Process for the treatment of children suffering from a hyperkinetic syndrome

Abstract

The present invention relates to a treatment of the "hyperkinetic syndrome" in children, wherein a medicine containing between 50 and 200 mg of 3-morpholino-ethylamino 4-methyl 6-phenylpyridazine is administered daily to patients, by oral route.

Description

The U.S. Pat. No. 4,169,158, issued Sept. 25, 1979, from application Ser. No. 820,489, filed July 29, 1977, describes one pharmaceutical use of the compound 3-morpholinoethylamino 4-methyl 6-phenyl pyridazine and of the pharmaceutically acceptable salts thereof.

This consists in using the compound as an anti-depressant; but it is specified in said patent that this anti-depressive activity did show some remarkable characteristics in relation to the anti-depressive activity of known anti-depressants.

A first table in the said patent shows the results obtained in clinical tests carried out for a whole series of depressive conditions, such as symptomatic depressive conditions, psychastenia, schizophrenia, psychosomatic diseases occurring in periods of tiredness and strain, and hypochondriac psychosis.

A second Table gives the results observed after different clinical tests, and showing that many clinical signs which are the consequence of the depressive conditions of the treated patients, could be improved when the anti-depressant described hereinabove is used.

It has now been found that this same product, namely the 3-morpholinoethylamino 4-methyl 6-phenyl pyridazine or a pharmaceutically acceptable salt thereof (hereinafter designated as 30038) when administered orally, in doses varying between 50 and 200 mg of active substance per day, could be used for treating "hyperactive children".

"Hyperactive children", i.e. children suffering from a "hyperkinetic syndrome" are described for example in the article written by P. H. WENDER of LIPTON M.A. et al. Psychopharmacology-A. Generation of Progress. Another analysis of the symptomatology of this syndrome is given by J. S. MILLER, Pediatries Vol. 61, pages 217-223 (1978).

A description of the major symptoms of the syndrome is given for example in Table 2, page 1430 of the aforesaid work of LIPTON; these symptoms are also mentioned by J. S. MILLER in his aforesaid article.

It is surprising to note that "hyperactive children" such as defined above may be advantageously treated by the 3-morpholinoethylamino 4-methyl 6-phenyl pyridazine (30038), which had been described as having anti-depressive properties, since the prevailing symptoms noted in hyperactive children are the opposite of the symptoms which lead to a diagnosis of depression. Indeed, the hyperactive syndrome essentially comprises the following signs:

psychomotor excitability agressivity irritability automatic opposition of antagonistic muscles to passive movements (oppositionism).

Until now, hyperactive children have been treated in most cases with amphetamine substances which have the disadvantages of having important side-effects, of toxicity and risks of toxicomania.

The observations reported hereinafter correspond to a clinical study carried out in pediatrics according to the method of the crossed double blind test; patients are given at random:

either, a first therapeutical period of four weeks at a dose of 50 mg of 30038 in the morning and 50 mg of 30038 at night, followed immediately by a second four-week period consisting in the administering of placebo tablets at the same daily dose; or, the reverse, a first four-week sequence using the placebo, followed immediately by a second four-week sequence with the aforesaid daily doses of 30038.

Purely by chance, 3 hyperactive children (obs. Nos. 3, 7 and 16) were treated first with the 30038 (first four weeks of the test), and then with the placebo-non active product for the 4 following weeks. On the contrary, 5 children (obs. Nos. 5, 10, 11, 19 and 20) were treated first with the placebo--first four weeks of the treatment--then with the 30038--the following four weeks.

The main characteristic symptoms of the hyperactive syndrome have been grouped in a scale of 8 symptoms (items).

The children were examined and questioned, on the day before the beginning of the treatment (day 0) as well as on the 14th day, on the 28th day (end of the first period of treatment with one of the two products), on the 42nd day and on the 56th day (end of the second period of treatment with the other product). The aforesaid scale of valuations was filled-in at each of the aforesaid interviews and for each child.

The gravity of each symptom (item) was rated with the following score:

0=no symptom 1=slight symptom 2=symptom of average intensity 3=symptom of strong intensity 4=symptom of very strong intensity.

The total of the scores obtained and the average total score (total divided by the number of symptoms) were compared so as to determine, quantitatively, the improvement (or aggravation) of the hyperkinetic disease during the treatment by either one of the two products; by comparing the percentage of improvement in the scores at the end of each of the two periods of treatment for the same child, it is possible to determine the suitable therapeutic effect of the 30038 and to compare it with the effect of the inactive substance (Placebo). Indeed, all the tests of clinical psychopharmacology show that the placebo can entail a slight favourable effect in a number of patients, but this effect, which is not lasting, still remains clearly inferior to the favorable effect which can be attributed to a drug known to be active vis-a-vis the disease under study.

