Clinico-pharmacological effects of 4-ethoxy-2-methyl-5-morpholino-3 (2H) -pyridazinone (M73101), a new anti-inflammatory analgesic agent synthesized at the Research Laboratories of Morishita Pharmaceutical Co., Ltd., were studied in twenty-one healthy male volunteers aged 25-42.
Nineteen volunteers were administered oral single dose of M73101 as follows: one volunteer with 0.5 mg/kg, 3 with 1.0 mg/kg, 5 with 2.5mg/kg, 3 with 5.0mg/kg, 5 with 10.0mg/kg and 2 with 15.0mg/kg. Two volunteers were medicated with oral repeated dose, three times of 5.0mg/kg at intervals of 4 hours.
The physiological function tests by means of a polygraph were done in single dose group except 8 volunteers. In all volunteers, analgesic effects of M73101 on electrically evoked pain responses were studied, and clinical symptoms, side effects and laboratory tests were checked before and after medications.
It was observed that the medication with M73101 in a dose range of 0.5-15.0mg/kg had no significant influences on blood pressure, heart rate, blood flow in the forehead skin, respiration and GSR, while the blood flow in the buccal skin was increased in a few volunteers. Bowel sounds as representative of the intestinal motility were increased except three volunteers medicated with 1.0, 2.5 and 15.0mg/kg. On the other hand, no abnormal findings in hematological tests, urinalysis and biochemical tests were observed after medication in all volunteers. The analgesic effect was expressed as the average of 5 volunteers. The administration of 5.0 and 10.0 mg/kg manifested an analgesic effect in 15 minutes, which lasted for 3-4 hoursorevenlonger.

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Blood levels and urinary excretion of 4-ethoxy-2-methyl-5-morpholino-3 (2H) -pyridazinone (M 73101) and its metabolites in man were studied. Eighteen healthy male volunteers were administered with oral single dose of M 73101 as follows: 3 volunteers with 1.0mg/kg, 5 with 2.5mg/kg, 3 with 5.0mg/kg, 5 with 10.0mg/kg and 2 with 15.0mg/kg. Two volunteers were medicated with oral repeated dose, three times of 5.0mg/kg at intervals of 4 hours.
The maximal level of unchanged M 73101 was observed at 1/2-1 hour after the single administration, which indicates rapid absorption into the blood from the gastrointestine. The administration of M 73101 did not show a significant ac-cumulation. Metabolites were also detected in the blood but their amount was even less than unchanged M 73101. Increase of blood levels of unchanged M 73101 and its metabolites depended on administered dose. Changes of these blood levels, furthermore, paralleled to the potency of analgesic effect.
The urinary excretion during 0-4 hours was about 50% to the administereddose, and about 70-80% during 0-24 hours. The major urinary metabolite was 5- [carboxymethyl- (2-hydroxyethyl) -amino] -4-ethoxy-2-methyl-3 (2H) -pyrida-zinone (M-6), about 60% to the administered dose, whereas unchanged M 73101 was hardly excreted.

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A new diuretic agent, FR 3068 (tienilic acid) was studied for effects on urinevolume, urinary and serum electrolytes and uric acid, for serum and urinary con-centration of unchanged FR 3068 and for tolerability in 33 healthy male volunteers. A single oral dose of 250mg of FR 3068 increased significantly urine volume for 4 hours and urinary excretion of Na and Cl for 6 hours, but didn't cause significant changes in urinary K excretion and serum electrolytes.
Urinary excretion of uric acid increased for 4 hours after administration of 125 mg and for 6 hours after 250mg, and serum uric acid at 8 hours after administration decreased significantlyin correlation with dosages of 62.5, 125 and 250mg.
Peak serum concentration of unchanged FR 3068 was obtained 1 to 2 hours after a single oral administration and urinary recovery of unchanged FR 3068 in 24 hours was 17.3% after 62.5 mg, 22.3% after 125 mg and 37.9% after 250 mg. Any side effects and abnormalities in laboratory tests, ECG and audiogram were not observed during the study.
It is considered that FR 3068 is an unique diuretic agent with a marked urico-suric effect.

