P. A. J. Janssen

Receptor binding profile of R 41 468, a novel antagonist at 5-HT2 receptors.

For a new antiserotonergic agent, R 41 468 and 13 reference compounds with alleged antiserotonergic activity, the receptor binding profile is reported, comprising Ki-values measured in ten different receptor binding models. R 41 468 appeared to be a particularly selective agent with respect to differentiation between two 5-hydroxytryptamine (5-HT) receptor models; it primarily displayed high binding affinity for 5-HT2 receptors and was inactive at 5-HT1 receptors. Besides showing a moderate binding affinity for histamine1 and α1 adrenergic receptors, the compound was very weakly active at dopamine receptors and inactive at the remaining receptors. Receptor binding profiles of the reference compounds differed widely. Apart from R 41 468 no other compound showed a similar selectivity towards 5-HT2 receptors. Reference compounds either poorly differentiated between 5-HT2 and 5-HT1 receptors, showed other primary effects, or were only moderately active. In the 5-HT2 and 5-HT1 receptor binding models the ‘D-receptor’ antagonist phenoxybenzamine was weakly active and the ‘M-receptor’ antagonist morphine was inactive. It is concluded that R 41 468 will be a particularly suitable tool to antagonize 5-HT action mediated by 5-HT2 receptors.

Delay of castor oil diarrhoea in rats: a new way to evaluate inhibitors of prostaglandin biosynthesis

Forty‐four non‐steroidal anti‐inflammatory compounds were tested for possible effects on castor oil‐induced diarrhoea in rats. A small but significant delay of intestinal evacuations was found with all compounds. Quantitatively, the oral doses required to delay diarrhoea beyond the first hour after castor oil challenge reflected the acute anti‐inflammatory potency of the tested compounds. Qualitatively, the evolution of the effective doses with increasing delay was linear for potent inhibitors of prostaglandin biosynthesis. The evolution for less potent compounds was markedly different and suggested the earlier occurrence of nonspecific drug effects. Suprofen, the most potent of the series of compounds, produced the 1 h delay at an oral dose of 1·11 mg kg−1; the ED50 increased linearly to 115 mg kg−1 for a 4 h delay. Compared with other compounds the activity pattern of suprofen was consistent with that of a very potent, short‐acting inhibitor of prostaglandin biosynthesis, which maintains its specific action over a wide dose range. It is concluded that delay of castor oil‐induced diarrhoea in rats allows a detailed characterization of aspirin‐like compounds, and that inhibition of prostaglandin biosynthesis is insufficient to suppress the intestinal effects of the oil.

pharmacological and Hemodynamic Profile of Nebivolol, * a Chemically Novel, Potent, and Selective β1-adrenergic Antagonist

The pharmacological profile of nebivolol (N), a chemically novel beta-adrenergic antagonist, was assessed in investigations on isolated tissues, awake spontaneously hypertensive rats (SHR), closed-chest anesthetized dogs, and humans. In vitro, N was found to be a potent antagonist of beta 1-adrenergic receptors (A2 value, 5.8 X 10(-9) M) and only a weak beta 2-adrenergic antagonist (A2 value, 1.7 X 10(-6) M). The selectivity for the beta 1-adrenergic receptor was higher for N than for any of the reference compounds. In dogs--similarly with atenolol--N was more potent in blocking the isoprenaline (I)-induced increases in left ventricular performance than the I-induced decrease in arterial pressure. In dogs, as compared with propranolol, N (0.025 and 0.01 mg.kg-1 i.v.) increased cardiac output and stroke volume, lowered systemic vascular resistance, and had no significant effect on the variables related to left ventricular contraction. In contrast to other beta-adrenergic antagonists, N acutely lowered arterial blood pressure in SHR (1.25 mg.kg-1 i.p.) and in hypertensive patients (1 oral dose of 5 mg) for several hours. In healthy volunteers N (5 mg) lowered systemic vascular resistance during daily oral treatment and did not negatively affect left ventricular function. In conclusion, N is a potent and selective beta 1-adrenergic blocking agent with an interesting hemodynamic profile. In hypertensive subjects and SHR, a single dose lowers arterial blood pressure for substantial periods of time.

Behavioral and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rat

The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced headtwitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.

Itraconazole, a new triazole that is orally active in aspergillosis.