If the improvement in the average score at the end of the treatment with the 30038 is found to be clearly superior to the slight improvement which may be noted when the Placebo is administered, then it can be said that the 30038 is specifically efficient in hyperkinetic disorders. And this is noted from the 8 observations reported hereunder.

The characteristic symptoms in a hyperkinetic child, noted in the scale of valuations of this test are as follows:

1. Agressivity 2. Irritability 3. Oppositionism 4. Relational difficulties 5. Verbal and ideatory excitation 6. Anxiety 7. Fears 6. Sleep perturbed by terrors.

The results obtained are summed up in Table I.

These results indicate by what percentage the total score of gravity of the disease (initial score taken at 100%) has reduced (improvement) or increased (aggravation) at the end of the treatment period using the 30038 and at the end of the Placebo treatment.

TABLE I______________________________________Obs. TreatmentNo. with 30038 Treatment with Placebo______________________________________ 30038 administered Placebo administered in in 1st period(1st day 2nd period (28th to to 27th day) 56th day)03 37.0% of improvement 22.0% of improvement07 42.6% of improvement 21.3% of improvement16 48.4% of improvement 2.9% of improvement 30038 administered Placebo administered in 2nd period (28th to 1st period (1st day to 56th day) 27th day)05 44.9% of improvement 0.0% unchanged10 59.2% of improvement 18.4% of improvement11 65.6% of improvement +4.3% of AGGRAVATION19 58.3% of improvement 0.0% unchanged20 87.7% of improvement 8.3% of improvementAver. 55.4% of improvement 8.5% of improvementout of8 cases______________________________________

These results show:

for the 30038: a 55.4% improvement of the disease for the Placebo: an 8.5% improvement of the disease (with one case of aggravation).

The results reported in Table I come from actual observations summed up hereunder:

