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Showing papers on "Toxicity published in 1992"


Journal ArticleDOI
TL;DR: Conditions have been established to optimize the production of DNA-liposome complexes that efficiently transfect cells that can be used for the delivery of recombinant genes in vivo with minimal toxicity.
Abstract: DNA can be introduced into a variety of cell types after formation of liposomal complexes with cationic lipids. In this report, conditions have been established to optimize the production of DNA-liposome complexes that efficiently transfect cells. The safety and toxicity of this method of gene delivery have been assessed after in vivo administration, either by intravenous or direct intratumor injection. Nine to eleven days after intravenous injection, DNA was found primarily in heart and lung tissue by PCR analysis. No abnormalities were evident from histologic examination of tissue, examination of tissue-specific serum enzymes, routine biochemical parameters, or electrocardiographic monitoring. DNA-liposome complexes can therefore be used for the delivery of recombinant genes in vivo with minimal toxicity.

304 citations


Journal ArticleDOI
TL;DR: Findings suggest a primary interference in Müller cell function, possibly through dexamethasone-induced alterations in retinal glutamate or glucose metabolism, and suggest the intravitreal injection of steroids may be potentially useful in the treatment of endophthalmitis and other ocular inflammatory diseases.
Abstract: • The intravitreal injection of steroids may be potentially useful in the treatment of endophthalmitis and other ocular inflammatory diseases. The retinal toxicity and intraocular turnover of aqueous solutions of dexamethasone sodium phosphate in doses ranging from 440 to 4000 μg were evaluated in the rabbit; evaluation was also performed for a 0.1-mL injection of a commercially available preparation (dexamethasone phosphate [Decadron] injection, 4 mg/mL). After the 440-μg dose, a transient increase in staining of the Muller cells was observed, which normalized after 2 days. Progressively higher doses resulted in an increasing spectrum of disorganization in Muller and other retinal cells. The half-life of the intravitreally injected drug was 3.48 hours. These findings suggest a primary interference in Muller cell function, possibly through dexamethasoneinduced alterations in retinal glutamate or glucose metabolism.

247 citations


Journal ArticleDOI
TL;DR: It is suggested that ECSOD increases CNS O2 toxicity by inhibiting O2(-)-mediated inactivation of NO, and the results implicate NO.
Abstract: Although reactive O2 species appear to participate in central nervous system (CNS) O2 toxicity, the exact roles of different reactive O2 species are undetermined To study the contribution of extracellular superoxide anion (O2-) to CNS O2 toxicity we constructed transgenic mice overexpressing human extracellular superoxide dismutase (ECSOD; superoxide:superoxide oxidoreductase, EC 11511) in the brain Remarkably, when exposed to 6 atm (1 atm = 1013 kPA) of hyperbaric oxygen for 25 min, transgenic mice demonstrated higher mortality (83%) than nontransgenic litter-mates (33%; P < 0017) Pretreatment with diethyldithiocarbamate, which inhibits both ECSOD and Cu/Zn superoxide dismutase (Cu/Zn SOD) activity, increased resistance to CNS O2 toxicity, in terms of both survival (100% in transgenics and 93% in nontransgenics) and resistance to seizures (4-fold increase in seizure latency in both transgenic and nontransgenic mice; P < 005) Thus, O2- apparently protects against CNS O2 toxicity We hypothesized that O2- decreased toxicity by inactivating nitric oxide (NO) To test this, we inhibited NO synthase (EC 11423) with N omega-nitro-L-arginine to determine whether NO contributes to enhanced CNS O2 toxicity in transgenic mice N omega-nitro-L-arginine protected both transgenic and nontransgenic mice against CNS O2 toxicity (100% survival and a 4-fold delay in time to first seizure; P < 005), as well as abolishing the difference in sensitivity to CNS O2 toxicity between transgenic and nontransgenic mice These results implicate NO as an important mediator in CNS O2 toxicity and suggest that ECSOD increases CNS O2 toxicity by inhibiting O2(-)-mediated inactivation of NO

242 citations


Journal ArticleDOI
TL;DR: The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice, and data indicate that GSH can be an endogenous modulator of TNF production in vivo.

