Aurelio Sacristan

Relationship between fetal weight and litter size in rats: Application to reproductive toxicology studies

The inverse relationship between mammalian fetal weight and litter size has been discussed by many authors, but their opinions reveal no agreement at all. As in toxicity studies of reproduction, both parameters must be correctly evaluated. We investigated the existence of such a relationship in 2466 fetuses from 203 litters of Sprague-Dawley CD control rats. The frequency distribution of fetal weights had a normal adjustment. From the mean weight of fetuses in each litter, the mean fetal weights in each litter size and correlation coefficient were calculated and the regression line was plotted; the correlation coefficient (r = 0.677) was highly significant (P = 0.002), which made evident that there was an inverse relationship between fetal weight and litter size. If fetal weight/litter size inverse relationship is not taken into account when toxicity on the fetal weight is analyzed, wrong conclusions may be reached if the test substance reduces the litter size, provoking embryofoetal mortality. The iatrogenic decrement in fetal weight can be masked by an increment due to the litter size reduction. We suggest that in all three segments of reproductive toxicity studies, litter size must be considered as a covariate to the effect of the test substance on the fetal weight, in order to perform a correct analysis of covariance (ANCOVA), in addition to the dose factor commonly used in common ANOVA.

Inhibitors of gastric acid secretion: N-sulphonyl formamidines in a series of new histamine H2-receptor antagonists

Abstract A series of 19 new N -sulphonyl formamidines have been synthesized and evaluated as inhibitors of gastric acid secretion. Compounds 4a and 4n were the most active and were selected for further pharmacological and toxicological studies.

Effects of Dotarizine on Peripheral and Pulmonary Circulation and Cardiac Dynamics in Dogs

The cardiovascular effects of dotarizine in 10-min intravenous infusions were studied in thiopental-anesthetized dogs. The effects of dotarizine 0.024 mg/kg/min almost paralleled those of saline controls; 0.079 mg/kg/min dotarizine significantly raised the stroke index and ejection fraction, and, at a rate of 0.25 mg/kg/min, further effects appeared and were dose-dependent. Dotarizine produced arterial dilation in both systemic and pulmonary circulation: the total peripheral resistance dropped, and femoral artery flow rose; aortic and pulmonary artery mean and diastolic pressures declined, and systolic pressures remained almost stable. A trend of bradycardia and pulmonary artery pressure reduction persisted for 30 min. As compared with the reduced total peripheral resistance, aortic pressure fell only moderately because of rising cardiac output due to a higher ejection fraction and stroke volume. Cardiac preload tended to decline; contractility tended to increase. Cardiac performance remained stable while myocardial oxygen consumption tended to fall, as did the pressure-rate product and the tension time index. Dotarizine exerted direct cardiovascular effects similar to those of the 5-HT2-receptor antagonist ketanserin and, more generally, to calcium channel blockers rather than to alpha-adrenoceptor blockers.

Ocular tolerance of sertaconazole gel

Summary. The in vitro and in vivo tolerance of sertaconazole gel, a new topical azole antifungal, was studied. Ketoconazole gel (Panfungol®) was used as a reference substance. The methods applied for tolerance assessment were the bovine corneal opacity and permeability test for the in vitro assay and a modified Draize test for the in vivo assay. The results obtained show that both substances can be classified as slightly irritant and with acceptable tolerance. However, unlike ketoconazole gel, sertaconazole gel did not cause a positive lesion index in vivo. Ketoconazole was 5.25 times more irritant in vitro than sertaconazole gel, whose effect was similar to that of saline solution. Consequently, the negligible irritant effect of sertaconazole gel on a type of epithelium that is extremely sensitive, i.e. the cornea, confirms the good tolerance of this new antifungal gel on other structures such as the skin and mucous membranes.

Twenty-four-month oral carcinogenicity study of ebrotidine in rats.

Three groups of Sprague-Dawley CD rats (males and females) were initially administered p.o. with ebrotidine, a novel H2-receptor antagonist, mixed with the diet, at 50, 200, and 500 mg/kg/d, respectively. Two concurrent control groups of animals were used. After 13 months, initial 200 mg/kg was lowered to 150 mg/kg, and a new group was administered with 300 mg/kg, due to the body weight reduction observed in the top dose group. After 24 months, survivors were killed and necropsied, and a histopathological study was performed. The frequencies of the different tumour types that were found were not raised due to the treatment. Lower frequencies of some types of pituitary and mammary gland tumours, in the groups treated with the higher doses, were the only statistically significant changes. Among the non-neoplastic effects, a lower body weight increment and food consumption (500 and 300 mg/kg, both sexes), lower survival (500 mg/kg, males), presence of lipoid pneumonia (500 mg/kg, only in males, and 300 mg/kg, both sexes), and lithiasis in urinary system (500 mg/kg) were observed. No changes in gastric mucosa (the main target organ) were attributable to ebrotidine. Regarding the non-neoplastic effects, 150 mg/kg was the no observed adverse effect level. According to the previous results of the carcinogenicity study in mice, conjointly with those of the study in rats reported here, there is no evidence of carcinogenic risk either in males or in females in these species.

Effect of ebrotidine on the density of antral G-cells in the gastric mucosa in the rat

Two groups of male rats were treated orally for 60 days with ebrotidine and cimetidine, used as reference standard, respectively. The dose used of both drugs was 500mg/kg. A third group, used as control, received 10 ml/kg of an aqueous agar suspension. After receiving the last dose, the animals were killed by inhalation of CO2 in a sealed chamber and the stomachs were removed for histological preparation.