Ritanserin, characterized as a long-acting ser0t0nin-S~ antagonist and as a pure and selective antagonist of LSD discrimination in rats, was found to be effective in the treatment of anxiety states. In these studies the observation that the patients felt less tired and more energetic with improved mood has led to study the effects of ritanserin 10 mg b.i.d. in dysthymic disorder and chronic schizophrenia, two conditions with a predominant symptomatology of anergy. The results obtained from two separate placebo-controlled studies showed significant improvement of depressive mood, early insomnia, agitation, and psychic anxiety in the dysthymic group, whereas negative and affective symptoms showed the best improvement in the schizophrenic group under concurrent decrease of extrapyramidal symptomatology. In both diagnostic groups the drug treatment was very well tolerated. Based on the results that ritanserin showed predominant improvement of anergy and depressed mood, the drug was ascribed thymosthenic properties, which are further supported by the specific property of ritanserin to increase human slow wave sleep.

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11-deoxycorticosterone to corticosterone in human placenta microsomes, subcellular fraction of rat testis, bovine adrenocortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side-chain cleavage was found at concentrations up to 10 microM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17 alpha-hydroxyprogesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco- and mineralocorticoids such as 11-deoxycortisol and 11-deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase are the target enzymes for R 75251.

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Summary

The new H1-receptor antagonist levocabastine is the most potent antihistamine available, as shown in classical animal tests for antihistamine activity. Its effects also are very specific, with doses as high as 40,000 times the effective antihistamine dose not displaying other pharmacological effects. In nasal and ocular provocation tests, levocabastine nasal spray and eye drops protected against allergen-induced nasal and ocular symptoms. Twenty-three clinical trials have been performed with levocabastine nasal spray in 1363 patients with allergic rhinitis. At a dose of two sprays per nostril twice daily (if necessary to be increased up to four times daily), levocabastine was significantly better than placebo and as good as or slightly better than cromoglycate in alleviating nasal symptoms. Good to excellent results were reported in about 60% of patients on levocabastine, compared with 37% with placebo and 47% with cromoglycate. Levocabastine eye drops were studied in 21 clinical trials including 1218 patients with allergic conjunctivitis. One drop per eye twice daily (up to four times daily) provided significantly better symptom control than placebo and similar effects as those observed with cromoglycate. Response rates were 71-80% with levocabastine, 55% with placebo and 76% with cromoglycate. Levocabastine has a fast onset of action, with 94% of patients experiencing symptom relief within 15 min after the first instillation of levocabastine eye drops. Three long-term studies (10-16 weeks' duration) showed absence of tachyphylaxis during prolonged treatment with levocabastine. The incidence of adverse experiences was similar for levocabastine, cromoglycate and placebo, for nasal spray as well as eye drops.(ABSTRACT TRUNCATED AT 250 WORDS)