234 citations


Journal ArticleDOI
TL;DR: Under the conditions of these 2-year studies quercetin showed carcinogenic activity in the kidney of the male rat, causing primarily benign tumors of the renal tubular epithelium, and did not cause tumors at other sites.

229 citations


Journal ArticleDOI
TL;DR: In the short-term context of clinical trials, antimalarial drugs and MTX have the best efficacy/toxicity tradeoffs and may, therefore, be the preferred drugs.
Abstract: Objective Preferred drugs for rheumatoid arthritis (RA) should be those that have maximal efficacy with the least toxicity. We evaluated the efficacy and toxicity tradeoffs for drugs frequently used in the treatment of RA. Methods We updated 2 metaanalyses of published clinical trials, by adding trials published through 1990 and trials of azathioprine (AZA). We tested 3 different definitions of efficacy, each plotted against 3 different toxicity measures, for antimalarial drugs, methotrexate (MTX), auranofin, injectable gold, D-penicillamine, sulfasalazine (SSZ), AZA, and placebo. Efficacy measures included composite efficacy (a combination of joint count, grip strength, and erythrocyte sedimentation rate), tender joint count alone, and a measure based on how many patients dropped out due to inefficacy. Toxicity measures were the proportion dropping out due to toxicity, the same dropouts with side effects weighted for severity using a modification of a published toxicity index, and the proportion with severe toxicities (defined as a score of at least 7 of 10 on the toxicity index). The latter were usually organ toxicities (e.g., cytopenias and renal involvement). Results All 9 efficacy/toxicity tradeoff plots suggested that MTX and antimalarial drugs had the highest efficacy relative to toxicity. MTX scored among the most efficacious of the drugs and, of these, had the least toxicity. Antimalarial drugs, though showing only moderate efficacy, had the lowest toxicity rate of all the drugs. SSZ scored close to MTX but was, in general, slightly more toxic. Conclusion In the short-term context of clinical trials, antimalarial drugs and MTX have the best efficacy/toxicity tradeoffs and may, therefore, be the preferred drugs.

227 citations


Journal Article
TL;DR: Analysis of morphologic and biochemical data support the hypothesis that VOD is caused by cytoreductive injury to hepatocytes and endothelium in zone three of the liver acinus, and in turn strongly influenced by factors which induce the release of tumor necrosis factor-alpha (TNF-alpha) leading to enhancement or activation of coagulation with obstruction of hepatic sinusoids and venules.
Abstract: Hepatic veno-occlusive disease (VOD) is the most common life threatening complication of preparative-regimen-related toxicity for bone marrow transplantation (BMT). The frequency of VOD varies greatly, from 1-2% in centers performing pediatric BMT for thalassemia to over 50% in some centers doing BMT for hematologic malignancy. The term liver toxicity syndrome is a clinicopathologic definition which encompasses the range of histopathology within the hepatic venules and surrounding sinusoids and hepatocytes. These histologic abnormalities are statistically associated with a clinical syndrome of jaundice, ascites, and painful hepatomegaly developing early post-transplant. Newer modalities which may aid accuracy are transvenous liver biopsy along with determination of the gradient between the wedged and free hepatic venous pressures, and measurement of blood coagulatory components, particularly protein C levels. Analyses of clinical risk factors for VOD are confounded by lack of a clear hierarchy of risk when comparing heterogeneous patient populations, the methods of patient selection and choice of controls, and whether analysis is univariate or multivariate. Prospective multivariate analyses indicate that the risk of developing liver toxicity is independently correlated with intensity of conditioning therapy, pre-transplant viral hepatitis, use of antimicrobial therapy with acyclovir, amphotericin, or vancomycin (reflecting fever), and mismatched or unrelated allogeneic marrow grafts. These analyses plus morphologic and biochemical data support the hypothesis that VOD is caused by cytoreductive injury to hepatocytes and endothelium in zone three of the liver acinus, and in turn strongly influenced by factors which induce the release of tumor necrosis factor-alpha (TNF-alpha) leading to enhancement or activation of coagulation with obstruction of hepatic sinusoids and venules. Pharmacokinetic measurements of busulfan as a conditioning agent demonstrate a correlation between high steady-state busulfan levels and liver toxicity and suggest that safer and/or more efficacious plasma busulfan concentrations can be obtained by making individual dose adjustments and by changing the schedule of administration. Conservative therapy of severe VOD, including the use of peritoneal-pleural shunts for relief of ascites, is unsatisfactory. Results from prophylactic studies aimed at preventing VOD by heparin or prostaglandin E1 indicate considerable differences with toxicity and efficacy. Use of the TNF-alpha blocker, pentoxifylline, has also shown promise in lessening VOD. A statistical model which predicts patients likely to have an unfavorable outcome from VOD has been used to select premorbid patients for promising new therapeutic modalities, such as recombinant tissue plasminogen activator.

