The effects of feeding with different levels of zinc and chromium on plasma thiobarbituric acid reactive substances and antioxidant enzymes in rats.

This study was designed to investigate the effects of supplementation and deficiency of dietary chromium (Cr), zinc (Zn) and combination of zinc and chromium on lipid peroxidation and antioxidant enzymes. A total of 84 male Wistar albino rats were fed rat chow containing different levels of Zn and Cr throughout the 84 days. Blood samples were collected for analysis of Thiobarbituric acid reactive substances (TBARS), Superoxide dismutase (SOD), Catalase (CAT) and Glutathione peroxidase (GSH-Px). TBARS concentrations in rats fed high-Cr diet, high-Zn and Cr diet and low-Zn diet were significantly higher than those determined in the control group (p < or = 0.05). CAT activities in rats fed high-Cr diet were significantly higher than those observed in the control group. Cu-Zn SOD and GSH-Px activities were significantly higher in rats fed high-Cr diet, high-Zn and Cr diet, low-Zn diet, and low-Zn and Cr diet when compared to the activities found in the controls. These results suggest that trivalent chromium supplementation increase antioxidant enzymes by enhancement of lipid peroxidation, but Zn supplementation does not have any effect on lipid peroxidation. Also Zn deficiency resulted in increased lipid peroxidation, SOD and GSH-Px activities because of the oxidative stress caused by zinc deficiency.

Effects of a GnRH agonist on fertility following administration to prepubertal male and female rats.

Leuprolide, a GnRH agonist, was administered daily to male and female rats for 90 days. Animals were sexually immature (25 days old) at the outset. Dosages were 20 and 200 micrograms/kg/day. Five males and five females were euthanized on Day 91. Sex organs were weighed and evaluated for histopathologic changes. These procedures were repeated 140 days later. Following a recovery period lasting 45 days (onset of normal-appearing estrous cycles) in females and 140 days (two spermatogenic cycles) in males, the fertility of these rats was assessed by mating with untreated animals. Treated males gained less weight while treated females gained more weight than controls. Weights of primary and secondary sex organs were reduced below control, but returned to normal following 140 days of recovery. Treated males were fertile and produced normal litters. Reproductive performance of low-dosage (20 micrograms/kg/day) females was normal 45 days after treatment cessation, but half of the high-dosage (200 micrograms/kg/day) females failed to become pregnant. However, reproductive performance of this group compared well with control performance after an additional 6 weeks of recovery. Atrophic changes were noted in male and female sex organs. Following 140 days of recovery, ovaries, uterus, vagina, prostate, and seminal vesicle were normal. Although testes and epididymides showed partial recovery at this time, multifocal or segmental atrophy and mineralization were noted in portions of some seminiferous tubules.

Comparative vestibular toxicity study with 3-O-demethylfortimicin A disulfate and gentamicin sulfate in cats.

3-O-demethylfortimicin A disulfate (ODMF), a novel aminocyclitol antibiotic, was administered subcutaneously for three months to groups of male and female cats at 15, 30 or 60 mg base/kg/day. Gentamicin sulfate (GS) at doses of 6 and 13 mg base/kg/day served as a reference compound. Signs of vestibular toxicity were considered to include persistent unsteady gait and stance, impaired righting reflex and abnormally diminished postrotatory vestibular nystagmus. Renal toxicities produced by ODMF and GS were also determined and compared. ODMF at 15 and 30 mg base/kg/day produced no signs of vestibular toxicity, while a dosage of 60 mg base/kg/day of ODMF produced vestibular toxicity in 7/10 cats. Three affected male cats died or were killed in moribund condition between study days 49 and 64. Vestibular toxicity was observed in 10/10 cats treated with GS at 13 mg base/kg/day and in 3/10 cats at 6 mg base/kg/day. All ten cats treated with GS at 13 mg base/kg/day died or were killed in moribund condition between study days 30 and 81. The deaths and moribundity in cats treated with ODMF or GS were attributed to renal toxicity. The vestibular toxicity and nephrotoxicity produced by ODMF and GS were more severe in male cats than in females. In conclusion, ODMF given at doses up to 60 mg base/kg/day for three months induced comparatively less vestibular toxicity and renal pathology than did GS at a dose of 13 mg base/kg/day.

Acute, subchronic, and chronic toxicity studies with 3-O-demethylfortimicin A disulfate, a new aminocyclitol antibiotic.

