Showing papers on "Toxicity published in 1982"

Intracellular cysteine delivery system that protects against toxicity by promoting glutathione synthesis.

Abstract: Depletion of glutathione by inhibition of its synthesis by buthionine sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, leads to increased sensitivity to (i) irradiation and (ii) oxidative stress. In the present work, an intracellular cysteine delivery system was used to promote glutathione synthesis, and this was found to protect against toxicity. Thus, administration of L-2-oxothiazolidine-4-carboxylate protected against acetaminophen toxicity in mice; the thiazolidine, which is converted to L-cysteine by the enzyme 5-oxo-L-prolinase (present in many animal tissues and in plants) promotes the synthesis of glutathione, which is the actual protectant. The effect of this thiazolidine in increasing the level of glutathione is prevented by administration of buthionine sulfoximine. This thiazolidine may be useful in the treatment of other toxicities and in the treatment of certain diseases. It may also be valuable as a component of amino acid mixtures used in therapy and as a safener in agriculture.

Increased Toxicity and Reduced Clearance of Lidocaine by Cimetidine

Abstract: Cimetidine reduced liver blood flow and the systemic clearance of drugs, such as propranolol, that are highly extracted by the liver. In a randomized placebo-controlled study, we examined the influence of cimetidine, 300 mg four times daily for 1 d, on the disposition of lidocaine, 1 mg/kg body weight by a 10-minute intravenous infusion. Cimetidine reduced the systemic clearance of lidocaine from 766 +/- 50 mL/min to 576 +/- 47 mL/min (p less than 0.05); the apparent volume of distribution at steady-state and the degree of plasma protein binding of lidocaine also were decreased. Five of the six subjects noted lidocaine toxicity during the cimetidine infusion in contrast to one subject on the placebo day. The peak lidocaine concentration (mean +/- SE) was 50% +/- 10% higher when subjects received cimetidine. This study provides additional evidence that the effect of cimetidine on the elimination of other drugs has multiple factors, and shows a previously unrecognized mechanism, involving altered initial drug distribution, whereby the interaction of cimetidine with other drugs may cause toxicity.

Toxicity of 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD)

Abstract: In summary, the toxicity of TCDD has been comprehensively examined in multiple acute, subchronic, and chronic studies. Acute toxicity studies have shown marked species differences, with up to a 10,000-fold difference between the single oral LD50 dose for the guinea pig and hamster. TCDD is capable of causing an acnegenic response in man and a similar skin response in certain animals. It is also a potent inducer of microsomal enzymes in some but not all species. A dose-related suppression of cell-mediated immunity has been observed at higher dose levels in laboratory animals but not in humans manifesting TCDD-induced acnegenic response. TCDD causes a dose-related teratogenic response in mice, with the no-adverse-effect level of 0.1 micrograms TCDD/kg/day. In rats, TCDD causes embryo- and fetotoxicity above the no-adverse-effect level of 0.03-0.125 micrograms/kg/day. Dose-related reproductive effects have also been noted in monkeys at doses that elicit maternal toxicity, and additional long-term studies are presently underway. A multigeneration reproduction study as well as a lifetime chronic toxicity study have been completed with TCDD in rats; in both studies, the no-adverse-effect level was found to be 0.001 microgram TCDD/kg/day. Numerous mutagenic studies have been performed using in vitro plant and microbial test systems as well as in vivo tests in mammals and man. A mutagenic response was noted in a few of the vitro test systems, but there are no definitive in vivo correlates of TCDD mutagenicity in higher mammals or man. TCDD has been studied for carcinogenic potential in rats and mice. There is good correlation of the results, with a carcinogenic response noted in both species only after long-term ingestion of higher dose levels that induce toxicity. No carcinogenic response occurred at continuous dose levels of 0.001-0.0014 micrograms/kg/day in rats and 0.001-0.03 micrograms/kg/day in mice. Data presently available are more supportive of a nongenetic (?promotor) rather than a genetic mechanism of carcinogenesis. The most recent research, some of which is still underway, indicates that the biologic uptake and toxicity of TCDD may be significantly decreased if the TCDD is adsorbed onto carbon or soil particles. This information is helpful in hazard assessment of exposure to TCDD.

