 3 doses. By the middle of the second week of treatment (third day of oral treatment) evaluation by the same panel of physicians revealed approximately 65% reduction in rigidity, 80% reduction in tremor, and a 20% improvement in motor ability. Oral treatment according to this regime was continued through the second and third Weeks. The reduction in rigidity and tremor was maintained, and by the end of the third week motor ability had improved to 70% of normal. In the fourth week treatment with a placebo Was substituted for the melatonin. After several days of treatment with the placebo rigidity and tremor increased and motor ability began to deteriorate. Measurement of the EEG following the initial dose of melatonin revealed that within 11 min. there was a decrease in amplitude in the EEG and that muscle tremor diminished. 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.

What is claimed is:

1. 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.

2. The process of claim 1 wherein a daily dose of from 0.25 to 30 mg./kg. of body weight of melatonin is administered.

3. A process according to claim 1 wherein a daily dose of from 0.25 to 30 mg./ kg. of body weight of melatonin is administered to a patient sulfering from epilepsy.

4. A process according to claim 1 wherein a daily dose of from 0.25 to 30 mg./kg. of body weight of melatonin is administered to a patient suffering from Parkinsons disease.

5. A process according to claim 1 wherein a daily dose of from 0.25 to 30 mg./kg. of body weight of melatonin is administered to a patient suifering from a behavioral disorder.

References Cited Barchas et al., Nature, 214, 912920 1967). Gessner et al., Nature, 190, 179-180 (1961).

STANLEY J. FRIEDMAN, Primary Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,642,994 Dated February 15, 1972 Inventor (s) Fernando Anton-Tav It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 1, 1. 49 "frequentlyy" should be "frequently" Col 1, 1. 63 I "912" should be .9929" Col. 2, l. 39 "claming" should be "calming" Col. 3, l. 51 "8" (First No. 8) should be "7" Col. 3, 1. 55 After "X" insert and insert I X before "11.10"

Col. 3, l. 70 After "X" insert and insert x before "10.44"

Col. 4, l. 49 Delete "c.p.s." and insert cps Col. 4, l. 57 "grapholements" should be "graphoelements" References cited:

Col. 6, l. 19 "912" should be "919" Signed and sealed this 1st day of August 1972.

(SEAL) Attest':

EDWARD M-FLETCHER ,JR. ROBERT GOT'I'SCHALK Attesting Officer Commissioner of Patents FORM PO-105O (10-69) USCOMM-DC 60376-P69 U.5, GOVERNMENT PRINTlNG OFFICE: I969 O-366-334