Showing papers on "Toxicity published in 1990"

Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations.

Abstract: There is now convincing evidence that excessive accumulation of the excitatory amino acid glutamate (GLU) in the extracellular space is toxic to central mammalian neurons. However, the role of different GLU receptors in producing this toxicity has not been adequately ascertained. There is also no adequate information about the correlation of free intracellular calcium concentration with eventual excitotoxic death. We have used cultured rat hippocampal neurons to address these issues. Approximately 75% of our neurons died after a 20- min GLU exposure. The potent kainate/quisqualate receptor antagonist 6- cyano-7-nitroquinoxaline-2,3-dione did not significantly ameliorate the GLU toxicity, while the selective noncompetitive N-methyl-D-aspartate (NMDA) antagonist methyl-10,11-dihydro-5-H-dibenzocyclohepten-5,10- imine (MK-801) blocked the GLU toxicity for periods of at least 2 hr. Interestingly, kainate was very toxic to the hippocampal neurons, but this toxicity was markedly attenuated by MK-801. These results suggest that the major toxicity of GLU is mediated by NMDA receptors and that under some conditions kainate toxicity reflects nonspecific opening of NMDA channels. The intracellular calcium concentrations in these neurons at the end of exposure to GLU and kainate (in the presence and absence of different antagonists) correlated poorly with eventual survival. Antagonists that limited the rise in calcium were still ineffective in preventing death. These results confirm earlier observations that stressed the importance of NMDA receptors in mediating GLU toxicity. However, they indicate that the relationship between toxicity and neuronal calcium concentration may be very complicated. An unexpected finding of these experiments was that MK- 801, unlike competitive antagonists of GLU, elevated intracellular calcium.

Chemoprevention of 1,2-dimethylhydrazine-induced colon cancer in mice by naturally occurring organosulfur compounds.

Abstract: Organosulfur compounds (OSCs) present in garlic and onion oil have been shown to inhibit chemical carcinogenesis. In this study, we compared the chemopreventive efficacy of five lipid- and four water-soluble OSCs using the murine nuclear aberration assay. Administration of diallyl sulfide and S-allyl cysteine p.o. at a dose of 200 mg/kg 3 h prior to i.p. 1,2-dimethylhydrazine (DMH) injection (20 mg/kg) significantly inhibited colonic nuclear damage in female C57Bl/6J mice by 47% and 36%, respectively. The inhibitory effect of S-allyl cysteine was found to be dose dependent. The other OSCs did not affect the level of DMH-induced nuclear toxicity. Furthermore, the incidence and frequency of colonic tumors induced by DMH (20 mg/kg, 10 weekly i.p. injections) in female CF-1 mice were significantly inhibited by S-allyl cysteine pretreatment, given 3 h prior to each carcinogen injection. These data indicate that the allyl group coupled to a single sulfur atom might play an important structural role in inhibition of DMH-induced colonic nuclear toxicity and carcinogenesis. OSCs containing allyl groups stimulated glutathione S-transferase activity in both the liver and colon. However, their saturated analogues stimulated little or no hepatic and colonic glutathione S-transferase activity. Induction of hepatic and colonic glutathione S-transferase might assist in detoxification of carcinogens and could be necessary for some aspects of chemoprevention.

The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis.

Abstract: Thirty-two patients with rheumatoid arthritis completed a 24-week, placebo-controlled, double-blind trial of folic acid (FA) supplementation during low-dose methotrexate (MTX) therapy. Administration of the daily FA supplement significantly lowered toxicity scores without affecting efficacy, as measured by joint counts, joint indices, and patient and physician evaluation of disease activity. Fifteen patients experienced some sort of toxicity; 67% were in the placebo group, and 33% were in the FA supplement group. Four patients in the placebo group had toxicity levels serious enough to require discontinuation of the MTX, while no patients in the FA supplement group discontinued MTX because of toxicity. Low-normal initial plasma and red blood cell folate levels were predictive of future toxicity with MTX therapy. We conclude that a daily supplement of 1 mg of FA during low-dose MTX therapy (median dose 7.5 mg/week [16.4 mumoles]) is usefull in lessening toxicity without altering efficacy during the first 6 months of treatment.

