Showing papers on "Toxicity published in 1985"

Toxicological studies on omeprazole.

Abstract: As part of the safety evaluation of the gastric antisecretory drug, omeprazole, toxicological studies have been performed in several species of animals. The acute toxicity after oral administration to rodents was low. The oral LD50 value was above 4 g/kg. The general toxicity after repeated administration has been studied in rats and dogs. No clinical signs of adverse reactions were seen. Some minor changes in hematology parameters were observed. In rats and mice decreases in the erythrocyte count, hematocrit and hemoglobin have occasionally been found at doses of 125 mumol/kg/day and more. Hyperplasia of oxyntic mucosal cells, concomitant with increases in stomach weight, oxyntic mucosal thickness and folding, has been observed in the species investigated, the dog, rat and mouse. In addition, slight chief cell atrophy and eosinophilia of the chief cell granules were observed in rats. The oxyntic mucosal effects were reversible upon treatment being discontinued. In the oncogenicity studies, gastric carcinoids occurred in the rat but not in the mouse. Investigations of the carcinoids showed that the vast majority of the endocrine cells could be characterised as ECL-cells. The hyperplasia of oxyntic mucosal cells, including hyperplasia of endocrine ECL-cells and development of gastric carcinoids in rats, is attributable to the pronounced hypergastrinemia produced as a secondary effect of almost complete inhibition of acid secretion by the large doses of omeprazole used in the toxicity studies. In agreement with this hypothesis, the hyperplasia of the oxyntic cells was prevented by antrectomy. The reproduction studies performed in rats and rabbits showed no sign of fetal toxicity or teratogenic effect. The results of the short-term mutagenicity tests, Ames test, the micronucleus test in mice and the mouse lymphoma test were all negative.

Effects of environmental factors on toxicity of a cyanobacterium (Microcystis aeruginosa) under culture conditions.

Abstract: Effects of light intensity, temperature, and nutrients on the toxicity of Microcystis aeruginosa were investigated, using a toxic strain which kills mice A marked change in toxicity was observed in the light intensity experiment, and slight changes were observed to be caused by temperature and phosphorus deficiency

Effect of temperature and light on the toxicity and growth of the blue-green alga Microcystis aeruginosa (UV-006).

Abstract: The toxicity and growth of Microcystis aeruginosa (UV-006) from the Hartbeespoort Dam, South Africa were investigated at different temperatures and photon fluence rates under laboratory conditions. Cells harvested in late logarithmic growth phase were most toxic when grown at 20°C (LD50) median lethal dose [IP, mouse]=25.4 mg kg(-1)). Toxicity was markedly reduced at growth temperatures above 28° C. Fluence rate had a smaller effect on the toxicity of the cells, but toxicity tended to be less at the very low and high light fluences. Optimal conditions for growth did not coincide with those for toxin production. Well-aerated cultures of this isolate kept at pH 9.5 by CO2 addition, a temperature of 20-24° C, a fluence rate of 145 μmol photons m(-2) s(-1) and harvested in the late logarithmic growth phase yielded the maximum quantity of toxin.

Cellular and bacterial toxicities of topical antimicrobials.

Abstract: Cellular and bacterial toxicities of four commonly used topical antimicrobials (1% povidone-iodine, 3% hydrogen peroxide, 0.25% acetic acid, and 0.5% sodium hypochlorite) were assayed in vitro using cultures of human fibroblasts and Staphylococcus aureus. All agents tested at full strength killed 100 percent of exposed fibroblasts. Fibroblast toxicity exceeded bacterial toxicity with serial dilutions of hydrogen peroxide and acetic acid. Dilutions of povidone-iodine (1:1000) and sodium hypochlorite (1:100) were identified where no fibroblast toxicity occurred while full bactericidal activity persisted.

