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At least 973 records · Page 54Linked to original sources
PubMed1986

Biological reactive intermediates of mycotoxins.

The various reactions involved in the formation and actions of biological reactive intermediates of AFB1 are undoubtedly common to the wide variety of mycotoxins. The structural diversity of mycotoxins and their widespread occurrence in nature has made them a significant class of model environmental toxicants for mode of action studies. Identification of the reactive intermediates of prototype mycotoxins and elucidation of their reactions with molecular receptors will provide information useful for the design of antidotes of other remedial measures and for a better understanding of the mechanisms of action of comparable environmental toxicants. This type of studies will also permit the more precise biochemical analyses to be applied to the assessment of health risk due to exposure to mycotoxins.

Aflatoxin B1↗
PubMed1988

Correlations between cis-platinum dosage and toxicity in a guinea pig model.

A guinea pig model was used to study correlations between cis-platinum dosage and level of hearing loss, hair cell loss in the cochlea. Other parameters measured included weight loss and serum urea, creatinine, and cis-platinum levels. The damage to the inner ear expressed as hearing loss and hair cell loss demonstrated a highly positive correlation with the dosage of cis-platinum, and only a moderately positive correlation with the cis-platinum serum levels. Weight loss correlated well with hearing loss.

Animals↗
PubMed1993

Phase II trial and pharmacokinetic assessment of intravenous melphalan in patients with advanced prostate cancer.

Alkylating agents have been reported to yield response rates of up to 20% in hormone-refractory prostate cancer. Melphalan was studied in four small trials in which the drug was given orally. In this phase II trial, melphalan (30 mg/m2) was given intravenously every 28 days to 27 patients with hormone-refractory prostate cancer. Pharmacokinetic sampling was performed so as to describe the clearance of melphalan in this population and in an attempt to carry out pharmacodynamic modeling for toxicity and response. Prostate-specific antigen (PSA) was also assessed prospectively. No objective responses to this regimen were documented. The median survival for patients on this trial was 11.5 months. There was no correlation between drug clearance and measured creatinine clearance and no relationship between systemic exposure and toxicity. A decrease of > 50% in serum PSA that was sustained for > 6 weeks was documented in two patients, most notably in one patient who has survived for more than 29 months. Intravenous melphalan is not an active agent in hormone-refractory prostate cancer.

Aged↗
PubMed1993

Effects of pentachlorophenol-contaminated food organisms on toxicity and bioaccumulation in the frog Xenopus laevis.

Sub-adult African clawed frogs (Xenopus laevis) were fed pentachlorophenol (PCP)-injected mealworms containing 64.8 to 2604 ug of PCP per gram of worm for 27 days. There was no mortality and no significant bioaccumulation of PCP in the frogs. After three weeks, frogs fed 2,604 micrograms/g of PCP ceased eating. The no observed adverse effects level (NOAEL) based on significantly reduced food consumption (PCP-injected mealworms) was 638 micrograms/g. This corresponded to a NOAEL based on PCP intake of about 8 micrograms PCP/g frog/day. A toxicity threshold model estimated that about 800 micrograms/L of waterborne PCP may be a threshold for adverse effects in Xenopus or similar amphibians. Further study is needed to verify threshold estimates.

Animals↗
PubMed1993

Platinum complex-induced dysfunction of cultured renal proximal tubule cells. A comparative study of carboplatin and transplatin with cisplatin.