Methods for the evaluation of biocompatibility of soluble synthetic polymers which have potential for biomedical use: 1 - Use of the tetrazolium-based colorimetric assay (MTT) as a preliminary screen for evaluation of in vitro cytotoxicity

Abstract: A tetrazolium-based colorimetric assay (MTT) was first introduced by Mossman in 1983 to assess the potential of novel antitumour agents, and it has been used here to evaluate the cytotoxicity of several soluble synthetic polymers proposed as drug carriers Polymers including poly-l-lysine (molecular weight 57 000) were incubated (up to 1 mg ml−1) with two human cell lines, hepatocellular carcinoma (HepG2) and lymphoblastoid leukaemia (CCRF), adherent and suspension cells, respectively Tests were carried out in the presence and absence of serum proteins The assay was first modified to optimize the colorimetric profiles produced by the cell lines following incubation with MTT, to increase both the test sensitivity and the reproducibility of the method Polymer toxicity observed using the MTT test was compared with data obtained using other methods; [3H]thymidine or [3H]leucine incorporation and counting cell numbers Poly-l-lysine was very toxic to both cell lines with approximate IC50-values of 60 and 30 µg ml−1 for HepG2 and CCRF, respectively, the values obtained being similar for each of the three different viability methods used In the absence of serum proteins the toxicity of poly-l-lysine increased, the IC50-values falling to 255 µg ml−1 for the adherent and 08 µg ml−1 for the suspension cell line Other polymers such as poly-l-proline, polyethylene glycol, dextran, polyvinylpyrrolidone and poly-l-glutamic acid were not cytotoxic (MTT assay), either in the presence or in the absence of serum proteins The MTT assay is a useful technique for the primary and rapid evaluation of the cytotoxicity of soluble polymers

Clinical features of amiodarone-induced pulmonary toxicity.

Abstract: The incidence and clinical predictors of amiodarone pulmonary toxicity were examined in 573 patients treated with amiodarone for recurrent ventricular (456 patients) or supraventricular (117 patients) tachyarrhythmias. Amiodarone pulmonary toxicity was diagnosed in 33 of the 573 patients (5.8%), based on symptoms and new chest radiographic abnormalities (32 of 33 patients) and supported by abnormal pulmonary biopsy (13 of 14 patients), low pulmonary diffusion capacity (DLCO) (nine of 13 patients), and/or abnormal gallium lung scan (11 of 16 patients). Toxicity occurred between 6 days and 60 months of treatment for a cumulative risk of 9.1%, with the highest incidence occurring during the first 12 months (18 of 33 patients). Older patients developed it more frequently (62.7 +/- 1.7 versus 57.4 +/- 0.5 years, p = 0.018), with no cases diagnosed in patients who started therapy at less than 40 years of age. Gender, underlying heart disease, arrhythmia, and pretreatment chest radiographic, spirometric, or lung volume abnormalities did not predict development of amiodarone pulmonary toxicity, whereas pretreatment DLCO was lower in the group developing it (76.0 +/- 5.5% versus 90.4 +/- 1.4%, p = 0.01). There was a higher mean daily amiodarone maintenance dose in the pulmonary toxicity group (517 +/- 25 versus 409 +/- 6 mg, p less than 0.001) but no difference in loading dose. No patient receiving a mean daily maintenance dose less than 305 mg developed pulmonary toxicity. Patients who developed toxicity had higher plasma desethylamiodarone (2.34 +/- 0.18 versus 1.92 +/- 0.04 micrograms/ml, p = 0.009) but not amiodarone concentrations during maintenance therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

A critical review of the developmental toxicity and teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: recent advances toward understanding the mechanism.