Pharmacokinetics, Single-Dose Tolerance, and Biological Activity of Recombinant γ-lnterferon in Cancer Patients

Abstract: We report a clinical study of the pharmacokinetics, toxicity, and biological activity of iv- and im-administered recombinant γ-interferon (rlFN-γ) consisting of 143 amino acids Ten patients with metastatic cancer were given rlFN-γ at doses of 001 to 25 mg/sq m by alternating im and iv bolus injections with a minimum intervening period of 72 h After iv administration, rlFN-γ was cleared monoexponentially with a short half-life of 25 to 35 min as determined by bioassay and enzyme immunoassay After im injection, a longer half-life of 227 to 462 min was measured by enzyme immunoassay Serum titers were detected by bioassay only at high doses, suggesting partial loss of antiviral activity at the im site However, other biological effects were retained as evidence by fever, chills, and fatigue after both routes of administration and granulocytopenia after im, but not iv, doses Two of ten patients showed objective evidence of tumor regression These data suggest that further studies with im as well as prolonged iv infusions of rlFN-γ are indicated

Synergism between myristicin and xanthotoxin, a naturally cooccurring plant toxicant.

Abstract: Myristicin, a methylenedioxyphenyl (MDP)-containing phenylpropene constituent of the leaves of many plants in the family Umbelliferae, is a highly effective Synergist of the cooccurring furanocoumarin xanthotoxin. As little as 0.10 % in an artificial diet can increase the toxicity of xanthotoxin toHeliothis zea (Lepidotera: Noctuidae) fivefold. In addition to increasing the proportion of caterpillars dying at a given xanthotoxin concentration, myristicin also increases the rate at which they die and increases the time to molt of surviving larvae. That there was no increase in the deterrency of xanthotoxin in the presence of myristicin suggests that the mechanism of synergism is not behaviorial but rather is biochemical, via MDP competitive inhibition of microsomal mixed function oxidases.

Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity.

Abstract: We assessed the frequency of retinal toxicity in patients receiving either chloroquine or hydroxychloroquine and factors which may predict patient susceptibility to toxicity. The overall frequency of retinopathy was 6% (7 of 110 patients). Of the 31 patients receiving chloroquine alone, 6 developed toxicity (19%). In contrast, of the 66 patients receiving hydroxychloroquine, none developed retinopathy. Retinopathy was associated with greater age and with greater accumulative doses of chloroquine. Thus, hydroxychloroquine can be used safely with minimal risk of toxicity.

Quinones as toxic metabolites of benzene.

Abstract: Occupational exposure to benzene has long been associated with toxicity to the blood and bone marrow, including lymphocytopenia, pancytopenia, aplastic anemia, acute myelogenous leukemia, and possible lymphoma. A variety of studies have established that benzene itself is not the toxic species but requires metabolism to reactive intermediates. The bioactivation of benzene is complex. Both primary and secondary oxidation of benzene and its metabolites are mediated via cytochrome P-450 in the liver, although the role of secondary metabolism in the bone marrow is not clear. Toxicity is associated with the dihydroxy metabolites, hydroquinone and catechol, which concentrate in bone marrow. Hydroquinone and its terminal oxidation product, p-benzoquinone, have been demonstrated to be potent suppressors of cell growth in culture. Suppression of lymphocyte blastogenesis by these compounds is a sulfhydryl-dependent process and occurs at concentrations that do not result in cell death, or in detectable alterations in energy metabolism, intracellular glutathione concentration, or protein synthesis. Recent studies suggest that these compounds and other membrane-penetrating sulfyhdryl alkylating agents, such as N-ethylmaleimide and cytochalasin A, and endogenous regulatory molecules, such as soluble immune response suppressor (SIRS), interfere with microtubule assembly in vitro and selectively interfere with microtubule-dependent cell functions at identical concentrations. These agentsmore » appear to react with nucleophilic sulfhydryl groups essential for guanosine triphosphate binding to tubulin that are particularly sensitive to sulfhydryl-alkylating agents.« less

Toxicity of low dose methotrexate in rheumatoid arthritis.

Abstract: The efficacy and acceptability of low dose weekly methotrexate therapy in rheumatoid arthritis was reviewed in 587 patients in open and randomized trials. Gastrointestinal toxicity was reported most frequently. Bone marrow suppression, stomatitis, alopecia, headaches, and fever also occurred. A review of these adverse reactions, as well as of the effects of this drug on the reproductive, renal, and pulmonary systems, is discussed.

