DE2125427A1 - Therapeutic agent - Google Patents

Description

F ^ attorneys

PROF. DR. DR. J. REITSTOTTER ..._.

DR.-ING. WOLFRAM BUNTE L \ £ Ό Η £. I.

DR. KARL GEORG LOSCH

D - UOOO MÜNCHEN 13, BAUERSTRASSE 22, FERNRUF (ΌθΙΟ 37 GS B3

Munich, May 21, 1971 M / 11558

FERNANDO ANTON-TAY

Instituto de Investigacioneis Biomedicas, Apartado Postal 70228 Ciudad Universitaria, Mexico 20, D.F., MEXICO

Therapeutic agent

The present invention relates to the heterocyclic indole compound Jjelatonin, of the formula I, in a bioactive, agents acting on the body and in particular an encephalotherapeutic agent used in combating or treatment of the symptoms of epilepsy and parkinsonism and in psychotherapeutic mastery of certain mental illnesses.

1098 507 1819.

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Parkinson's disease is an inability to move ι disease caused by stiffness and tremors of the! Limbs is marked. The disease has mainly been treated with anticholinergic agents. The reaction j is different and the dosage must be carefully adjusted for each patient i. At best the treatment had; treatment of the symptoms only modest success. More recently, attempts have been made with L-dihydroxyphenylalanine (L-Dopa), ι ι. · ■ ·.

that is a major improvement in the treatment of the condition promises to the anticholinergic agents. However, the required L-Dopa dose is very high and; j many undesirable side effects go with treatment; j along with it. Accordingly, there is another therapeutic improvement j desirable. > j

The treatment of symptoms in epilepsy was similar; mainly from the use of anticonvulsant and ! sedative agents such as diphenylhydantoin and phenobarbital. The reaction is very different and a dosage with several drugs in combination is often necessary, to get any improvement at all.

Melatonin, the substance now found useful in controlling the foregoing conditions, is a hormone of the hypophysis. It is a well-known compound that has been associated with the pineal gland since it opened in 1959

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has been identified as a hormone of the epiphysis (Lerner and Case, J. Am. Chem. Soc. 81, 6084-5 (1959)) Although substantial biochemical and physiological research has been carried out on the epiphysis and melatonin over the past 10 years no clinically useful treatment method based on the 'knowledge developed so far' has yet been proposed. j The acute pharmacology of the compound has been described by Barchas, et.al.i in Nature 214, 929-20 (1967). Gessner et. al. already reported in Nature _x 190, 179-60 (196I), in particular with regard to the effect on the smooth muscles, blood pressure and behavioral activity in the rat. The compound is described as sleep-inducing in rats, but otherwise completely pharmacologically inert and non-toxic. When the toxicity of melatonin was examined in mice, the compound caused no death at doses up to 800 mg / kg. The LDcQ value for injections could not be determined because sufficiently concentrated solutions that allow the injection of a toxic dose could not be prepared.

The most prominent already known biological effect of melatonin is its ability to change the color of frog skin lighten (melanophore contractor).

The present invention accordingly provides a pharmaceutical Composition comprising a pharmaceutical carrier and an effective, non-toxic dose of melatonin of the formula

CH ₂ CH ₂ NHCOCH ₃

(D

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contains.

The invention also provides a therapeutic method

ι *

! that is, the administration of an effective, non-toxic dose : Melatonin, orally or parenterally to a human patient

■ comprising the, Parki / suffers from epilepsy nson ^f's disease or behavioral disorders I. ? '

The administration of this substance has a strong calming effect on the patient and causes changes in the [ electroencephalogram. Generally, a period of sleep j follows the administration of the drug, but other desired effects j persist for a considerable time after subject j is awakened. Both in healthy patients and in those who suffer from epilepsy and parkinsonism, the EEG shows an increase in α-rhythms and in epileptics

the paroxystic activity is significantly reduced or ; eliminated. In Parkinsonism there is a prompt decrease in the muscle tremor and after daily administration over I experienced a sharp decrease in stiffness for several days with a simultaneous increase in mobility.

: The administration of melatonin has essentially no undesirable side effects. The substance is well absorbed,

i tolerate it well and essentially irritates the tissue and the iGastrointestinal tract not. Subjective comments from

healthy people who have been given the drug are allowed to ; suppose that there is a very pleasant feeling associated with it. 'After a normal sleep, the patient wakes up easily

and reports a pleasant feeling of well-being. I This does not result in any impairment of vigilance

or judgment. The effects shown are in ■ the treatment of patients, which behavior disorders ! have, such as manic depressive psychosis, dementia senilis and dementia präsenilis, in which either arousal or

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ι Depression occurs, desirable, as the drug has a calming effect and yet creates an elevated mood .

