[Pharmacology of ritodrine]. / Farmacologia della ritodrina.

Tocolytic drugs are used in order to delay or to abolish preterm labour. These drugs inhibit uterine contractions and have different pharmacological properties. The most used tocolytic agents today are beta 2-adrenergic agonists (isoxuprine, ritodrine). The pharmacological actions, pharmacokinetics, toxicological and clinical aspects of ritodrine, a synthetic beta 2-adrenergic agonist with tocolytic properties are described. Findings of many clinical trials are also discussed.

Synthesis and biological evaluation of [alpha-(1,5-disubstituted 1H-pyrazol-4-yl)benzyl]azoles, analogues of bifonazole.

A series of pyrazole analogues of bifonazole, an antifungal drug used in clinical practice, 2a-h and 4a-h were synthesized and tested in vitro against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus, with no significant results. Imidazoles 2a-h were also tested in vivo for antiarrhythmic and antihypertensive activities; two of these compounds showed moderate activity against ventricular fibrillation caused by aconitine in rats. The above compounds were prepared by reaction of phenyl-[5 substituted 1-phenyl (or 1-methyl)-1H-pyrazol-4-yl]methanols with N,N'-carbonyldiimidazole (2a-h) or of the respective chloro derivatives with 1H-1,2,4-triazole (4a-h).

Endothelin-1 affects capsaicin-evoked release of neuropeptides from rat vas deferens.

Capsaicin-sensitive neurones release a number of neuropeptides, such as substance P, neurokinin A, somatostatin and calcitonin gene-related peptide (CGRP), which exert a number of effects on smooth muscle tissues. Endothelin-1 was thought to potentiate the capsaicin-evoked release of neuropeptides from sensory neurones of the rat. We have investigated the neuromodulatory effects of endothelin-1 on capsaicin-induced release of neurotransmitters from rat vas deferens. Capsaicin and human alpha calcitonin gene-related peptide (human alphaCGRP) reduced the rat vas deferens twitch responses induced by electrical field stimulation. Human beta calcitonin gene-related peptide-(8-37) [human betaCGRP-(8-37)] (1 microM), a selective alphaCGRP receptor antagonist, antagonized the inhibitory effects of both drugs. Endothelin-1 concentration dependently evoked an increase in basal tone of the musculature and potentiated the amplitude of the electrically stimulated responses, blocking inhibitory effects of capsaicin but not of human alphaCGRP. Moreover, endothelin-1 did not markedly change the inhibitory effects of papaverine (0.1-100 microM) or isoprenaline (1 nM-100 microM) on responses to electrical field stimulation. FR 139317 [(N,N-hexamethylene) carbamoyl-Leu-D-Trp(N-Me)-D-2-Pya], a selective endothelin ET(A) receptor antagonist, administered 30 min before endothelin-1 restored the capsaicin effects whereas BQ 788 [Dmpc-gamma-MeLeu-D-Trp-(1-methoxycarbonyl)-D-Nle], a selective endothelin ET(B) receptor antagonist, was completely ineffective. The endothelin-1-induced block of the capsaicin effect was resistant to tetrodotoxin (1 microM) and 30-min pre-treatment with MEN 10.627 (cyclo[(Met-Asp-Trp-Phe-Dap-Leu) cyclo (2beta-5beta)]), a selective tachykinin NK2 receptor antagonist, did not abolish the endothelin-1 effect on the inhibitory response to capsaicin. These results suggest that endothelin-1 selectively inhibits the capsaicin-induced release of neurotransmitters from rat vas deferens and these effects are mediated via endothelin ET(A) receptors but not by tachykinin release.

[Intensive hospital monitoring of adverse reactions to benzodiazepines and neuroleptic agents]. / Monitoraggio intensivo ospedaliero delle reazioni avverse da benzodiazepine e neurolettici.

BACKGROUND: The main aims of the programme were to highlight the incidence of adverse reactions to the drugs monitored and to define the risk/benefit ratio taking account of the main physiological and physiopathological variations of patients. This paper reports the results of the programme regarding to adverse effects correlated to the use of some psychiatric drugs (benzodiazepines and neuroleptics). METHODS: A total of 73 records were compiled for 64 patients treated with benzodiazepines and/or neuroleptics. RESULTS: A very high mean incidence of adverse events was documented (48%) without any severe undesirable effects. 92% of patients treated with neuroleptics reported adverse events. Haloperidol, which caused adverse effects in 80% of patients, revealed mild or moderate forms of parkinsonism (15%), spasm (15%), rigidity (10%), akathisia (5%), reversible postural hypotension (10%), temporary reduction of the visual field (10%), delayed menstrual flow (5%), xerostomia (10%), excessive sweating (10%) and sialorrhea (10%). All the patients treated with clozapine showed adverse effects including postural hypotension (29%), persistent tachycardia (14%), sialorrhea (29%), excessive sweating (14%) and akathisia (14%). Spasms (25%), rigidity (25%) and akathisia (25%) were correlated to the use of clothiapine, whereas postural hypotension was referred to clopenthixol. 44% of patients treated with benzodiazepines showed undesired effects. 20% of those taking chlordemethyldiazepam showed somnolence (33%), sedation (22%) and dysar-thria (44%). Prolonged sedation was observed in 30% of all patients treated with lorazepam. Prazepam was correlated with adverse effects in 75% of cases. No adverse event was documented with bromazepam. CONCLUSIONS: A higher incidence of adverse events was documented than literature data. Further periods of intensive monitoring will be required to obtain a greater quantity of data from the intensive monitoring of adverse events through the MIO '97 programme.

Preparation of new 5-aroylamino substituted 3-nicotinoyl/isonicotinoyl-1,3,4-thiadiazol-2(3H)-ones with anti-inflammatory activity.

A series of 1,3,4-thiadiazol-2(3H)-ones (2a-j) with a nicotinoyl/isonicotinoyl group in position 3 and an aroylamino substituent in position 5 of the ring was prepared and evaluated for antipyretic and anti-inflammatory activities. All the title compounds and in particular 2e, 2i and 2j exhibited anti-inflammatory activity and were devoid of antipyretic properties.

Synthesis of angelicin heteroanalogues: preliminary photobiological and pharmacological studies.

A series of angelicin heteroanalogues, in which the furan was replaced by thiophene or a 1-substituted pyrazole moiety, was synthesised in order to obtain potential therapeutic agents with antiproliferative and/or other biological activities. In general, the antiproliferative activity of the new thioangelicin, tested in different biological substrates, appeared to be higher than that of the angelicin, the natural parent compound, but lower than that of 8-MOP, the furocoumarin ordinarily used in PUVA therapy and photopheresis. Thioangelicin 6 induced strong inhibition of T2 bacteriophage infectivity and was able to significantly repress the DNA synthesis in Ehrlich ascites cells and the clonal growth in HeLa cells. The pyrazolocoumarins did not show any noticeable effect upon UVA irradiation in all the biological systems considered. All the new angelicin heteroanalogues appeared to be free of the known phototoxicity of furocoumarins on the skin. The pyrazolocoumarins have also been tested as anti-inflammatory, analgesic, antipyretic, local anaesthetic, anti-arrhythmic and platelet anti-aggregating agents by standard procedures. In this class of derivatives, 10a showed good anti-inflammatory and antipyretic properties, while 9a and 11a showed significant local anaesthetic activity.