227 citations


Journal ArticleDOI
TL;DR: The remarkable protection afforded by MK‐801 indicates that ammonia toxicity is mediated by the NMDA receptor.

186 citations


Journal ArticleDOI
TL;DR: The HSCAS reduced theoxicity of aflatoxin, but had little effect on either the toxicity of ochratoxin A alone or the toxicity resulting from the combination of a Flatoxin and ochRatoxin A.

176 citations


Journal Article
TL;DR: Although not as effective as Se, vitamin E significantly alters methylmercury toxicity and is more effective than Se against silver toxicity and vitamin E is very effective against lead toxicity but Se has little effect.
Abstract: Selenium (Se) has been shown to counteract the toxicity of heavy metals such as cadmium, inorganic mercury, methylmercury, thallium and to a limited extent silver. Although not as effective as Se, vitamin E significantly alters methylmercury toxicity and is more effective than Se against silver toxicity. Vitamin E is very effective against lead toxicity but Se has little effect. The presumed protective effect of Se against cadmium and mercury toxicity is through the diversion in their binding from low molecular weight proteins to higher molecular weight ones. Se appears effective in counteracting the chemical carcinogens (3-methyl-4-dimethyl-aminoazobenzene, 2-acetylaminofluorene, diethylnitrosamine, aflatoxin, 7,12-dimethylben (a) anthracene, benzopyrene and 3-methylcholanthrene) used to induce skin, liver and mammary tumors, but much less effective against those (dimethylhydrazine, azoxymethane, methylazoxymethanol, bis (2-oxopropyl) nitrosamine, benzopyrene, 1 methyl-1-nitrosourea and n-methyl-n-nitro-nitrosoguanidine) used to produce tumors in the colon, lungs, trachea and pancreas in laboratory animals. In contrast, Se many even increase pancreatic carcinomas in animals treated with bis (2-oxopropyl) nitrosamine. The health implications in humans of Se and heavy metal toxicities and in cancer are discussed.

173 citations


Book
11 Feb 1992
TL;DR: Introduction Preliminary Considerations Introduction The Agent Being Tested The Vehicle Routes of Administration Species Pharmacokinetics/Toxicokinetics Biotransformation Diet Endpoints of Toxicity Animal Numbers Acute Toxicity Studies Purpose and Objectives Study Design Interpretation of Data Utility of the LD50 Studies Dermal T toxicity Studies Ocular Toxicity studies Utility of Alternative Studies Conclusions Subchronic and Chronic Studies.
Abstract: Introduction Preliminary Considerations Introduction The Agent Being Tested The Vehicle Routes of Administration Species Pharmacokinetics/Toxicokinetics Biotransformation Diet Endpoints of Toxicity Animal Numbers Acute Toxicity Studies Purpose and Objectives Study Design Interpretation of Data Utility of the LD50 Studies Dermal Toxicity Studies Ocular Toxicity Studies Utility of Alternative Studies Conclusions Subchronic and Chronic Studies Introduction Experimental Design Evaluation of Results Carcinogenicity Studies Reproductive Toxicology Introduction Male Reproductive Toxicity Female Reproductive Toxicity Preimplantation Studies Teratogenicity Embryo Culture Harmonization Screening Tests Mutagenesis Carcinogenesis Introduction Mutagenesis Mutagenicity Testing with Prokaryotic Cell Systems Mutagenicity Testing with Eukaryotic Cell Systems In Vitro Mutagenicity Testing with Eukaryotic Cells In Vivo The Impossibility A Test for All Mutagens Carcinogenicity Testing Strategies for Limited Bioassays