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The dosage is in the range from 0.5 to 2.0 g per day, preferably divided into two ^; or three dosage units. The preferred dose is 1 g per day orally. Lower "doses can be used effectively, especially when given intravenously. The lowest dose that was found effective was 0.25 mg / kg intravenous body weight. Generally speaking, the" range of doses that can be used is for treating all of the diseases with to which the present invention is concerned, 0.25 to 30 m ^ / kg of body weight per day. Oral administration is preferred, but intravenous administration is used in emergencies where prompt action is required. The latter is also preferred by patients who cannot or refuse to take oral medication. Other modes of parenteral administration can be used.

For intravenous administration, a solution in 1% aqueous ethanol is used. In other parenteral modes of administration, solutions or suspensions are in others parenteral liquid carriers such as peanut oil are useful. For oral use, flavored suspensions or Solutions are used, but tablets and capsules are im generally appropriate and preferred.

example Psychotropic effect

Graduated doses of melatonin from 0.25 mg / kg body weight up to 1.25 mg / kg body weight are given by intravenous injection of solutions in 1% aqueous ethanol 5 healthy free

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M / 11558 2125 A 27

consent given one after the other. All subjects are monitored by means of polygraphic recordings of parietal occipital electroencephalogram (EEG), breathing and electrocardiogram. After the action / ler dose is evaluated on a subject, the next '\ subject to the next higher ·' is administered dose. Virtually the same effects are found at all doses; although it is more noticeable at the largest dosage. ; In no case were undesirable side effects observed. Five additional volunteers were then treated with an intravenous [ dose of 1.25 mg / kg melatonin. As 'before', poligraphic records are made. Shortly after administration of this dose, the EEG activity is characterized by a slight deactivation. The test subjects fall asleep 15 to 20 minutes later. You will be 45 ^! Easily awakened minutes later. Most of them say that they had vivid dream periods during sleep. j In the following hour, the EEG activity is continuously over-; wakes up. During this time the EEG shows an increase in the j percentage and amplitude of α rhythms. For the objective measurement of the mental alertness and ability of the test persons, they must have the; one hour after the treatment; Estimate the duration of a 10 second interval and compare the results j with those obtained from a similar experiment prior to treatment. Your average estimate is 11.22 + 0.25 seconds before treatment and 11.10 + 0.34 seconds 1 hour after treatment.

j In a similar experiment in which the volunteers listened to their own heart rhythm as a baseline, the average estimate over a 10 second period was ^; 10.34 + 0.22 seconds before treatment and 10.44 + 0.33; Seconds 90 minutes after treatment. The data is in . \ \ Tables I and II. As a further objective 'measurement of the effect of the drug on the mental activity are \ reaction times before and 90 minutes after treatment with [Melatonin measured as above. The response time is electronic!

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measured as the time elapsed between when a light flashes in front of the patient and when he presses a button after seeing the signal. There is no significant change in the reaction time from the treatment. The average reaction time for the 10 subjects before treatment is 233.77 ± 10.3 msec and 90 minutes after treatment 272.4 ± 17.8 msec. The experiment is ended after two hours. At this time, report the subjects' that it has a sense of 'feel' well-being, contentment and a H _o chgefühl.

Table I.

Effect of the administration of melatonin on the estimate of a unit of time of 10 seconds

No reference basis

Volunteer dose control melatonin No. mg / kg

1 0.25 16.5. + 0.66 13.46 ± 0.32 0.001

2 0.50 8.85 + 0.17 9.35 + 0.15 0.1

3 0.75 10.03 + 0.12 ₍ 9.82 + 0.10 0.1 |

4, 1.00 10.99 + 0.09 11.69 + 0.11 '0.001 j

5 "1.25. 10.49 ± 0.09 10.00 + 0.07 0.01 |

6 1.25 9.08 + 0.18 "8.52 +0.27 0.1 |

7 1.25 16.5 +0.66 19.43 + 1.39 0.05 j

8 1.25 8.57 ± 0.07 9.18 + 0.15 0.01

9 1.25 9.92 + 0.35, 9.9 ± 0.67 0.1

10 1.25 11.31 + 0.10 10.50 ± 0.18 0.01

X = 11.22 ± 0.25 X = 11.10 ± 0.34

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, Table II

Effect of the administration of melatonin on the estimate of a unit of time of 10 seconds

X = 10.34 + 0.20 X = 10.44 + 0.33

Example 2 .

