Chronopharmacological Study Research Articles

Chronopharmacological study of furosemide in rats.

The present experiment was undertaken to determine whether or not the effects of furosemide depend upon the administration time and, if so, to study the mechanism(s) for these variations. After administration of furosemide (5 mg/kg) in Wistar rats at 10:00 or at 22:00, urine volume and urinary excretion of sodium, furosemide, and prostaglandin E2 (PGE2) were measured. Urine volume and urinary excretion of sodium and furosemide, but not PGE2, were significantly greater when furosemide was administered at 10:00 than when it was administered at 22:00. There was a good correlation between the urinary output of furosemide and the urine volume, or the urinary sodium. It is concluded that the effects of furosemide vary with the administration time and these variations depend upon the amount of furosemide secreted in urine.

Chronopharmacological studies of phenylbutazone in the rat

Temporal variations in the anti-inflammatory action and in the ulcerogenic and lethal effects of phenylbutazone were studied in rats. The results indicate that small doses of the drug produced a larger reduction of paw edema in the morning than in the evening. At 0900, doses of 10, 30, and 100 mg/kg of phenylbutazone reduced the carrageenan-induced paw edema by 23, 44, and 66%, respectively. At 2000, the same doses of the drug decreased the paw edema by 9, 22, and 62%, respectively. No circadian variation was observed in the ulcerogenic effect of phenylbutazone. The mean lethal dose (LD50) of the drug was larger in the morning than in the evening and the values obtained were 710 +/- 24 (SE) mg/kg at 0900 in comparison to 525 +/- 38 (SE) mg/kg at 2000.

Antagonism by chlorisondamine and propranolol, but not by atenolol, of the circadian phase-dependent phentolamine-induced changes in the cardiac noradrenaline turnover in the rat.

The effects of phentolamine alone or in combination with propranolol, atenolol and chlorisondamine were studied on the concentration and turnover of noradrenaline in the heart of light-dark (L:D = 12:12 h) synchronized rats. In order to detect possible circadian phase-dependent variations in the drug effects, the same experiments were performed in the light-period and dark-period, respectively. The parameters of the turnover were calculated from the exponential decline of i.v. injected 3H-(-)-noradrenaline. Phentolamine significantly decreased the noradrenaline concentration during L, but not during D. Reduction in 3H-noradrenaline accumulation by phentolamine was 42.3% during L and 22.2% during D. Phentolamine increased the turnover rate of cardiac noradrenaline more than 3-fold in either photoperiod. Chlorisondamine reversed all the effects of phentolamine studied. Propranolol, but not atenolol, antagonized the effects of phentolamine in a dose-dependent and stereospecific way, being more effective when applied during D. Thus, the chronopharmacological studies in unrestrained rats show a circadian phase-dependency of the effects of adrenoceptor blocking drugs. It is concluded that a central site of action is responsible for the antagonism by propranolol of the phentolamine-induced increase in the turnover of the cardiac noradrenaline in vivo.

Chromopharmacological study of neuroleptics. III. Circadian rhythm of brain susceptibility to haloperidol.

Chromopharmacological study of neuroleptics. III. Circadian rhythm of brain susceptibility to haloperidol.

Chronopharmacological study of neuroleptics. II. Circadian susceptibility rhythm to chlorpromazine.

In order to study differences in the effect of the neuroleptics due to time of administration, rats were administered chlorpromazine (CPZ) in a variety of combinations of dose and time and the sedation period was measured. There was daily fluctuation in the sedative effect and the pattern of fluctuation differed according to dosage. A similar study under the condition of reversed light and dark gave a reversed curve of the daily fluctuation, showing that the rhythm of light and dark controls the fluctuation externally. In an attempt to elucidate the mechanism of these phenomena, CPZ was administered at two different times, between which there was a significant difference in the sedation period, and time-course changes in plasma and brain concentration of the drug and its metabolites were measured. No difference was found. These results are interpreted as indicating that the phenomena could arise at the level of amine-receptor activity in the brain. In addidtion, daily fluctuation due to time of administration was noted in lethality.