Platinum coordination complexes (PtCx) are potent against several types of cancer but are often nephrotoxic. With a view to developing a PtCx nephrotoxicity model, the toxicity of cisplatin (cDDP), transplatin (tDDP) and carboplatin (CBDCA) was studied in primary cultures of rabbit proximal tubule (RPT) cells and in the renal epithelial OK cell line. The cytotoxicity of these PtCx (10-3000 microM) was assessed after 24 h exposure of confluent monolayers in terms of LDH release; their effects at non-cytotoxic concentrations (1-1000 microM) on DNA and protein synthesis, glucose transport, marker enzymes and the total glutathione concentration were also determined, together with cellular platinum uptakes. The cytotoxicity ranking of the studied compounds differed for OK and RPT cells (cDDP > tDDP; cDDP > CBDCA and tDDP > cDDP; cDDP > CBDCA, respectively). Only results which were obtained in RPT cells corresponded to reported nephrotoxicity in vivo, making OK cells inappropriate for the study of PtCx nephrotoxicity in vitro. cDDP was about 10 times less cytotoxic for OK cells than for RPT cells because of lower cellular uptake. tDDP was unable markedly to inhibit biochemical and functional parameters in RPT cells below cytotoxic concentrations. At non-cytotoxic concentrations, cDDP and CBDCA depressed synthetic activity (mainly DNA) and, to a lesser extent, Na(+)-K(+)-ATPase activity and glucose transport in RPT cells. Total glutathione levels in RPT cells steadily increased during exposure to cDDP, tDDP and CBDCA, before the onset of cell death, arguing against an early role of glutathione depletion in PtCx toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Species specificity and involvement of other cytokines in endotoxic shock action of recombinant tumour necrosis factor in mice.

We compared the effects of human rTNF and murine rTNF in murine models of toxicity, esp. the induction of endotoxic shock. As was the case for the antitumour activity, we found a marked difference in activity between these two TNFs. Only murine rTNF was able to cause lethality, while human rTNF needed the synergistic action of sensitizing agents to become lethal. Further experiments, such as the study of IL-6 induction by TNF in mice, allowed us to distinguish two types of TNF effects: those that can equally well be exerted by human rTNF and by murine rTNF (type I effects) and those that can only be exerted by murine rTNF (type II effects). Both types of effects, the "toxic" (a type I effect) and the sensitizing (a type II effect) are needed to produce a lethal outcome. Other cytokines such as IL-1 and IFN-gamma, however, can also exert such a sensitizing effect and consequently lead to a fatal outcome when co-administered with human rTNF.

Animals↗
PubMedDate not supplied

Does lead provoke the peroxidation process in rat brain synaptosomes?

Up to now there has been no information concerning the effect of lead on the peroxidation process in brain nerve endings. We have examined whether lead acetate (in chronic and acute models of toxicity in vivo and in vitro) affected the level of free radicals in synaptosomes obtained from rat brain. Simultaneously, we have checked the effect of peroxidation of Pb2+ on brain homogenates and microsomal fraction. Our results indicated that the lead level in synaptosomal fraction obtained from lead-treated rats was much higher than in controls. We did not observe induction of spontaneous and Fe(3+)-dependent peroxidation either in synaptosomes or in homogenates and brain microsomes after chronic and acute lead administration to the rats. Lead itself also did not enhance both processes when added in vitro to the control brain synaptosomes in micromolar concentrations. The lack of the lead effect on the peroxidation process in subcellular fractions of brain was rather surprising, because lead is known to be the accelerator of Fe(3+)-dependent peroxidation processes in liver. Additionally, livers from rats under the same toxicity conditions were examined. We have found that lead did not provoke spontaneous peroxidation in liver, but contrary to brain fractions, it drastically increased iron-dependent peroxidation in liver homogenates and microsomes. The lack of the effect of lead on inducing peroxidation processes in brain is probably the consequence of the brain having stronger protective mechanisms against its toxicity than the liver.

Acute Disease↗
PubMed2005

What is the dominant Abeta species in human brain tissue? A review.

