General pharmacology of the novel centrally acting antihypertensive agent moxonidine.

Moxonidine (4-chloro-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, BDF 5895) reduces blood pressure and heart rate in rats with genetic hypertension (SHR/Okamoto) and in rats with renovascular hypertension (Goldblatt 1 k/1 c). The hypotensive action was also confirmed in renal-hypertensive dogs. The hypotensive action is preceded by a reduction in plasma noradrenaline concentration, thus reflecting a reduction in sympathetic activity. In anesthetized cats, administration of moxonidine into the vertebral artery induces a greater hypotensive effect than i.v. injection of same doses, indicating the central nervous system as the site of hypotensive action. Similar to clonidine, the hypotensive action of moxonidine is abolished by pretreatment of the animals with a selective alpha 2-antagonist. Direct application of moxonidine into the cisterna magna of anesthetized rabbits revealed a 10-fold greater hypotensive potency than clonidine, in contrast to i.v. application where moxonidine was 10-fold less potent than clonidine. At least 10-fold higher doses of moxonidine were needed to cause side effects (sedation, inhibition of gastric secretion), when compared with clonidine. Interruption of presynaptic noradrenergic pathways completely abolished the hypotensive action of moxonidine. Thus moxonidine is endowed with a specific central site of action, presumably by stimulating central presynaptic alpha 2-adrenoceptors. This specific central hypotensive action enables a greater dissociation between the antihypertensive effect on the one hand, and the side effects on the other.

Pharmacological properties of the positive inotropic and alpha 1-adrenoceptor blocking agent saterinone.

The pharmacological properties of saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) were investigated in isolated organs of the guinea pig and in human platelets. Saterinone was found to be a potent antagonist at vascular alpha 1-adrenoceptors with a pA2-value of 8.46 +/- 0.12. Besides its affinity for alpha 1-adrenoceptors saterinone exerted a positive inotropic effect in the isolated papillary muscle at an EC50-value of 3.2 X 10(-6)mol/l indicating 10-fold greater potency than milrinone. Comparable EC50-values were also found for the inotropic, chronotropic and bronchodilatory actions of the drug, indicating a common mechanism for these effects. The inotropic effects were not mediated by beta-adrenergic or H2-histaminergic receptors, but were shown to involve an elevation of myocardial cyclic adenosine monophosphate (cAMP) content. Saterinone also inhibited crude cAMP phosphodiesterase (PDE) activity in homogenates obtained from guinea pig right ventricles. The IC50-value for PDE-inhibition was 2.3 X 10(-5) mol/l and thus at a higher concentration than the inotropic effect. Saterinone was a potent inhibitor of human platelet aggregation induced by adenosine diphosphate, collagen and arachidonate. Against the latter agonist, saterinone was about 40-fold more effective than acetylsalicylic acid. In conclusion, saterinone exhibited a dual mechanism of action--direct inotropic effects in the myocardium and alpha 1-receptor blockade in the guinea pig vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)

Positive inotropic and vasodilatory actions of saterinone in vivo.

The cardiovascular actions of the newly developed inotropic and alpha 1-receptor blocking agent saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) was investigated in small laboratory animals in vivo. Saterinone caused a direct inotropic effect in pithed guinea pigs without affecting heart rate. In the same animal species saterinone competitively antagonized the pressor effects of phenylephrine at inotropic doses. In conscious rabbits saterinone exerted dose-dependent increase in left ventricular dP/dtmax and in heart rate, whilst reducing arterial blood pressure in the same dose range. The drug dose-dependently antagonized phenylephrine as evidence of its alpha 1-receptor blocking effects in the conscious rabbit. The duration of alpha 1-receptor blockade was longer than the duration of inotropic effects. The onset of inotropic and vascular effects of saterinone was found to be simultaneous, when the drug was slowly infused into the femoral vein of anesthetized cats. The saterinone dose which caused a significant inhibition of the pressor effects of phenylephrine (comparable to prazosin) still caused a reduction of femoral perfusion pressure and systemic blood pressure in anesthetized cats pretreated with phenoxybenzamine. Thus in contrast to prazosin, which was rendered ineffective after phenoxybenzamine, saterinone possesses an additional mechanism for vasodilation. Saterinone exhibited good oral efficacy in spontaneously hypertensive rats and in conscious cats, in which an oral dose of 10-30 mg/kg significantly reduced arterial blood pressure or increased left ventricular dP/dtmax, respectively. Thus saterinone exerts in vivo direct positive inotropic and vasodilating effects.(ABSTRACT TRUNCATED AT 250 WORDS)

[Penetration kinetics of fluocortolone from a new base for ointment and creme (author's transl)]. / Penetrationskinetik von Fluocortolon aus einer neuen Salben- und Cremegrundlage.

The penetration of fluocortolone from topically administered Syracort ointment and creme was investigated in guinea pigs. Two fluocortolone standards were tested as reference preparations (ointment and creme). 1. Fluocortolone liberation from the ointments and Syracort Creme within 24 h varied between 55% and 62% of the administered dose. The reference creme gave lower drug liberation values (39%). 2. The penetration profile of fluocortolone changed gradually. Non-absorbed portions and the concentrations in the upper layers of the stratum corneum decreased during inunction up to 24 h. Within the same time concentrations in the deeper layers of the skin increased. 3. The two ointments showed comparably good penetration properties, whereas Syracort creme gave flux values higher than those obtained from the reference creme. 4. 24 h after removal of the non-absorbed portion of the ointments a further persistence of the drug could be observed within the skin: 14.3% to 18.5% after additional 6 days. The mean renal elimination rate was found to be 3 days, a total amount between 28% to 30% of the dose was excreted via urine and feaces. Consequently, fluocortolone can be considered a fast penetrating topical which is accumulated especially in the layers of the epidermis and cutis.

[On the pharmacology of the alpha-receptor blocker BE 2254 (HEAT) (author's transl)]. / Zur Pharmakologie des alpha-Rezeptoren-Blockers BE 2254 (HEAT).

The alpha-adrenolytic activity of BE 2254 was investigated in in vitro as well as in vivo assays. On the isolated rat anococcygeus muscle, 2-[beta-(4-hydroxyphenyl)-ethyl-amino-methyl]tetralone(1) (BE 2254) shows a high affinity for postsynaptic alpha-adrenoceptors (pA2 = 8.9), in contrast to its much weaker potency (pA2 = 6.7) in inhibiting clonidine on the electrically driven rat vas deferens, thus suggesting a relative preference for postsynaptic alpha-adrenoceptors. BE 2254 effects on other catecholamine receptors are either negligible or not detectable. The hypotensive action of BE 2254 is shown to be solely due to alpha-blockade. All alpha-adrenolytic actions studied were of competitive nature.