Abstract: A specific teratogenic response is elicited in the mouse as a result of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). The characteristic spectrum of structural malformations induced in mice following exposure to TCDD and structurally related congeners is highly reproducible and includes both hydronephrosis and cleft palate. In addition, prenatal exposure to TCDD has been shown to induce thymic hypoplasia. These three abnormalities occur at doses well below those producing maternal or embryo/fetal toxicity and are thus among the most sensitive indicators of dioxin toxicity. In all other laboratory species tested, TCDD causes maternal and embryo/fetal toxicity but does not induce a significant increase in the incidence of structural abnormalities even at toxic dose levels. Developmental toxicity occurs in a similar dose range across species; however, mice are particularly susceptible to development of TCDD-induced terata. Recent experiments using an organ culture were an attempt to address the issue of species and organ differences in sensitivity to TCDD. Human palatal shelves examined in this in vitro system were found to approximate the rat in terms of sensitivity for induction of cleft palate. Investigators have suggested that altered regulation of growth factors and their receptors may involve inappropriate proliferation and differentiation of target cells, ultimately producing TCDD-induced terata. Why the teratogenic effects of TCDD are so highly species and tissue specific, and which animal species most accurately predicts the response of the human embryo/fetus, at the levels of exposure experienced by humans, still remains to be clarified.

Analgesic and behavioural effects of Morinda citrifolia.

Abstract: The traditional therapeutic indications for the use of Morinda citrifolia L. (Rubiaceae) have been investigated. The lyophilised aqueous extract of roots of M. citrifolia was evaluated for analgesic and behavioural effects in mice. The extract did not exhibit any toxic effects but did show a significant, dose-related, central analgesic activity in the writhing and hotplate tests; this effect was confirmed by the antagonistic action of naloxone. Furthermore, administration of M. citrifolia extract at high dosages decreased all behavioural parameters in the two compartment test, the light/dark choice situation test, and the staircase test; together with the induced sleeping time, these results are suggestive of sedative properties.

Effects of bioremediation on residues, activity and toxicity in soil contaminated by fuel spills

Abstract: Triplicate outdoor lysimeters were contaminated by 2.3 ml cm−2 spills of jet fuel, heating oil and diesel oil, respectively. One of each set of triplicates was left untreated, one was tilled only, and one received complete bioremediation treatment consisting of liming, fertilization and weekly tilling. For 20 weeks during summer, hydrocarbon residues were monitored by quantitative gas chromatography. Microbial activity was measured by fluorescein diacetate hydrolysis. Toxicity was assessed by Microtox measurements, seed germination and plant growth bioassays. Persistence and toxicity of the fuels increased in the order of jet fuel < heating oil < diesel oil. In each case, bioremediation treatment strongly decreased fuel persistence and toxicity and increased microbial activity as compared to contaminated but untreated soil. Tilling alone had a favorable but more limited effect. Good correlations were found between residue decline, microbial activity and toxicity reduction. Persistence and toxicity also correlated with the hydrocarbon composition of these three fuels. Our findings indicate that bioremediation treatment can restore fuel spill contaminated soils in 4–6 weeks to a degree that they can support plant cover. Recovery of the soil is complete in 20 weeks.

Protection against cisplatin toxicity by administration of glutathione ester

Abstract: The role of cellular glutathione in the prevention of toxicity due to the anti-cancer drug cisplatin (cis-diamminedichloroplatinum) was explored in mice treated with buthionine sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase (and therefore of glutathione synthesis), and with glutathione and glutathione monoisopropyl ester. Pretreatment of mice with BSO enhanced the lethal toxicity of cisplatin by about twofold. Administration of glutathione ester (dose, 2.5-7.5 mmol/kg) protected against lethal cisplatin toxicity; glutathione was also effective, but much less so. Glutathione ester, in contrast to glutathione, is effectively transported into cells and split to glutathione intracellularly. The previous findings that administered glutathione does not protect against lethal toxicity due to cadmium ions and mercuric ions, whereas glutathione ester does, suggest that intracellular glutathione is required for protection against these heavy metal ions. That administration of glutathione has a protective effect on cisplatin toxicity suggests that the toxic effects of cisplatin may be exerted both intracellularly and extracellularly, and that extracellular glutathione (or its degradation products) may form a complex with cisplatin extracellularly. The finding that glutathione ester is more effective than glutathione in protecting against the toxicity of cisplatin suggests that use of glutathione ester may be therapeutically advantageous.