Interest in the beta amyloid (Abeta) peptides continues to grow due to their known accumulation in the brains of patients with Alzheimer's disease and recent tantalising evidence that reducing such accumulations can reverse disease-associated functional deficits. Abeta peptides are naturally produced in every cell by proteolytic cleavage of the amyloid precursor protein with two main alloforms (40 or 42 amino acids) both of which are disease associated. The identification that genetic mutations causing Alzheimer's disease impact on Abeta production and clearance have allowed for the manipulation of these pathways in cellular and animal models. These studies show that the amount and type of Abeta in the brain has significant consequences on neural function. However, there have been significant difficulties in the conversion of these findings into successful treatments in humans. In this review we concentrate on data from human studies to determine any comparative differences in Abeta production and clearance that may assist with better treatment design and delivery. Abeta40 is the dominant peptide species in human cerebrospinal fluid accounting for approximately 90% of total Abeta under normal conditions. However, similar studies using disease free human brain tissue do not correlate with these findings. In these studies, concentrations of Abeta40 are low with Abeta42 often identified as the dominant species. The data suggest preferential brain tissue utilisation and/or clearance of Abeta40 compared with Abeta42, findings which may have been predicted by their physiochemical differences. In Alzheimer's disease this equilibrium is disrupted significantly increasing Abeta peptide levels in brain tissue. The disease-specific increase in Abeta40 brain tissue levels in Alzheimer's disease appears to be an important though overlooked pathological change compared with the well-documented Abeta42 change observed both in the aged and in Alzheimer's disease. These findings are discussed in association with Abeta peptide function and a model of toxicity developed.

Amyloid beta-Peptides↗
PubMed2005

Neuroprotective properties of afobazol in vitro.

The effects of a novel selective anxiolytic afobazol on survival of HT-22 neurons were studied in the model of oxidative stress and glutamate toxicity. In both models, the neuroprotective effect of afobazol was established.

Animals↗
PubMed1995

Effect of nerve growth factor on peptide neurons in dorsal root ganglia after taxol or cisplatin treatment and in diabetic (db/db) mice.

In our study we have used morphological and radio-immunological methods for the investigation of calcitonin gene-related peptide (CGRP) and substance P in cervical dorsal root ganglia (DRGs) in mice after administration of taxol or cisplatin and in spontaneously diabetic animals (db/db mice). The results were compared to findings in animals receiving recombinant human nerve growth factor (rhNGF). Morphometric analysis did not reveal any significant changes of cell size distribution in diabetic and taxol-treated mice, whereas cisplatin induced a significant decrease in the number of large- and medium-sized neurons, indicating neuronal atrophy. This finding correlated with a highly significant loss of neuropeptides after cisplatin-application. Measurement of peptide levels in the taxol-treated groups and in diabetic mice demonstrated a decrease predominantly for CGRP. Application of 10 mg/kg NGF caused a significant elevation in peptide-immunoreactivity in control animals and in taxol-treated mice, i.e., statistically significant increase in peptide concentrations and in the number of substance P- and CGRP-immunoreactive DRG-neurons, suggesting a recruitment of additional peptide cells. In diabetic animals a restoration in CGRP-content was observed under NGF-treatment; however, in this model the quantitative parameters did not demonstrate further elevation above control levels. Our data support the hypothesis that NGF exerts a major effect on the metabolism of transmitters associated with nociception and sensation in "healthy" controls and in various models of toxic and metabolic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Reduced tolerance to digitalis-induced arrhythmias caused by coronary-flow alterations in isolated perfused heart of guinea pigs.

The ligation of a main branch of coronary vein elevates the sensitivity of isolated, perfused (Langendorff) preparations of guinea-pig heart to arrhythmogenic actions of digoxin. Retrograde perfusion studies indicate that the presence of an area with a high extracellular K+ concentration, adjacent to an area with normal K+ concentration and exposed to the glycoside, predisposes the heart to digitalis-induced toxicity. This model may be useful in studying the mechanism by which acute myocardial infarction decreases the therapeutic index of cardiac glycosides.

Animals↗
PubMed1992

Effect of nifedipine and S-adenosylmethionine in the liver of rats treated with CCl4 and ethanol for one month.

An experimental model of toxic liver injury in rats was employed to assay the effect of Nifedipine (a calcium antagonist blocker) and S-Adenosylmethionine (a precursor of glutathione). An important decrease in both perivenular fibrosis and cirrhosis was found. Furthermore, a significant decrease in lactic acid levels was found in the group of animals treated with pharmacologic therapy, although no correlation was seen between lactic acid levels and the different degrees of perivenular fibrosis. No significant variations in ALT and AST enzymes were observed between both groups, as opposed to a significant decrease in LDH enzyme in the Nifedipine+S-Adenosylmethionine group. The results indicate an improvement in the histologic picture of the liver in rats treated by means of pharmacological association, without any change in inflammatory infiltrate and with a slight decrease in necrosis, indicating an action mechanism via creeping fibrosis (instead of a hepatitis pathway).

