General pharmacology of the anxiolytic compound metaclazepam in comparison to other benzodiazepines.

7-Bromo-5-(2-chlorophenyl)-2,3-dihydro-2-(methoxymethyl)-1H-1,4- benzodiazepine X HCl (metaclazepam, KC-2547, Ka-2547, Talis) is a novel 1,4-benzodiazepine characterized by a high selectivity of its anxiolytic effects. The present experiments were performed to contribute to its general pharmacological profile and to evaluate possible risks especially on the cardiovascular field in comparison to standard benzodiazepines. The experiments were performed in guinea pig isolated ileal and papillary muscle preparations, anesthetized cats and dogs, conscious renal hypertensive (RHR) and pithed rats. At intravenous, intraduodenal and repeated oral administration of metaclazepam in anesthetized cats and dogs and RHR arterial hypotension, if any, occurred only at rather high dosages. Tilting experiments in dogs did not show any risk for postural hypotension due to metaclazepam. In guinea pig papillary muscles and in anesthetized dogs (i.v.), metaclazepam had a moderate negative inotropic effect. A diminution of stroke volume was seen only at high i.v. doses whereas cardiac output was maintained nearly constant by an increase in heart rate. In guinea pig papillary muscles metaclazepam, like diazepam, had only a tendency to prolong the refractory period. Unlike diazepam, i.v. metaclazepam had no relevant depressant effect on respiration in anesthetized cats. No specific interaction of metaclazepam with alpha- or beta-adrenoceptors was found in pithed rats and anesthetized cats. The papaverine-like, unspecific spasmolytic profile in the guinea pig isolated ileum suggests that metaclazepam has no relevant antimuscarinic properties. In anesthetized cats neither metaclazepam nor diazepam showed an effect on neuromuscular transmission; metaclazepam caused a markedly weaker inhibition of the polysynaptic linguomandibular reflex than diazepam and did not influence the monosynaptic patellar reflex. In conclusion, the results with metaclazepam did not indicate side effects limiting its therapeutic use as an anxiolytic. Its potential in producing untoward side effects on the cardiovascular and respiratory systems and its central muscle relaxant properties appear to be considerably weaker than with diazepam or bromazepam. Substantial overdosage may result in hypotension and/or impairment of cardiac contractility.

Evaluation of the effect of dopamine and other catecholamines on the electrocardiogram and blood pressure of rats by means of on-line biosignal processing.

We compared the effects of dopamine and other catecholamines under identical conditions on electrocardiograms (ECG), heart rate, and blood pressure of rats. The experiments were carried out on anesthetized male Wistar rats weighting 330-370 g. The ECG was taken by a bipolar ECG lead in the direction of the heart axis, mean arterial pressure was measured in the carotid artery. Dopamine, adrenaline, noradrenaline, isoproterenol, and isotonic saline (control) were administered by continuous intravenous infusion. The infusion rate was increased 10-fold every 10 min starting with therapeutic dosages. All data were evaluated by continuous on-line biosignal processing. The results confirmed the well-known cardiovascular effects of the catecholamines; heart rate and mean arterial pressure increased after all adrenergic drugs except for isoproterenol, which caused a fall in pressure. In the ECG the PRc interval was significantly increased only by the highest doses of adrenaline and noradrenaline. A widening of the QRS complex was not observed during dopamine infusion, whereas it was present during adrenaline, noradrenaline, and especially, isoproterenol infusions. Taking the widening of QRS as indicative of cardiotoxic drug effects, the tested catecholamines may be arranged in the following order of cardiotoxicity; dopamine > adrenaline congruent to noradrenaline < isoproterenol.

[Studies on the pharmacodynamic activity of several drug solvents. 1st communication: Diethyleneglycol monoethylether, N,N-diethylacetamide, dimethylsufoxide (author's transl)]. / Ausgewählte Untersuchungen zur pharmakodynamischen Eigenwirkung verschiedener Lösungsvermittler. 1. Mitteilung: Athyldiäthylenglycol, N,N-Diäthylacetamid, Dimethylsulfoxid.

The drug solvents diethyleneglycol monoethylether (Transcutol), N,N-diethylacetamide, and dimethylsulfoxide were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats and dogs including the i.v. toxicity. Except for the cat, N,N-diethylacetamide exhibited the highest toxicity; this solvent, too, was particularly potent in inducing behavioural changes and in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed unspecific spasmolytic activities with histamine, carbachol, or BaCl2 as spasmogens. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.

[Studies on the pharmacodynamic activity of several drug solvents. 2. Glycerin, N-(beta-hydroxyethyl)-lactamide, polyethylene glycol 400]. / Ausgewählte Untersuchungen zur pharmakodynamischen Eigenwirkung verschiedener Lösungsvermittler. 2. Mitteilung: Glycerin, N-Hydroxythyllactamid, Polythylenglycol 400.

The drug solvents glycerin, N-(beta-hydroxyethyl)-lactamide, and polyethylene glycol 400 (Lutrol 9) were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats, and dogs including the i.v. toxicity. In mice and rats glycerin exhibited the highest tocicity as well as the greatest activity in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed unspecific spasmolytic activities with histamine, carbachol, and BaCl2 as spasmogens. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties, doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.

[Studies on the parmacodynamic activity of several drug solvents. 3. 1,2-Propanediol, tetrahydrofurfuryl alcohol-polyethylene glycol ether (THFP), olyoxyethylene sorbitan monooleate (PSM)]. / Ausgewählte Untersuchungen zur pharmakodynamischen Eigenwirkung verschiedener Lösungsvermittler. 3. Mitteilung: (1,2)-Propandiol, Tetrahydrofurfurylalkohol-polythylenglycolther (THFP), Polyoxyäthylensorbitanmonooleat (PSM).

The drug solvents 1,2-propanediol, tetrahydrofurfuryl alcohol polyethylene glycolether (THFP, Tetraglycol), and polyoxyethylene sorbitan monooleate (PSM, Tween 80) were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats, and dogs including the i.v. toxicity. The solvents showed only small differences in their toxicity in the mouse and rat; PSM, however, was more toxic than 1,2-propanediol and THFP in the cat and dogs. The latter solvent, on the other hand, was the most potent in inducing behavioural changes and in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed different spasmolytic potencies, depending on whether histamine, carbachol or BaCl2 was used as a spasmogen. The spasmolytic activity of 1,2-propanediol and THFP is classified as unspecific, whereas PSM seemed to have a specific anticholinergic pattern in the isolated ileum. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties, doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.