Intralesional interferon gamma treatment for keloids and hypertrophic scars

Abstract: • Keloids and hypertrophic scars are characterized by excessive collagen formation. Interferon gamma is a lymphokine that can down-regulate collagen synthesis in vitro and in vivo and, therefore, has potential therapeutic benefit in the management of abnormal scars. Intralesional scar injections of interferon gamma were performed to determine the tolerance toxicity and to obtain preliminary evidence for the efficacy of this treatment in the management of hypertropic and keloid lesions. All scars decreased in linear dimensions and flattened out. Five of 10 scars studied decreased at least 50% in linear dimensions. Interferon gamma can safely be administered intralesionally once per week up to a dosage of 0.05 mg for 10 weeks with no serious toxic effects. The commonest reported side effect was a mild headache. ( Arch Otolaryngol Head Neck Surg . 1990;116:1159-1162)

Chronic toxicity studies with vigabatrin, a GABA-transaminase inhibitor.

Abstract: The GABA-transaminase inhibitor, vigabatrin, has been shown to have a rather low degree of acute toxicity in several animal species. Oral administration of the drug at 1,000 mg/kg/day for 2-4 weeks caused decreased food consumption and weight loss with resultant prostration and death in both rats and dogs. Dosages of 200 mg/kg/day were tolerated for a year without clinical signs in dogs, although rats suffered reduced weight gains and convulsions after 3-4 months when given the drug in the diet. The convulsions continued to occur frequently throughout the one-yr study, but abated 3-4 months after cessation of treatment. The only consistent histopathologic evidence of toxicity in rats and dogs has been the finding of intramyelinic edema (microvacuolation) in the brain, most notably in certain areas of white matter (cerebellum, reticular formation and optic tract in rats and columns of fornix and optic tract in dogs). No lesions were found in the spinal cord or peripheral nervous system. It took several weeks for the microvacuolation to develop, even at high dosages, but it did not continue to progress thereafter, even though a slight effect was noted at dosages as low as 30-50 mg/kg/day after one yr of treatment. The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn. No residual effects were observed in dogs, whereas rats exhibited swollen axons and microscopic mineralized bodies in the cerebellum. Monkeys exhibited no adverse clinical effects except for occasional loose stools at 300 mg/kg/day. After 16 months of oral treatment at 300 mg/kg/day any suggestion of intramyelinic edema was considered to be equivocal, and there was no evidence of any effect in the 50 or 100 mg/kg/day monkeys after 6 yr of treatment. Higher doses caused chronic diarrhea, thus limiting the dosage in this species. Vigabatrin was shown to be well absorbed in rat, dog and man, whereas dose-limited absorption occurred in the monkey. Metabolism is practically nil in all 4 species and the primary elimination pathway is by glomerular filtration. Because vigabatrin is an irreversible inhibitor of GABA-transaminase and the enzyme has a slow turnover rate, plasma levels of the drug are not indicative of its pharmacologic activity. For this reason cerebrospinal fluid levels of GABA and vigabatrin were evaluated, with considerable species differences being noted. The significance of these differences in relation to the differences in toxic response is discussed.

Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group Study.

Abstract: Objective To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease. Design Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history. Setting Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). Patients Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed. Interventions Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity. Measurements and main results Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy. Conclusion The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious-CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion.

The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine.

Abstract: Previous studies have indicated that the generation of H2O2 may be a key step in the mechanism mediating the in vitro cytotoxicity of 3-hydroxykynurenine (3HK). An exposure protocol resulting in a delayed toxicity was utilized in order to further examine the role of H2O2 in the in vitro toxicity of 3HK in a neural hybrid cell line. 3HK-induced cell lysis was significantly attenuated by administration of catalase after termination of 3HK exposure and was abolished when intracellular peroxidase activity was elevated by pretreatment of cultures with horseradish peroxidase. In addition, a dose-dependent attenuation of 3HK toxicity was observed when cultures were exposed to 3HK in the presence of the iron chelator, desferrioxamine (DFO). Pretreatment with DFO also resulted in a significant attenuation of 3HK toxicity. These data suggest a direct role for H2O2 and metal ions in the cytotoxic action of 3HK and indicate that cell lysis results from the intracellular accumulation of toxic levels of H2O2.