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A new anti-inflammatory, analgesic and antipyretic drug MK-647 was given orally in varying doses to a total of thirteen healthy Japanese volunteers for the observation of its influence on the findings of their physiological functions, heamtological tests, urinary analysis and sero-biochemical tests. At the same times, surveys were made on the changes produced in its blood level, urinary excretion and analgesic effects.
As the result, no abnormality was observed on the physiological functions except an increase in the bowel sound provided the dosage employed was below 500mg at a time. This enhancement of the bowel sound, however, indicates a possibility for the development of gastrointestinal side effects.
As for laboratory tests, an increase in alkaline phophatase was observed. A care should be taken on this matter when carrying out clinical studies in the future.
Accumulation may be negated in view of the change in its blood level, however. Compared with acetylsalicylic acid, its effect was rather delayed in onset and lasted longer. Satisfactory clinical effect may be expected with administration twice a day.

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The present experiments were designed to study the effects of prolonged tolbu-tamide (Tolb) administration on diabetic symptoms, using alloxan rabbits as model. Eighty seven diabetic rabbits obtained by the intravenous injection of 100-130mg/kg of alloxan monohydrate were divided into three groups-untreated control, Tolb 100 mg/kg treated group and Tolb 200mg/kg treated group. Tolb was given consecutively for 3 and 6 months, and during these periods, body weight, morning blood glucose and the daily amount of urinary sugar were measured. And also ECG recording, PSP excretion test and ophtalmologic test were performed. During the 6 months period, body weight tended to increase and blood glucose and urinary sugar tended to diminish gradually, but there was no difference in death rate among the three groups.
As for ECG, bradycardia and abnormal ST-T were observed in several alloxanized rabbits, and in the Tolb treated groups their incidences were significantly increased. As for PSP test, no abnormal values were obtained from the alloxanized animals, and also no effect of Tolb was found.
The longer the expeimental course, the number of incidence of cataract was found to become higher. But neither retinal vessel alteration nor other pathological changes were observed in the alloxan animals, with no difference observed between the control and the treated group.

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I. An inhibitory effect of intravenously administered 10 mg metoprolol on isoproterenol-induced cardiac acceleration was compared with that of 10 mg propranolol and 40mg practolol based on hemodynamics and mechanocardiogram in ten healthy controls.
1) Intravenously administered metoprolol produced a significant decrease in heart rate (HR), systolic blood pressure (sBP), cardiac effort index (CEI) and an elongation of corrected preejection period (PEPc) and isometric contraction period (ICP) and an increase of PEPc/ET (ET: ejection time). While propranolol produced a significant rise in diastolic blood pressure (dBP) and no change in sBP, the other effects produced by metoprolol were almost same as those obtained by propranolol. Practolol did not produce any significant effect.
2) Although isoproterenol induced cardiac acceleration (tachycardia, increase of sBP, decrease of dBP, shortening of PEPc and ICP, and decrease of PEPc/ET) was inhibited significantly by propranolol, both metoprolol and practolol did not inhibit it.
II. An inhibitory effect of orally administered metoprolol on catecholamine-induced cardiac ischemia was compared with that of practolol based on clinical symptoms, hemodynamics and electrocardiogram (ECG) in eleven patients with angina pectoris.
1) Orally administered 40 mg of metoprolol produced a significant decrease in heart rate, CEI and pressure rate index (PRI). The effect was more marked than that obtained with 100 mg of practolol.
2) Both metoprolol and practolol
a) maintained low levels of heart rate, CEI and PRI, inhibited ischemic alterations of ECG, and reduced anginal episodes following adrenaline administration;
b) did not inhibit the elevation of blood pressure, but maintained heart rate, CEI and PRI at low levels and inhibited ischemic alterations of ECG produced by noradrenaline;
c) inhibited tachycardia, increase of CEI and PRI, ischemic alterations of ECG and anginal episodes produced by isoproterenol.
Metoprolol 40mg was clearly effective in inhibiting catecholamine-induced angina and equivalent to, or more effective than, practolol 100 mg.

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