Acute and twenty-eight days repeated oral dose toxicity study of besifloxacin in Wistar albino rats.

The purpose of this study was to investigate the potential acute and 28-day repeated oral toxicities of besifloxacin (BAF) in Wistar albino rats. In oral acute and repeated dose study, BAF was administered to both sex of rats, at dose levels of 0, 300, 600, 900 mg/kg/day and 0, 100, 200, 500 mg/kg/day, respectively. In the acute study, total white blood cell (WBC) (male, 43.74%; female, 42.60%) and total bilirubin (T-BIL) (male, 80%; female, 60%) were significantly increase, total protein (TP) (male, 23.24%; 27.80%) was significantly decreased, and significant incidence of pericholangitis (male, 83.33%; female, 75%) was shown in males and females of high-dose groups. In repeated oral dose toxicity study, similar type effects were also observed after serum hematological and serum biochemical analysis, whereas additionally sever hepatic injury and focal ulceration in gastric mucosa also observed in high dose groups of both sexes after histopathological analysis. However these toxic effects of besifloxacin were transient and reversible and no-observed adverse effect level (NOAEL) were 300 mg/kg/day for acute and 100 mg/kg/day for repeated dose toxicity study, respectively.

Synthesis and evaluation of (S,S)-N,N'-bis-[3-(2,2',6,6'-tetramethylbenzhydryloxy)-2-hydroxy-propyl]-ethylenediamine (S2824) analogs with anti-tuberculosis activity.

In order to identify new and potent candidate drugs to treat tuberculosis, a library of compounds was screened, and (S,S)-N,N'-bis-[3-(2,2',6,6'-tetramethylbenzhydryloxy)-2-hydroxy-propyl]-ethylenediamine (S2824) was identified as a hit in the screen. This research discusses our efforts to synthesize and test 30 analogs of this hit for activity against Mycobacterium tuberculosis. Two compounds with homopiperazine ring possess high in vitro activity against drug sensitive and resistant M. tuberculosis with MICs 0.78-3.13 microg/mL (or 1.22-4.88 microM).

Acute exposure to molinate alters neuroendocrine control of ovulation in the rat.

Molinate, a thiocarbamate herbicide, has been reported to impair reproductive capability in the male rat and alter pregnancy outcome in a two-generation study. Published data are lacking on the effects of acute exposure to molinate in the female. Based on this work and our previous observations with related dithiocarbamate compounds, we hypothesized that a single exposure to molinate during the critical window for the neural trigger of ovulation on the day of proestrus (PRO) would block the luteinizing hormone (LH) surge and delay ovulation. To examine the effect of molinate on the LH surge, ovariectomized (OVX) rats were implanted with Silastic capsules containing estradiol benzoate to mimic physiological levels on proestrus. Doses of 25 and 50 mg/kg molinate significantly suppressed LH and prolactin secretion. Intact regularly cycling females gavaged with 0, 25, or 50 mg/kg molinate at 1300 h on PRO were examined on estrus or estrus +1 day for the presence of oocytes in the oviduct. All control females had oocytes in the oviduct on estrus. Molinate doses of 6.25 to 50 mg/kg delayed ovulation for 24 h. Estrous cyclicity was examined after daily exposure to 50 mg/kg (21 days). Estrous cyclicity was irregular in the molinate group, showing extended days in estrus. Two experiments were conducted to determine whether molinate blocked the LH surge via a central nervous system (CNS) mode of action or via an alteration in pituitary response. In the first experiment, we evaluated the release of LH in control and molinate-treated rats after a bolus dose of exogenous GnRH. Luteinizing hormone release was comparable in the two groups, suggesting that the effect of molinate is centrally mediated. To further examine the potential role of the CNS, we examined the pulsatile release of LH present in the long-term OVX females. In this model, the pulsatile pattern of LH secretion is directly correlated with GnRH release from the hypothalamus. A significant decrease in the LH pulse frequency was observed in molinate-treated females. These results indicate that molinate is able to delay ovulation by suppressing the LH surge on the day of proestrus and that the brain is the primary target site for the effects on pituitary hormone secretion.

The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor, in rat models of venous and arterial thrombosis.

The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis. After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50, (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively. In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P < 0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively. The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times. These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.

[Pharmacological comparison between virosecurinine and securinine].

Pharmacological activities of virosecurinine (Vse) and securinine (Sec) were studied. The results showed that acute toxicity of Vse was 1/13.6 that of Sec, and Vse had no convulsive effects on rats or frogs, while Sec had. The results also showed that Vse and Sec could elevate blood pressure and excite respiration in cats.

Developmental toxicity studies of caprolactam in the rat and rabbit.

Caprolactam was evaluated for developmental toxicity potential in both rats and rabbits by the oral route. In rats dosed on days 6-15 of gestation with 100, 500 or 1000 mg/kg/day of caprolactam, the maternal survival rate was significantly lower in the high-dose group and implantation efficiencies were slightly lower in the 100 and 1000 mg/groups (but not the 500 mg/kg) than in the control. The incidence of fetal death was comparable for all groups, and the incidence of fetal viability was considerably lower in the high-dose group (but not the mid or low) than in the control group. Visceral anomalies and one visceral variant were observed in one 100 mg/kg and one 500 mg/kg pup, respectively. The anomalies included exencephaly, an incomplete left eyelid, microphthalmia (right), and a protruding tongue. No skeletal anomalies were observed. It was concluded that caprolactam at levels up to at least 500 mg/kg of body weight produced no teratogenic effects in the Fischer 344 rats. In rabbits receiving 50, 150 or 250 mg/kg caprolactam on days 6-28 of gestation, the pregnancy rate in all groups was at least 80%. The numbers of corpora lutea, live and dead fetuses, resorptions, the sex ratio and the pre- and post-implantation losses were not significantly different among the test and control groups. The incidence of major malformations and of minor skeletal anomalies was unaffected by treatment with caprolactam. Maternal weights were depressed in the group receiving 250 mg/kg. Treatment of a separate group with a positive control substance (6-aminonicotinamide) resulted in significantly (P less than 0.001) increased incidences of major malformations, minor visceral anomalies and minor skeletal anomalies. Maternal toxicity in terms of mortality was observed in pregnant rabbits treated with caprolactam at a dose of 250 mg/kg/day. Fetotoxicity was evidenced by lower fetal weights at the 150 and 250 mg/kg/day levels, and an increased incidence of thirteenth ribs was observed at the 250 mg/kg/day dose level. Neither embryotoxicity nor teratogenicity occurred at any dose level.