A new local anesthetic, ropivacaine. Its epidural effects in humans.

Abstract: The current study was initiated to evaluate the epidural anesthetic properties of 0.5%, 0.75%, and 1.0% ropivacaine, a new local anesthetic agent structurally similar to bupivacaine. Fifteen patients scheduled for lower limb orthopedic surgery were enrolled in the study. As the concentration of ropivacaine increased from 0.5% to 1.0%, the time to onset of sensory anesthesia decreased from 6.4 +/- 1.7 (SD) min to 2.4 +/- 0.6 min and the maximum level of sensory anesthesia increased from T6 to T1. These changes were not statistically significant. Time to regression of anesthesia to T12 increased from 255 +/- 73 min with the 0.5% solution to 356 +/- 75 min with 1.0% ropivacaine (P less than 0.05). The degree of motor blockade using the Bromage scale varied with the concentration. When the 0.5% concentration was used, only one patient (20%) had greater than 1+ motor blockade. However, all of the patients receiving the 0.75% or 1.0% solution had at least 2+ motor blockade. Sensory anesthesia was adequate for surgery in 14 of the 15 patients. The mean peak plasma concentration of ropivacaine (Cmax) increased from 0.65 +/- 0.15 micrograms/mL with the 100-mg dose to 1.30 +/- 0.43 microgram/mL with the 200-mg dose. No adverse effects were noted in any patient in the study. These initial studies in humans suggest that ropivacaine provides satisfactory sensory anesthesia with minimal motor blockade at a concentration of 0.5%. An increase in concentration resulted in a more profound motor blockade. The Cmax of ropivacaine in this study was below levels associated with toxicity in animal studies.

Central nervous system toxicity of tricyclic antidepressants: phenomenology, course, risk factors, and role of therapeutic drug monitoring

Abstract: Central nervous system (CNS) toxicity of tricyclic antidepressants (TCAs) is serious, costly, frequent, and difficult to diagnose early in its course. We first reviewed all published, systematic population studies of such CNS toxicity. Of 976 TCA-treated patients, 58 (6%) developed TCA-induced CNS toxicity. The risk of this toxicity was positively correlated with TCA plasma levels. For levels greater than 450 ng/ml, the risk increased more than 10-fold (to 67%). We further analyzed 36 cases in terms of phenomenology, course, and potential risk factors of TCA-induced toxicity. A protean prodrome involving affective, psychotic, and cognitive symptoms preceded the delirium, which on average took 2 weeks to develop. The variability of this prodrome often leads to erroneous clinical decisions. Risk factors for delirium, in order of importance, included TCA concentration in plasma, age, and female gender.

Normobaric pulmonary oxygen toxicity.

Abstract: At the time of the discovery of oxygen (O,), Joseph Priestley speculated that it might prove of benefit in the treatment of some disease. At the same time he warned that the effects of 0, might not be uniformly beneficial: \"From the greater strength and vivacity of the flame of a candle, in this pure air, it may be conjectured, that it might be peculiarly salutary to the lungs in certain morbid cases, when the common air would not be sufficient to carry off the phlogistic putrid effluvium fast enough. But, perhaps, we may also infer from these experiments, that though pure dephlogisted air might be very useful as a medicine, it might not be so proper for us in the usual healthy state of the body: for, as a candle bums out much faster in dephlogisticated than in common air, so we might, as may be said, live out too fast, and the animal powers be too soon exhausted in this pure kind of air. A moralist, at least, may say, that the air which nature has provided for us is as good as we deserve.\" (1) The classic nineteenthcentury experiments of Paul Bert and Lorraine Smith proved that 0, in high concentrations was indeed toxic to healthy mammalian lungs (2,3). Bert demonstrated that it was the increase in partial pressure rather than concentration of 0, in the inspired atmosphere that was responsible for these deleterious effects. In recent years, a biochemical mechanism involving cellular production of partially reduced metabolites of 0, has been proposed as a basis for 0, toxicity. The importance of