Journal ArticleDOI
TL;DR: Observations show that synergistic interactions between growth factors and excitotoxic amino acids may play critical roles in the developing nervous system and that antioxidants attenuate this toxicity.
Abstract: The sympathetic nerve cell line PC-12 is killed by glutamate in a concentration-dependent manner. Although glycine and the deletion of magnesium weakly potentiate glutamate toxicity and PC-12 cells express N-methyl-D-aspartate-receptor mRNA, most toxicity is mediated by means of a mechanism independent of typical N-methyl-D-aspartate receptors. Glutamate toxicity is, however, greatly enhanced by prior exposure to nerve growth factor or basic fibroblast growth factor. Glutamate killing is blocked by epidermal growth factor and, to a lesser extent, by vitamin E. These observations show that synergistic interactions between growth factors and excitotoxic amino acids may play critical roles in the developing nervous system and that antioxidants attenuate this toxicity.

Journal ArticleDOI
TL;DR: A good correlation was found between the in vivo toxicity and the aggregation state of AmB in injected solutions, and two surfactants, lauryl sucrose and sodium deoxycholate and Tween 80, substantially decreased the acute toxicity of Amb to mice.
Abstract: Amphotericin B (AmB) is a very effective antifungal agent for most systemic fungal infections. However, the relatively high toxicity of this drug imposes limits on its clinical usefulness. Most of the current work in this field is devoted to the search for less-toxic formulations of the drug. Here we describe the effects of three surfactants, one anionic and the other two nonionic, on the aggregation state of AmB in solutions which were injected intravenously into mice. The degree of aggregation of AmB was monitored spectroscopically and by light scattering. The toxicity was expressed as percentage of survivors. These results were compared with those obtained with doses of AmB the same as those present in a commercial formulation of AmB, Fungizone. Two surfactants, lauryl sucrose and sodium deoxycholate, used at concentrations which induced monomerization of AmB, substantially decreased the acute toxicity of AmB to mice. Conversely, the third surfactant, Tween 80, showed a synergistic potentiation of the toxicity of the antibiotic. A good correlation was found between the in vivo toxicity and the aggregation state of AmB in injected solutions. Solutions in which AmB was almost entirely monomeric were half as toxic after 24 h and about six times less toxic after 1 week than the corresponding solutions of Fungizone.

Journal ArticleDOI
TL;DR: Predict the sex-related difference in drug toxicity on the basis of difference in the expression levels of sex-specific cytochrome P450s is predicted.

Journal ArticleDOI
TL;DR: A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities.
Abstract: PURPOSEThe purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC).PATIENTS AND METHODSTwenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed.RESULTSSignificant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major t...

Journal ArticleDOI
TL;DR: The results suggest that in vivo inhibitory potency of the three OPs towards either brain or plasma ChE activity is highly correlated with sensitivity to acute toxicity in both neonatal and adult rats.

Journal ArticleDOI
TL;DR: This drug provides the clinician with a rapidly acting, safe antidote for all commonly used digitalis preparations, and provides a needed safety net for the continuing use of cardiac glycosides as first-line inotropic agents in the modern therapy of chronic CHF.
Abstract: The most important step in the management of toxicity due to any of the cardiac glycosides is its recognition. Despite the development of an accurate clinical assay for serum levels of digoxin greater than 20 years ago, digitalis toxicity remains common and difficult to confirm, even if suspected, due primarily to 2 factors. First, the signs and symptoms of digitalis toxicity, most commonly an abnormal electrocardiogram showing ventricular or atrial arrhythmias, with or without some degree of concurrent atrioventricular block, often also occur in patients with congestive heart failure (CHF) and underlying coronary atherosclerosis who are not receiving a cardiac glycoside. Second, due to digoxin's narrow therapeutic ratio, the marked degree of variability in the sensitivity of individual patients to its toxic effects, and the common problem of obtaining blood samples inappropriately during the early distribution phase following dosing, a serum digoxin concentration often does not serve as a reliable indicator of toxicity. Despite these difficulties in diagnosis, the management of digoxin toxicity has been made much more effective with the widespread availability of F(ab) fragments of anti-digoxin antibodies. This drug provides the clinician with a rapidly acting, safe antidote for all commonly used digitalis preparations. Conventional therapy for digoxin toxicity remains the maintenance of serum potassium levels greater than or equal to 4 mEq/liter, reversal of decompensated CHF or overt myocardial ischemia, attention to serum magnesium levels and the patient's acid-base status, appropriate antiarrhythmics in the event of ventricular arrhythmias, and a temporary pacemaker for high-grade atrioventricular block. Nevertheless, the high specificity and documented safety of the antibody preparation provides a needed safety net for the continuing use of cardiac glycosides as first-line inotropic agents in the modern therapy of chronic CHF.