The acute LD50 for 3-O-demethylfortimicin A disulfate (ODMF) in mice and rats were 419 and 778 mg activity/kg (dosages are expressed in terms of antibiotic activity (potency), rather than on a weight basis) for single-dose im administration and, 90 and 96 mg activity/kg for single-dose iv administration, respectively. No drug-related gross or microscopic lesions were found in rabbits given single iv infusions of ODMF at dosages of 10 to 400 mg activity/kg. Minimal to mild muscle irritation was seen in rabbits given im concentrations of 3.8 or 7.5% ODMF at dosages of 48 or 93 mg ODMF activity/kg. In 1-month iv studies in dogs treated with ODMF at dosages of 0.4, 1, 4, or 8 mg activity/kg/day, and in concurrent studies in rats treated with ODMF dosages of 1, 3, 6, or 12 mg activity/kg/day, treated animals remained essentially free of adverse effects. In 1-month im studies in dogs treated with ODMF at dosages of 1, 4, 8, or 16 mg activity/kg/day, no renal lesions occurred after an ODMF dosage of 1 mg activity/kg/day. Concurrent im studies in rats treated with ODMF at dosages of 6, 12, 24, or 48 mg activity/kg/day showed that ODMF dosages of 6 and 12 mg activity/kg/day did not produce renal lesions. In 6-month chronic im studies in dogs with ODMF dosages of 0.5, 1, or 4 mg activity/kg/day or gentamicin sulfate (GS) dosages of 2 mg activity/kg/day, and in concurrent studies in rats treated with ODMF dosages of 0.5, 2, or 6 mg activity/kg/day or GS dosages of 3 mg activity/kg/day, less severe local irritation and nephrotoxicity occurred after treatments with ODMF than with GS. In both rats and dogs treated by either the iv or the im route of administration, higher concentrations of ODMF and GS were found in the kidneys than in the sera. Mean serum and tissue concentrations of GS were higher than those of ODMF. Local tissue irritation and nephrotoxicity were lower with ODMF than with GS on a milligram activity per kilogram basis.

Carcinogenic evaluation of estazolam via diet in CD strain Sprague-Dawley rats and B6C3F1 mice for 2 years.

A comparative toxicity and carcinogenicity study was carried out for 2 years with estazolam, a benzodiazepine, via diet in Sprague-Dawley rats (0.5, 2, and 10 mg/kg/day) and in B6C3F1 mice (0.8, 3, and 10 mg/kg/day). In rats, no biologically significant changes were seen with respect to mortality, clinical signs, food consumption, or occurrence of palpable masses. Body weight gain in females (10 mg/kg/day) was depressed 12.6% and reflected a maximum-tolerated dosage (females). Spontaneous and incidental nonneoplastic lesions were consistent with aging in this species and unrelated to drug treatment. No biologically significant differences in tumor incidences occurred. Mice were more responsive to estazolam as suggested by (1) increased mortality (males) at 10 mg/kg/day, (2) increased food consumption and body weight gains (females), (3) withdrawal signs characterized by hyperactivity/aggressiveness and convulsions, and (4) appearance of dose-related nodular hyperplasia of the liver due to the relatively high dosages used coupled with the propensity of benzodiazepines to enhance liver enzyme induction. Several spontaneous benign and malignant tumors observed in all groups were not considered to be drug related. Based on the findings in these studies, estazolam was not considered to be carcinogenic when administered via diet to either rats at 0.5, 2, and 10 mg/kg/day or to mice at 0.8, 3, and 10 mg/kg/day for 2 consecutive years.

Terazosin: intravenous safety evaluation in rats.

Terazosin, an alpha-adrenergic antagonist, was administered as a 15 mg/ml solution to rats intravenously at a rate of 2 ml/min. Under these conditions the LD50 was 277 mg/kg for males and 293 mg/kg for females. When administered daily for 1 month at dosages of 0, 10, 40 or 150 mg/kg/day, the no-toxic-effect dosage was 40 mg/kg/day. Evidence of toxicity at 150 mg/kg included hypothermia and deaths. Death resulted from acute, exaggerated pharmacologic effects leading to cardiorespiratory failure. Evidence of sympatholytic activity observed at lower dosages included hypoactivity, blepharoptosis, ptyalism and splenic congestion.

Tulobuterol: one-month intravenous safety studies in rats and dogs.

Tulobuterol was given intravenously to rats and dogs at dosages of 1, 5, or 25 mg/kg/day and 0.6, 2, or 6 mg/kg/day, respectively. The no-toxic-effect dosages were 5 mg/kg/day in rats and 6 mg/kg/day in dogs. Two rats died at 25 mg/kg/day. Convulsions, jerking movements, hyperactivity, tremors, hypoactivity and ptyalism were observed in rats given 25 mg/kg/day. Restlessness, ptyalism and hypoactivity were also observed in dogs at 2 and 6 mg/kg/day. Cutaneous and/or mucosal erythema were observed in rats and dogs at all dosages. Increased body weight gain occurred in drug-treated rats and in mid- and high-dose female dogs. Slight elevations in serum creatinine and BUN were seen in rats and dogs at the highest dosages. Heart weights were increased in rats at all dosages after 1 month of treatment and in rats given 25 mg/kg/day after 2 weeks of recovery. There were no treatment-related morphologic changes in either species.

Buflomedil: three month intravenous safety evaluation in rats.

Buflomedil was administered intravenously to rats at dosages of 1, 4, 12 or 30 mg/kg/day for up to three months. The no-adverse-effect dosage was considered to be 12 mg/kg/day. At 30 mg/kg/day several deaths and clinical signs, including ataxia, decreased activity, dyspnea and jerking movements after dosing, were observed. These were considered to result from the acute, exaggerated pharmacologic effects of buflomedil. Body weight gain and food consumption were decreased after six weeks in males at 30 mg/kg/day. Increases in the relative weights of the kidneys, brain and testes of males at 30 mg/kg/day were correlated with decreased body weight gain in this group. There were no effects on hematology or serum chemistry parameters, and no morphologic changes were found.