______________________________________ Observation 3:______________________________________Identification : A.C. Treatment duration : 8 weeksSex : MaleAge : 15Height : 150 cmWeight : 45 kg______________________________________Diagnosis : Hyperactive syndromePrevious treatment : noneTreatment from the 1st day to the 27th day: 30038- one 50 mg tablet morning and eveningTreatment from the 28th day to the 56th day: 1 tablet of Placebo morning and evening______________________________________Initial gravity of disease: the syndrome is severe sinceit corresponds to an average score of 2.91 beforetreatment.______________________________________Evolution of the syndrome Day 0 Initial 14th 28th 42nd state day day day 56th day______________________________________Average total 2.91 1.82 1.82 2.18 2.27score% of improve- -- 37.5% 37.5% 25.1% 22.0%ment______________________________________ 30038 PLACEBO______________________________________ ______________________________________ Observation 7:______________________________________Identification : J.D. Treatment duration: 8 weeksSex : MaleAge : 15Height : 157 cmWeight : 45 kg______________________________________Diagnosis: Hyperactive syndromePrevious treatment: noneTreatment from the 1st day to the 27th day : 30038- one 50 mg tablet morning and even- ing.Treatment from the 28th day to the 56th day: one tablet of Placebo morning and evening______________________________________Initial gravity of the disease: the condition of thepatient is of average gravity since the average totalscore is 1.27 before treament.______________________________________Evolution of the syndrome: Day 0 Initial 14th 28th 42nd 56th state day day day day______________________________________Average 1.27 1.27 0.73 1.00 1.00total score% of improve-ment -- 0.00% 42.6% 21.3% 21.3%______________________________________ 30038 PLACEBO______________________________________ ______________________________________ Observation 16:______________________________________Identification : C.B. Treatment duration: 8 weeksSex : MaleAge : 15Height : 169 cmWeight : 56.5 kg______________________________________Diagnosis : Hyperactive syndromePrevious treatment: noneTreatment from the 1st day to the 27th day: 30038 - one 50 mg tabl- et morning and eveningTreatment from the 28th day to the 56th day: one Place- bo tablet, morning and evening______________________________________Initial gravity of the disease: This is a severe casesince the average total score is 2.81 before the startof the treatment. Very aggressive and irritable child,strong attitude of opposition and great relationaldifficulty. The symptoms of anxiety and perturbedsleep are also important.______________________________________Evolution of the syndrome Day 0 Initial 14th 28th 42nd 56th state day day day day______________________________________Average total 2.81 2.09 1.45 1.63 2.73score% of improvement -- 25.7% 48.4% 42.0% 2.9%______________________________________ 30038 PLACEBO______________________________________ ______________________________________ Observation 5______________________________________Identification : J.L. Treatment duration: 8 weeksSex : MaleAge : 15Height : 161 cmWeight : 58 kg______________________________________Diagnosis: Hyperactive syndromePrevious treatment: noneTreatment from the 1st day to the 27th day: one Placebo tablet, morning and eveningTreatment from the 28th day to the 56th day: 30038 - one 50 mg tablet morning and evening______________________________________Initial gravity of the disease: Very hyperactivesubject with a high degree of aggressivity, irritabili-ty and oppositionism. The symptoms normally accompany-ing the hyperactive syndrome (anxiety, etc..) are -present and______________________________________important.Evolution of the syndrome Day 0 Initial 14th 28th 42nd 56th state day day day day______________________________________Average totalscore 2.63 2.63 2.63 2.27 1.45% of improvement -- 0.00% 0.00% 13.7% 44.9______________________________________ PLACEBO 30038______________________________________ ______________________________________ Observation 10:______________________________________Identification : C.R. Treatment duration : 8 weeksSex : MaleAge : 15Height : 165 cmWeight : 47.5 kg______________________________________Diagnosis : Hyperactive syndromePrevious treatment: noneTreatment from the 1st day to the 27th day: one Placebo - tablet, morning and eveningTreatment from the 28th day to the 56th day: 30038 - one 50 mg tablet morning and evening______________________________________Initial gravity of the disease: The initial symptoma-tology is strong for all the most characteristic signsof the syndrome (aggressivity, irritability, opposi-tionism, relational difficulty, verbal and ideatoryexcitation).______________________________________Evolution of the syndrome: Day 0 Initial 14th 28th 42nd 56th state day day day day______________________________________Average totalscore 2.45 2.45 2.00 1.00 1.00% of improvement -- 0.00% 18.4% 59.2% 59.2%______________________________________ PLACEBO 30038______________________________________ ______________________________________ Observation 11:______________________________________Identification : A.G. Treatment Duration : 8 weeksSex : MaleAge : 15Height : 156 cmWeight : 56 kg______________________________________Diagnosis : Hyperactive syndromePrevious treatment: NoneTreatment from the 1st day to the 27th day: one Placebo tablet morning and evening.Treatment from the 28th day to the 56th day: 30038 - one 50 mg tablet morning and evening______________________________________Initial gravity of the disease: the total symptomatolo-gy is of average intensity (initial average score:2.09) but the most characteristic symptoms are clearlyfound (in particular as far as verbal and ideatoryexcitation and relational difficulties are concerned).______________________________________Evolution of the syndrome: Day 0 Initial 14th 28th 42nd 56th state day day day day______________________________________Average totalscore 2.09 2.18 2.18 1.18 0.72% of improvement -- +4.3% +4.3% 43.6% 65.6%______________________________________ PLACEBO 30038______________________________________ ______________________________________ Observation 19______________________________________Identification : N.P. Treatment duration: 8 weeksSex : MaleAge : 13Height : 140 cmWeight : 46 kg______________________________________Diagnosis : Hyperactive syndromePrevious treatment: noneTreatment from the 1st to the 27th day: 1 Placebo tablet morning and evening.Treatment from the 28th to the 56th day: 30038 one 50 mg tablet, morning and evening______________________________________Initial gravity of the disease: The total symptoma-tology indicates an average gravity (initial averagetotal score: 2.18). The main symptoms of the hyperactiveclinical table are found and in particular the symptomsof irritability and of verbal and ideatory excitationare noted (rated : 3). The aggressivity and relationaldifficulties are average in intensity. Other symptomsconventionally known to accompany infantile hyperacti-vity are of course present, often in very strongproportions.______________________________________Evolution of the Syndrome Day 0 Initial 14th 28th 42nd 56th state day day day day______________________________________Average totalscore 2.18 1.63 2.18 1.36 0.91______________________________________% of improvement -- 25.3% 0.0% 37.7% 48.3% PLACEBO 30038______________________________________ ______________________________________ Observation 20:______________________________________Identification : O.R. Treatment duration: 8 weeksSex :MaleAge : 13Height : 146 cmWeight : 42 kg______________________________________Diagnosis: Hyperactive syndromePrevious treatment: noneTreatment from the 1st day to the 27th day: one Placebo tablet, morning and eveningTreatment from the 28th day to the 56th day: 30038 - one 50 mg tablet morning and evening______________________________________Initial gravity of the disease: The intensity of theoverall symptomatology is average (initial average totalscore: 2.18). The main target symptoms of thehyperactive syndrome are noted, and in particular,aggressivity and irritability are present in a highproportion. Most of the other symptoms are also found,and in some cases, in very high proportions.______________________________________Evolution of the Syndrome: Day 0 Initial 14th 28th 42nd 56th state day day day day______________________________________Average totalscore 2.18 2.18 2.00 0.54 0.27% of improvem- -- 0.0% 8.3% 75.3% 87.7%ent______________________________________ PLACEBO 30038______________________________________

No side-effects have been found to result from the administering of 30038, whether during or after the treatments.

Claims

1. A method for the treatment of hyperkinetic syndrome in children, comprising orally administering daily to the hyperactive child from 50 mg to 200 mg of 3-morpholinoethylamino-4-methyl-6-phenylpyridazine or a pharmaceutically acceptable salt thereof.