Journal ArticleDOI
TL;DR: In doses that achieve equivalent reductions in serum lipids, hepatic toxicity occurred more frequently with time-release preparations than with unmodified preparations.

Journal ArticleDOI
TL;DR: In vitro cytotoxicity assays using primary cultures of rabbit corneal epithelial cells may be used to rank the cytotoxic potential of surfactants, but only the lactate dehydrogenase leakage test was able to assess prolonged cell injury.

Journal ArticleDOI
TL;DR: The cases reported so far indicate that the incidence of flutamide-induced liver toxicity is very low, and serial blood aminotransferase measurements are recommended at 2 and 4 weeks of treatment in order to detect early signs of possible flutamia-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.

Journal ArticleDOI
TL;DR: Both intracellular GSH and MT levels may provide protection against cytotoxicity of Cd in liver and even at low GSH levels, MT could partially protect the hepatic cells from Cd cytot toxicity.

Journal ArticleDOI
TL;DR: Developmental toxicity occurred below maternally toxic levels in rats as well as in the presence of maternal toxicity in mice and rats, indicating steady-state exposure as early as possible during prenatal development.


Journal ArticleDOI
TL;DR: The hypothesis that simultaneous exposure to multiple environmental chemicals that utilize or deplete tissue GSH may predis pose fish to acute toxicity is supported.

Journal ArticleDOI
TL;DR: It is concluded that solvent effects play a major role in acute beta protein neurotoxicity and stereotaxically injected substance P failed to prevent toxicity.

Journal ArticleDOI
TL;DR: The results support the conclusion that in H2O2-resistant cells, catalase activity is a major determinant of cellular resistance to H 2O2 toxicity, whereas catal enzyme activity has a limited role in cellular Resistance to an acute exposure to 95% O2 and is unrelated to cellular resistanceto 4-hydroxy-2-nonenal.

Journal ArticleDOI
TL;DR: It is suggested that decreased plasma cholinesterase activity is associated with increased risk of life-threatening cocaine toxicity.

Journal ArticleDOI
TL;DR: These findings are consistent with the hypothesis that oxygen exposure induces TNF, which causes part of the toxicity of high-dose oxygen, and that pretreatment or early treatment with TNF induces the gene for an enzyme that recently has been shown to be very effective in protecting mice from the toxicity.
Abstract: mRNA from lungs of mice exposed to high-dose oxygen (greater than 95%) for 3 days demonstrated increased expression of the genes for tumor necrosis factor (TNF), interleukin-1, and interleukin-6 compared with mRNA from lungs of mice exposed to room air. Daily treatment of mice exposed to high-dose oxygen with an antibody to TNF improved survival compared with mice receiving a similar dose of control immunoglobulin G. Pretreatment of mice with repetitive sublethal intraperitoneal doses of recombinant human TNF for 3 days or a single intravenous dose followed by exposure to high-dose oxygen afforded a significant survival advantage compared with high-dose oxygen-exposed mice pretreated with vehicle or interleukin-1. The repetitive intraperitoneal TNF pretreatment reduced the development of interstitial pneumonitis, pulmonary edema, and lung weight gain associated with oxygen toxicity and enhanced expression of the gene for the free radical protective enzyme manganous superoxide dismutase in lung tissue, a gene that is augmented as mice are exposed to high-dose oxygen. Furthermore a single intravenous dose of TNF 24 h after oxygen exposure was still protective. The results suggest that the toxicity of oxygen therapy can be partially ameliorated by either treatment with anti-TNF antibody or pretreatment and early treatment with TNF. These findings are consistent with the hypothesis that oxygen exposure induces TNF, which causes part of the toxicity of high-dose oxygen, and that pretreatment or early treatment with TNF induces the gene for an enzyme that recently has been shown to be very effective in protecting mice from the toxicity of oxygen.