Treatment of epilepsy

A 24-year-old patient who has had grand mal and temporal lobe epilepsy for 21 years and is on treatment with sodium hydantoinate 300 mg / day, carbamazepine 600 mg / day and phenothiazine 100 mg / day is given a single dose of 0.25 mg / kg Melatonin treated intravenously as a solution in 1% aqueous ethanol. A second patient, 26 years old

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Pulse as a basis for payment Melatonin 0.74 ■ p «c j Volunteer dose control 0.58 No. mg / kg I.
12,, II + 0.14 o, i j 1 0.25 13.18 + 0.41 10.16+ 0.14 ■ o, i j 2 ^% 0.50 9.60 + 0.07 9.97 + 0.12 0.1 3 0.75 9.71 + 0.21 10.72 + 0.27 0.1 4th 1.00 10.48 + 0.08 9.82 + 0.56 0.1 5 1.25 9.56 + 0.10 - 8.79 + 0.54 0.1 6th 1.25 9.13 ± 0.17 • 12.93 + 0.11 0.1 7th 1.25 13.0.8 + 0.41 . 9.91 + 0.10 0.1 8th 1.25 9.12 + 0.20 9.29 + 0.1 9 1.25 8.50 _± 0.27 10.71 + 0.01 10 1.25 11.27 + 0.11

old, who has suffered from grand males, myoclonic seizures, temporal lobe epilepsy and dementia for the last 17 years and is treated with 300 mg / day. Sodium hydantoinate is treated similarly with a single dose of 1 mg / kg body weight of melatonin intravenously. In each of these patients changes occur which are similar to those in the healthy volunteers according to Example 1. In addition, changes are observed in the EEG, after depression of paroxysmal activity während.der first h hours, the melatonin treatment t show. One of these patients, who is normally prone to hyperventilation, has blockage of this susceptibility as a result of melatonin treatment.

Example 3
' Treatment of Epilepsy ι.

j A 27-year-old patient who had had grand mal, j petit mal, myoclonic seizures, focal temporal lobes for 13 years ! epilepsy, nonsense and secondary schizophrenia-like! Suffering from psychosis, was under treatment with 100 mg / day Sodium hydantoinate and 10 mg / day diazepam. This treatment is interrupted for a period of 5 days before the Treatment with melatonin is started ·. On the first day of treatment, 60 mg of melatonin are administered intravenously as a solution in 1% aqueous ethanol administered and on the 2nd and 3rd day 30 mg are administered intravenously. The following electroencephalographic Activity is observed on the first day after administration of the 60 mg dose.

Record report

(A) The activity is characterized by the presence of spikes and sharp waves. The peak activity appears in the amygdaloid nuclei and becomes both the hippocampus and the temporal rings projected. -9.- 109850/1819 ·

M / 11558 21 2 5 A 2

I (B) Eleven minutes after administration of melatonin will

[ the peak activity replaced by slow y> trains j in both cortices.

; The patient becomes drowsy ^: and sleeps 7 minutes later! a.

(C) During sleep, there are rapid eye movements and a decrease in the amplitude and frequency of the V> series observed. ' "

(D) The patient wakes up after 50 minutes and the vs-hippo-

; campus rows appear again. The background activity

I has a smaller amplitude. These states last

j 220 minutes.

j I.

I (E) At this point, rows from 15 to 25 Hz appear

temporarily stored.

j (F) 300 minutes after administration of melatonin, the I records show regulation of activity with a j complete disappearance of the graphic signs or j elements for paroxysm.

During the second and third ^{day (1} ) on which the patient receives 30 mg of melatonin per day, the EEG shows a decrease in the graphic signs or elements for paroxysm.

! Example 4

^; Treatment of Parkinson's Disease

; An adult male patient who has been attending for h years

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M / 11558

Parkinson's disease who has previously been treated with anticholinergic agents is left untreated for 5 days. During this time, a panel of three doctors examined him individually for stiffness, tremor and mobility. For 1 week, 120 mg of melatonin, divided into two doses per day, is administered intravenously as a solution in 1% aqueous ethanol. On the third day of treatment, the patient is again examined by the 3 doctors. At this point there was only a slight decrease in stiffness, but the tremor is essentially resolved. The mobility is not significantly improved. After the end of the first week, the intravenous treatment is ended and the oral treatment with 600 mg per day, divided into three doses, is started. By the middle of the second week of treatment (on the third day of oral treatment), an examination by the same medical panel reveals an approximately 65% decrease in stiffness, 80 % decrease in tremor and a 20% improvement in mobility In this plan, oral treatment continued during the second and third weeks. The decrease in stiffness and tremor persisted and by the end of the third week the ability to move is improved to 70% of normal.In the fourth week, the melatonin treatment is carried over After several days of treatment with the placebo, the stiffness and tremors increase and the ability to move begins to deteriorate. _ί

Measurements of the EEG after the first dose of melatonin show that the amplitude of the EEG decreases within 11 minutes and that the muscle tremor is reduced. The tremor occurs both when the patient is at rest and when the patient is trying to stop his Buttoning coat, which is considered maximum tremor, measured.

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M / 11558 ':. 2125A27

The maximum tremor is generally found to decrease during the course of the treatment 18 minutes after administration of melatonin decreases. Within .38 to minutes of treatment with Mßlatonin, the tremor is practically eliminated and a clear α-rhythm is observed in the EEG. . - .. '·'.

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Claims (1)

M / 11558 Patent claim A pharmaceutical agent comprising a pharmaceutical carrier and an effective, non-toxic dose of melatonin formula CH ₂ CH ₂ NHCOCH ₃ (D contains. - 13 - 10 9850/1819