Itraconazole is a new orally active triazole derivative with broad-spectrum antifungal activity. This drug is effective in experimental aspergillosis and possesses in vitro activity against various species and strains of Aspergillus. Morphological destruction of inoculated hyphae and complete inhibition of hyphal outgrowth in culture is obtained from 0.07 micrograms ml-1 (10(-7)M) onward. These properties make itraconazole a likely candidate for clinical evaluation in disseminated aspergillosis. Images

The head-twitch response to intraperitoneal injection of 5-hydroxytryptophan in the rat: Antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, an LSD antagonist

The putative 5-hydroxytryptamine (5-HT) antagonists 2-bromo-LSD, cinanserin, cyproheptadine, pizotifen, methysergide, metitepine, mianserin and metergoline were found to reduce the frequency of the head-twitch response induced by intraperitoneal injections of 320 mg/kg of 5-hydroxytryptophan (5-HTP) in the rat. The antagonist dose-effect curve of these agents was biphasic. It consisted of an initial, steep, phase and a subsequent, shallower, phase. Analysis of the data by means of quantitative and quantal methods yielded different rank orders of potency of antagonist drugs. Only pirenperone, a drug identified earlier as a pure antagonist, produced a simple, monophasic dose-effect curve in antagonizing the effects of 5-HTP. The antagonist effects of pirenperone, and the first phase of the curve of the putative 5-HT antagonists, may reflect antagonist activity at 5-HT2 receptors. The data are consistent with earlier behavioural evidence that the putative 5-HT antagonists act complexly as mixed agonist-antagonists; only pirenperone exerted behavioural effects that suggest it to be a pure antagonist.

Discriminative stimulus properties of cocaine and d-amphetamine, and antagonism by haloperidol: A comparative study

This paper presents a comparative study of the discriminative stimulus properties of cocaine and d-amphetamine in the rat. Using a discrete-trial, food-reward, two-lever drug discrimination procedure, one group of rats (n = 7) were trained to discriminate 10 mg/kg cocaine from saline, whereas 1.25 mg/kg d-amphetamine served as a cue to a second group (n = 6). Following training, stimulus generalization gradients were determined for cocaine and d-amphetamine in both groups, and so were the antagonistic effects of haloperidol vs the training drug conditions. The results indicate that the acquisition of discrimination proceeded at a comparable rate in the two groups. In both groups, d-amphetamine was about 5 times more potent than cocaine, and individual threshold doses for the two drugs showed a significant correlation. Haloperidol appeared equally effective in antagonizing 1.25 mg/kg d-amphetamine and 10 mg/kg cocaine. These findings converge to suggest that to a large extent the cueing properties of d-amphetamine and cocaine are similar.

The migrating motor complex: control mechanisms and its role in health and disease

The migrating motor complex (MMC) is a cyclic, recurring motility pattern that occurs in the stomach and small bowel during fasting; it is interrupted by feeding. The MMC is present in the gastrointestinal tract of many species, including humans. The complex can be subdivided into four phases, of which phase III is the most active, with a burst of contractions originating from the antrum or duodenum and migrating distally. Control of the MMC is complex. Phase III of the MMC with an antral origin can be induced in humans through intravenous administration of motilin, erythromycin or ghrelin, whereas administration of serotonin or somatostatin induces phase III activity with duodenal origin. The role of the vagus nerve in control of the MMC seems to be restricted to the stomach, as vagotomy abolishes the motor activity in the stomach, but leaves the periodic activity in the small bowel intact. The physiological role of the MMC is incompletely understood, but its absence has been associated with gastroparesis, intestinal pseudo-obstruction and small intestinal bacterial overgrowth. Measuring the motility of the gastrointestinal tract can be important for the diagnosis of gastrointestinal disorders. In this Review we summarize current knowledge of the MMC, especially its role in health and disease.

Ketoconazole -- a new broad spectrum orally active antimycotic.

Oral treatment with ketoconazole prevented and cured artificial crop candidosis of the turkey, vaginal candidosis of the rat and skin candidosis of the guinea-pig. It was also highly effective against artificial systemic candidosis of the guinea-pig and chicken as well as against dermatophytoses of the guinea-pig.

Factors regulating drug cue sensitivity: The effect of training dose in fentanyl-saline discrimination

Abstract In this study, rats were trained to discriminate fentanyl from saline at training doses of 0.0025, 0.005, 0.01, 0.02 and 0.04 mg/kg. It appeared that the training dose affected the length and the shape of the acquisition curve, and the asymptotic level of discriminative response control. The ED 50 -value of fentanyl and of morphine to induce stimulus generalization with the fentanyl training dose was proportional to this dose. However, the generalization gradient for both fentanyl and morphine became shallower as. the training dose was lower; this effect may reflect the deterioration of response control at lower training doses. Furthermore, the training dose co-determined the degree to which cyclazocine and d -amphetamine induced stimulus generalization with a narcotic agonist training drug, and also the degree to which naloxone antagonized the cuing properties of the training drug. Fentanyl training doses equal to or higher than 0.02 mg/kg seem to be required to produce a discriminative stimulus complex which is highly specific for narcotic drugs; the discriminative stimulus properties of lower training doses of fentanyl possess increasingly less pharmacological specificity. It is concluded that the training dose of a narcotic agonist contributes critically in determining the acquisition of discriminative response control as well as various quantitative and qualitative aspects of stimulus generalization with the training drug condition.