Journal ArticleDOI
TL;DR: It is concluded that with respect to the clinically used concentrations and methods of application of 5-FU and MMC in vivo endothelial toxicity is not to be expected, however, in cases of accidental access of MMC to the anterior eye chamber and following a reduction of aqueous turnover rate the safety of M MC is unwarranted.
Abstract: 5-Fluorouracil (5-FU) and Mitomycin C (MMC) are used as adjunct chemotherapy during glaucoma filtering surgery to suppress conjunctival fibroblast proliferation. Since part of these agents may gain access to the anterior chamber and cause cytotoxicity to the corneal endothelium we set up an in vitro system to establish a dose-response effect. Cytotoxicity of MMC and 5-FU was quantified using Mosmann's colorimetric assay in a bovine endothelial cell culture system. In this assay the respiratory activity of the cells is used as a marker for cell viability. After incubation for 5 minutes the 3.0 mg/ml concentration of MMC showed endothelial cytotoxicity, whereas no endothelial toxicity of 5-FU was noted in concentrations up to 50 mg/ml. After incubation for 30 minutes endothelial cytotoxicity was demonstrated for 50 mg/ml of 5-FU and 1 mg/ml of MMC. After an exposure-time of 60 minutes the toxicity level remained 50 mg/ml for 5-FU but decreased to 0.5 mg/ml for MMC. We conclude that with respect to the clinically used concentrations and methods of application of 5-FU and MMC in vivo endothelial toxicity is not to be expected. However, in cases of accidental access of MMC to the anterior eye chamber and following a reduction of aqueous turnover rate the safety of MMC is unwarranted.

Journal ArticleDOI
TL;DR: In this article, a theoretical model was proposed to predict that the diffusion of glutamate into brain tissue is countered by cellular uptake of the amino acid, and they argue against the idea that glutamate toxicity is inherently self-propagating.
Abstract: In slices of 8-day-old rat cerebellum, the lowest concentration of glutamate that induced toxicity (30 min exposure; 90 min recovery) was 100 microM, but the damage only occurred in the outermost regions. As the concentration was raised, the band of necrosis became progressively deeper until, at 3 mM, it was uniform across the slice thickness. At a test concentration of 300 microM, the width of the necrotic band did not change when either the exposure time or the recovery period was varied between 30 min and 3 h. These results are predicted by a theoretical model in which the diffusion of glutamate into brain tissue is countered by cellular uptake of the amino acid, and they argue against the idea that glutamate toxicity is inherently self-propagating. When slices were examined immediately after exposure (300 microM), a prominent swelling of glial cells was present at the slice surface. Swelling per se did not appear to compromise their uptake function, and the model predicts that cellular swelling, by reducing the rate of diffusion of glutamate, protects against glutamate toxicity. The damage produced by 3 mM glutamate, which was primarily exerted against granule cells, was prevented by N-methyl-d-aspartate (NMDA) receptor blockade, whereas antagonists acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors were ineffective. Under conditions of energy deprivation, the neurotoxic potency of glutamate was markedly enhanced and a normally non-toxic concentration (30 microM) became maximally toxic towards granule cells. Dark vacuolar degeneration of Purkinje cells was also present, and this could be inhibited by blocking AMPA receptors. The results and theoretical analysis suggest that intact brain tissue is remarkably resistant to glutamate toxicity, chiefly because of the formidable properties of the uptake system. However, under special circumstances, glutamate can become a potent neurotoxin and its toxicity can then involve both NMDA and AMPA receptors.