An in vivo teratology screen utilizing pregnant mice

Abstract: Twenty-eight compounds of known teratogenic potential were assayed by an in vivo screening procedure. Postnatal growth and viability of prenatally exposed offspring was used as a measure of developmental toxicity. Gravid CD-1 mice were administered maximum tolerated doses of the compounds for up to 5 consecutive days during the period of major organogenesis. The dams were allowed to give birth, and litter size and weight on postpartum d 1 and 3 were recorded and compared with concurrent controls. All 15 compounds that were teratogenic by standard teratology test criteria exhibited some form of developmental toxicity. Four chemicals known to produce only fetal toxicity (reduced weight or supernumerary ribs) were tested and the screen successfully identified those that reduced weight. Finally, of the 9 compounds that show no effect in standard tests, 6 were also negative in the screen and 3 demonstrated either reduced viability or weight.

A Phase I Study of Intracarotid Artery Infusion of Cis-Diamminedichloroplatinum(II) in Patients with Recurrent Malignant Intracerebral Tumors

Abstract: A Phase I study of intracarotid cis-diamminedichloroplatinum was performed in 11 patients with intracerebral tumors (five glioblastoma, four melanoma, one meningeal sarcoma, and one lung carcinoma) progressing after radiation ± chemotherapy. The internal carotid artery was temporarily cannulated by a percutaneous transfemoral approach. All patients received i.v. heparin, mannitol, and fluids; seven received dexamethasone, 50 mg i.v., twice the day before and the day of treatment. Intracarotid cis-diamminedichloroplatinum, 60 to 100 mg/sq m in 175 to 250 ml 0.45% NaCl solution with 1000 units heparin, was infused over 1 hr. Six patients received two or more courses (maximum of 6) at 2- to 8-week intervals. Gastrointestinal toxicity was mild to moderate. Ototoxicity was minor. Central nervous system (CNS) toxicity was focal, severe, permanent, and possibly due to embolus in one patient at 75 mg/sq m; focal and reversible in one patient at 100 mg/sq m; and generalized but reversible in one patient at 75 mg/sq m. Possible CNS toxicity was noted in two additional patients. Two patients with CNS toxicity developed permanent ipsilateral retinal toxicity, and one patient without CNS toxicity developed bilateral decreased visual and auditory acuity 2 weeks after his sixth treatment. Renal and hematological toxicity and orbital pain were mild. Response status included: early death, one; probable responses, six (2+, 4+, 6, 6+, 8, and 8+ months); stabilization, two (3+ and 4 months); and failure, two. We recommend cis-diamminedichloroplatinum (60 mg/sq m) every 2 to 4 weeks for Phase II studies. Severe CNS and retinal toxicity are possible.

Diphtheria Toxin and Related Proteins: Effect of Route of Injection on Toxicity and the Determination of Cytotoxicity for Various Cultured Cells

Abstract: The effect of route of injection on the toxicity of intact diphtheria toxin, cross-reacting material (CRM45), and diphtherial fragment A was compared in several animal species. By ordinary routes of injection, neither CRM45 nor fragment A was toxic, even in species for which 0.1 micrograms of toxin/kg of body weight was lethal. After intracerebral injection, however, small amounts of CRM45 led to paralysis and death, even in mice and rats--species that are resistant to toxin administered intravenously. High doses of fragment A were nontoxic even by the intracerebral route. The cytotoxic dose od CRM45 was approximately 10(-7) M for a variety of cell lines derived from toxin-sensitive or toxin-resistant species. Cultured at Schwann's cells, however, were more sensitive CRM45 than other cell lines tested and 50-100 times more sensitive to toxin than cells cultured from other adult rat tissues. Fragment A has virtually no cytotoxicity for any mammalian cell line tested.

Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination.