1α-Hydroxyvitamin D2 is Less Toxic than 1α-Hydroxyvitamin D3 in the Rat

Abstract: An LD50 of 0.2 mg/kg body wt has been determined for 1 alpha-hydroxyvitamin D3 in the rat. In comparison, the LD50 for 1 alpha-hydroxyvitamin D2 is between 3.5 and 6.5 mg/kg. In terms of chronic toxicity, 1 alpha-hydroxyvitamin D3 at a dose of 5 micrograms/kg/day causes death of one-half the animals in a 4-week period. On the other hand, 20 micrograms/kg/day of 1 alpha-hydroxyvitamin D2 is required to induce similar toxicity. The body weight record and renal calcium accumulation during chronic treatment support the above conclusion. It therefore appears that 1 alpha-hydroxyvitamin D2 is between 5 and 15 times less toxic than 1 alpha-hydroxyvitamin D3. This surprising result prompted a reexamination of the relative biological activity of 1 alpha-hydroxyvitamin D2 and 1 alpha-hydroxyvitamin D3. Both compounds are equally potent in the stimulation of intestinal calcium transport, bone calcium mobilization, in the elevation of serum phosphorus, and in the healing of rickets in the rat. The reason for lower toxicity of 1 alpha-hydroxyvitamin D2 is unknown. The results suggest that 1 alpha-hydroxyvitamin D2 might represent a therapeutically superior compound.

Subacute pulmonary failure complicating therapy with high-dose ara-C in acute leukemia

Abstract: Seventy-four adult patients with acute leukemia in relapse were studied. They received high-dose intravenous boluses of cytosine arabinoside (Ara-C) according to the following schedules: 3 g/m2 over 2 hours, every 12 hours for 4 to 12 consecutive doses, or a continuous infusion over 5 days at 200, 400, or 800 mg/m2/day. The patients' ages ranged from 16 to 68 years (median, 35). Subacute pulmonary failure attributable to Ara-C was observed in 16 of 72 evaluable patients (22%) and appeared 2 to 21 days (median, 6) after the first dose. None of the 28 patients who received up to six doses experienced any toxicity. With repeated courses or more than six doses in the first course there was a sharp increase in the incidence of toxicity. Thus, subacute pulmonary failure developed in 6 of 24 patients who received 9 doses and 6 of 19 patients who received 12 doses. The increase in toxicity with increasing number of doses is significant (P = 0.03). This suggests that the high-dose Ara-C regimen should be used with awareness of possible drug-induced pulmonary toxicity.

Modulation of oxidant lung injury by using liposome-entrapped superoxide dismutase and catalase

Abstract: Increased cellular generation of partially reduced species of oxygen mediates the toxicity of hyperoxia to cultured endothelial cells and rats exposed to 95-100% oxygen Liposomal entrapment and intracellular delivery of superoxide dismutase (SOD) to cultured porcine aortic endothelial cells increased the specific activity of cellular SOD up to 15-fold The liposome-mediated augmentation of SOD activity persisted in cell monolayers and rendered these cells resistant to oxygen-induced injury in a cell SOD activity-dependent manner Addition of free SOD to culture medium had no effect on cell SOD activity or resistance to oxygen toxicity SOD and catalase-containing liposomes injected iv into rats increased lung-associated enzyme specific activities two- to fourfold Liposome entrapment of both SOD and catalase significantly increased the circulating half-lives of these enzymes and was critical for prevention of in vivo oxygen toxicity Free SOD and catalase injected iv in the absence or presence of control liposomes did not increase corresponding lung enzyme activities or survival time in 100% oxygen These studies show that O2- and H2O2 are important mediators of oxygen toxicity and that intracellular delivery of oxygen protective enzymes can reduce tissue injury owing to overproduction of partially reduced oxygen species

Theophylline toxicity and the beta-adrenergic system

Abstract: After ingestion of 12 g of theophylline caused severe toxicity in a young woman, we developed an experimental canine model to study human theophylline toxicity. Our study involved four anesthetized dogs given theophylline in a continuous intravenous drip for 180 minutes in one of four protocols. The protocols included a low-dose infusion (400 mg/h), a high-dose infusion (1000 mg/h), a high-dose infusion with beta-blockade induced by propranolol at 125 minutes after infusion, and a high-dose infusion while maintaining beta-blockade with propranolol throughout the experiment. Toxic levels of theophylline were associated with hypokalemia, hypophosphatemia, hyperglycemia, metabolic acidosis, and hypotension in both the patient and the experimental series. These effects were either prevented or partially reversed after induction of beta-blockade with propranolol. Very high levels of theophylline were associated with elevated levels of norepinephrine and epinephrine in the animals.