Archives internationales de pharmacodynamie et de thérapie
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Arch Int Pharmacodyn Ther · Aug 1976
The cardiovascular pharmacology and hemodynamic activity of tazolol, a selective myocardial beta-stimulant.
The pharmacology and hemodynamics of tazolol (1-iso-propylamino-3-(2-thiazoloxy)-2-propranolol HC1), a selective myocardial beta-stimulant, were studied in pentobarbital anesthetized dogs. Tazolol, i.v., increased myocardial contractile force and heart rate, but induced only minimal changes in arterial pressure. The cardiac effects of tazolol were blocked by pretreatment with the beta-blockers propranolol or practolol and inhibited in animals made tachyphylactic to amphetamine. ⋯ Tazolol also increased superior mesenteric artery flow, whereas isoproterenol decreased it. Renal artery flow was not altered. Tazolol was also found to be orally active and to possess some mild general beta-blocking activity.
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Arch Int Pharmacodyn Ther · Nov 1975
The influence of temperature increase, elevation of extracellular h+-concentration, and of triiodothyronine on the actions of phenylephrine, histamine, and beta-sympathomimetic drugs on rabbit aortic strips.
In the isolated preparation from the rabbit thoracic aorta, the affinities of the vasoconstrictor agents phenylephrine and histamine, as well as of the vasodilator beta-sympathomimetic drugs isoprenaline, fenoterol (TH 1165a), terbutaline, and salbutamol under the conditions of temperature increase, triiodothyronine and decrease of extracellular pH were investigated. It was observed that (1) a temperature increase from 25 degrees to 42 degrees C significantly indreased the maximal tension evoked by histamine, whereas that induced by the alpha-sympathomimetic drug phenylephrine was not altered significantly; the maximal relaxation caused by beta-sympathomimetic drugs either at 25 degrees or at 42 degrees C did not differ from one another; (2) the affinities of histamine, phenylephrine and of the beta-sympathomimetic drugs isoprenaline, fenoterol, terbutaline, and salbutamol each were comparable at either 25 degrees or 42 degrees C; the rank order of efficacy of the beta-sympathomimetic drugs is isoprenaline greater than fenoterol greater than salbutamol greater than terbutaline; (3) a decrease of the pH from 7.37 to 7.15 diminished the affinities of histamine and of the beta sympathomimetic drugs whereas that of the alpha-adrenergic drug phenylephrine was not altered. A further decrease of the pH to 6.8 diminished additionally the affinity of histamine and of isoprenaline, and especially that of the other beta-sympathomimetic drugs to such an extent that in the latter case complete dose-response curves could not be determined any more; (4) pretreatment of the animals with 0.4 mg/kg of triiodothyronine (T3) for two days, which strongly depressed the tension induced by either histamine or phenylephrine, did not alter the affinity of both drugs; T3 in vitro (10(-6) M) only diminished the affinity of histamine but left that of phenylephrine unaltered; pretreatment for two days with 0.2 mg/kg of T3 yielded a significant diminution of the pD2-values for two beta-sympathomimetic drugs investigated, namely isoprenaline and fenoterol; also the administration of T3 in vitro in a final concentration of 10(-6) M resulted in a diminution of the affinity of both beta-sympathomimetic drugs; (5) the results obtained show that also on the aorta beta-adrenoceptor stimulants are dependent on the metabolic state while alpha-adrenoceptor stimulants are not.
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Arch Int Pharmacodyn Ther · Jul 1975
Comparative StudyDistribution, metabolism and excretion of etomidate, a short-acting hypnotic drug, in the rat. Comparative study of (R)-(+)-(--)-Etomidate.
Tritium-labelled (R)-(+) and (S)-(--)-etomidate was injected intravenously in male Wistar rats at four dose levels. Initial plasma clearance was high and the largest part of etomidate was rapidly distributed over those tissues, that had entered in equilibrium with plasma, such as brain, erythrocytes, heart, spleen, lung, kidney, muscle and intestines. Only in subcutaneous fat, testicles and stomach peak levels appeared after 28 minutes. ⋯ Capacity-limited ester hydrolysis in the liver was the main metabolic pathway, yielding a single amphoteric metabolite. The rate of metabolization of (R)-(+)-etomidate was higher than that of the (S)-(--)-isomer. Excretion of the metabolite was mainly with the urine.
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Arch Int Pharmacodyn Ther · Mar 1975
Etomidate, a potent non-barbiturate hypnotic. Intravenous etomidate in mice, rats, guinea-pigs, rabbits and dogs.
Etomidate, R-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate was found to be a potent, short-acting and safe hypnotic; when given intravenously in single doses to mice, rats, guinea-pigs, rabbits and dogs. In rats of different body weight (50, 100, 200 and 300 g) two injection rates were used (2 sec and 2 min). By rapid iv injection in rats of 200 g etomidate (ED50 equal to 0.57 mg/kg) is about 6 times more potent than methohexital (ED50 equal to 3.51 mg/kg) and 25 times more potent than propanidid and thiopental (ED50's equal to 13.4 mg/kg). ⋯ No tolerance was observed after repeated administration. Etomidate is devoid of any teratogenic effect in rats (highest dose: 5.0 mg/kg daily from day 6 through day 15 of pregnancy), and in New Zealand white rabbits (highest dose: 4.5 mg/kg daily from day 6 through day 18 of pregnancy). The hypnotic effects of etomidate at very low dose levels in different laboratory animals are compared with the effects obtained in human subjects, in which successful induction of anaesthesia was obtained without producing any release of histamine and with only minimal effects on cardiovascular and respiratory functions.
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Arch Int Pharmacodyn Ther · Jan 1975
Drugs and punished responding. V. Effects of drugs on responding suppressed by response-dependent and response-independent electric shock.
A procedure was used where responses by a pigeon produced electric shock both to that pigeon (response-dependent shock) and to another pigeon (response-independent shock) working under the same schedule of food presentation. Both response-dependent and response-independent shock partially suppressed responding. Pentobarbital, chlordiazepoxide and ethanol increased responding suppressed by response-dependent shock, but only pentobarbital increased responding suppressed by response-independent shock. Morphine, d-amphetamine, chlorpromazine, doxepin, and pentazocine either had no effect, or further decreased rates of responding suppressed by response-dependent or response-independent shock.