Abstract: In an uncontrolled trial, 29 patients with chronic hepatitis B virus infection were treated with 93 courses of adenine arabinoside at doses ranging from 2.5 to 15 mg/kg per day. Most patients were treated concomitantly with human leukocyte interferon. Significant, but transient, neurotoxicity was seen with adenine arabinoside therapy in 44% of all courses. Manifestations of toxicity were mainly neurological and ranged from pain syndromes to tremors and, rarely, seizures. Suppression of numbers of lymphocytes was also noted. All effects were reversible with time. The extent of toxicity was dependent upon the dosage of adenine arabinoside. Treatment with interferon appeared to potentiate the occurrence of toxicity with adenine arabinoside. Arabinofuranosylhypoxanthine serum levels increased in a dose-dependent manner and tended to accumulate in interferon-treated hepatitis patients during a course of therapy. Elevated blood levels and drug accumulation were associated with toxicity in a significant fashion. Human leukocyte interferon was administered to 38 patients in 113 separate courses. Interferon side effects were rapidly reversible upon cessation of therapy. These included initial fever, myalgias, and hair loss as well as suppression of granulocytes, platelets, and lymphocytes in the blood.

The modification of melphalan toxicity in tumor bearing mice by s-2-(3-aminopropylamino)- ethylphosphorothioic acid (WR 2721)

Abstract: The toxicity of melphalan in mice was reduced by the injection of S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR2721). This was seen in terms of reduced toxicity to the stem cells of the bone marrow and intestinal epithelium as well as improved animal survival. Using human melanoma xenografts and growth delay as an end-point, it was demonstrated that WR2721 did not protect this tumor from melphalan. With radio-labelled WR2721, it was shown that WR2721 was rapidly cleared from the blood and actively accumulated by all normal tissues except the CNS. Intact human tumor xenografts and Lewis lung tumors were less able to accumulate WR2721 than normal tissues, but in vitro studies showed that tissue fragments or single cell suspensions of tumors were as efficient as liver fragments or bone marrow cells in accumulating the drug. The rapid clearance of WR2721 and poor vascularity of the intact tumors were thought to be responsible for the differential uptake and protection of normal tissues by WR2721.

Effect of oral 13-cis-retinoic acid on serum lipids

Abstract: SUMMARY Serum lipid concentrations were measured in eighteen patients with severe acne before, during and after treatment with 0.8 mg/kg 13-cis-retinoic acid for 3 months. Cholesterol and trigtyceride concentrations increased and HDL-cholesterol concentrations fell significantly during therapy. There were significant abnormalities of liver function and small decreases in indices of thyroid function. These changes had reverted to normal by 1 month after treatment. The data suggest that use of the drug in acne is likely to be limited by its toxicity.

Evaluation of a Bacterial Bioluminescence Bioassay as a Method for Predicting Acute Toxicity of Organic Chemicals to Fish

Abstract: The relationship between the toxicity of 68 organic chemicals to fish and luminescent bacteria was evaluated. Chemicals for which 96-h median lethal concentration (LC 5 0 ) values had been measured for fathead minnows (Pimephales promelas) in flow-through tests at the U.S. Environmental Protection Agency (EPA) Environmental Research Laboratory-Duluth, Minn., were tested using the Microtox toxicity analyzer (Beckman Instruments, Inc.). The Microtox system measures the decrease in luminescence of the bacterium Photobacterium phosphoreum in response to a toxicant. The toxicity end point is the 5-min median effective concentration (EC 5 0 ), which is the concentration that causes a 50 percent reduction in light output. The correlation between fish and bacteria toxicity for a composite of industrial chemicals and pesticides had an R 2 value of 0.65. However, the relationship of these two end points for a semihomologous series of industrial chemicals appeared to be firm, with R 2 being 0.96 for common alcohols. The feasibility of using the bacterial bioassay as a screening test in a cost-effective testing scheme is discussed.

Optimal Scheduling of Methotrexate and 5-Fluorouracil in Human Breast Cancer

Abstract: We have shown previously that methotrexate pretreatment of murine leukemia and human colon carcinoma cell cultures results in augmented intracellular accumulation of 5-fluorouracil metabolites. Both of these drugs are commonly used for the treatment of women with breast cancer; thus, sequencing of methotrexate before 5-fluorouracil was evaluated in vitro using a human mammary carcinoma cell line, 47-DN. Intracellular 5-fluorouracil accumulation was maximally increased 4-fold in cultures pretreated with 10 µm methotrexate for 24 hr. This enhancement of 5-fluorouracil metabolism was associated with increased intracellular levels of 5-phosphoribosyl 1-pyrophosphate, resulting from the antipurine effect of methotrexate. Brief exposure to exogenous hypoxanthine at physiological concentrations reversed the biochemical synergism between methotrexate and 5-fluorouracil. Other antimetabolites associated with elevations of 5-phosphoribosyl 1-pyrophosphate enhanced intracellular accumulation of 5-fluorouracil up to 2.5-fold. In cloning assays, 18 hr of methotrexate pretreatment followed by 5-fluorouracil resulted in optimal synergistic cytotoxicity, which could be prevented if high concentrations of leucovorin were given between methotrexate and 5-fluorouracil administration. Since these results indicated that optimal breast tumor toxicity in vitro was achieved by 18- to 24-hr sequencing of methotrexate and 5-fluorouracil, a clinical toxicity study was carried out to assess whether this drug schedule could be tolerated. Seven patients with advanced cancer were treated with 21 courses of sequential therapy. No toxicity occurred with 38% of treatment courses; mild to moderate leukopenia and mucositis occurred with 29 and 38% of courses, respectively. Toxicity was related to retreatment interval and not cumulative drug dose or elevated serum methotrexate levels. These clinical results suggest that Phase II studies evaluating 24-hr-sequenced methotrexate and 5-fluorouracil in breast cancer are warranted.

Usefulness and rapidity of screening for the toxicity and carcinogenicity of chemicals in medaka, Oryzias latipes.

Abstract: The toxicity and carcinogenicity of number of chemicals, for which there are toxicity and/or carcinogenicity data in mouse and rat, were tested in medaka, a small aquarium fish (Oryzias latipes). The water-soluble chemicals were dissolved in the water and the water-insoluble chemicals were incorporated into the diet. Observation for 24 wk revealed induction of liver cell carcinoma by 6 chemicals; aflatoxins B1 and G1, sterigmatocystin, ortho-aminoazotoluene, methylazoxymethanol acetate and N-nitrosodiethylamine. In medaka fed PCB or DDT only preneoplastic liver cell nodules were observed. No evident carcinogenicity was found in medaka treated with 2-fluorenylamine, 2-fluorenylacetamide, DL-ethionine, luteoskyrin, ochratoxin A, phenobarbital, 1-(2-tetrahydrofuryl)-5-fluorouracil, sodium benzoate, 2,3,4,5,6-penta-O-acetyl-D-gluconyl isothiocyanate, citrinin and fusarenon X, respectively, although toxic lesions or hyperplastic changes were demonstrated histologically. These results confirm the practical utility and rapidity of the use of medaka for screening carcinogenicity and toxicity of chemicals, since neoplastic or toxic morphological changes develop rapidly following administration of relatively small quantities of test materials.

Hepatic centrilobular necrosis in rats after exposure to halothane, enflurane, or isoflurane.

Abstract: Exposure of phenobarbital-pretreated rats to low concentrations of halothane (0.5%) and reduced oxygen tension (FIO2 0.08) resulted in the development of liver necrosis in 51% of the animals. Fasting of rats for 24 hours before the same type of exposure increased the incidence of liver necrosis to 80%. Exposure of fed rats to enflurane (1.5%) and isoflurane (1.4%) in conjunction with low oxygen tensions resulted in no liver necrosis; however, in fasting animals, these same concentrations, when accompanied by low oxygen concentrations, produced an incidence of liver necrosis of 35% and 80%, respectively. Lower concentrations of enflurane or isoflurane failed to produce hepatotoxicity. In this study, in addition to increasing the incidence of toxicity, fasting reduced the glutathione levels and also increased cytochrome P-450 concentrations. Exposure to halothane and to isoflurane, but not to enflurane, further decreased the glutathione level. Perhaps the mechanism of liver toxicity associated with anesthesia, at least in this animal model, is related more directly to severe hypoxia than to a direct toxic intermediate produced as a result of metabolism.