Animals↗
PubMed1991

The effects of fructose on adenosine triphosphate depletion following mitochondrial dysfunction and lethal cell injury in isolated rat hepatocytes.

Mitochondrial injury in aerobic mammalian cells is associated with a rapid depletion of adenosine triphosphate (ATP) which occurs prior to the onset of lethal cell injury. In this report, the relationships between ATP depletion and lethal cell injury were examined in rat hepatocytes using oligomycin as a model mitochondrial toxicant and fructose as an alternative carbohydrate source for glycolysis. Oligomycin was more potent in causing lethal cell injury in hepatocytes isolated from fasted animals than cells from fed animals. The onset of cell injury (leakage of lactate dehydrogenase) in cells from fed animals correlated with the depletion of stored glycogen and ATP. The degree and time course profile of oligomycin-induced ATP depletion could be duplicated with 50 mM fructose alone in hepatocytes from fasted animals; however, fructose did not cause lethal cell injury. Oligomycin caused marked accumulation of adenosine monophosphate (AMP) and inorganic phosphate (Pi) and a conservation of adenine nucleotides. In contrast, fructose (50 mM) caused a decrease in Pi, no persistent change in AMP, and a depletion of the adenine nucleotide pool. Fructose, at concentrations greater than 1.0 mM, protected hepatocytes from oligomycin-induced toxicity. Blockade of mitochondrial ATP synthesis with oligomycin resulted in massive ATP depletion. In the presence of oligomycin, 5.0 mM fructose maintained cellular ATP content similar to that of control cells, whereas 50 mM fructose did not, demonstrating the biphasic effect of increasing fructose concentrations on cellular ATP content. Fructose-induced protection of hepatocytes from oligomycin toxicity was due to glycolytic fructose metabolism as hepatocytes incubated with iodoacetate (30 microM), fructose, and oligomycin had reduced viability and ATP content. In conclusion, interruption of mitochondrial ATP synthesis leads to marked ATP depletion and lethal cell injury. Cell injury is clearly not due to ATP depletion alone since increased glycolytic ATP production from either glycogen or fructose can maintain cell integrity in the absence of mitochondrial ATP synthesis and at low cellular ATP levels.

Adenosine Triphosphate↗
PubMed1991

In vivo protection against scorpion toxins by liposomal immunization.

The possibility of raising a humoral immune response able to induce protection from the lethal effects of scorpion toxins was evaluated in the mouse model. A toxic fraction from the venom of the scorpion Tityus serrulatus was entrapped in sphingomyelin-cholesterol liposomes which yielded a conveniently detoxified immunogen. After three injections of this immunogen, all but three of a group of 18 mice developed an IgG response which was shown to be both specific and of good affinity for the toxic antigen. In vitro neutralization assays indicated that pre-incubation of a lethal dose of the toxic fraction with immune sera strongly diminished its toxicity. In vivo protection assays showed that mice with the highest levels of circulating anti-toxin antibodies could resist the challenge by double the normal LD50 of the toxic fraction, which killed all control non-immune mice. The protection was, however, found to be limited both in its duration and its effectiveness against higher amounts of toxin.

Animals↗
PubMed1984

A model system for measuring comparative toxicities of cardiotoxic drugs with cultured rat heart myocytes, endothelial cells and fibroblasts. I. Emetine, chloroquine and metronidazole.

Neonatal rat hearts were separated into separate cultures of beating myocytes (M cells), endothelial cells (E cells) and fibroblasts (F cells). Their susceptibilities to the toxic effects of emetine, chloroquine and metronidazole were then compared using a quantitative metabolic inhibition test (QMIT) and morphologic and beating changes as indices of injury. Measurements on the same cultures were made at 6 h and 12 h daily for 7 days with E and F cells; with M cells for 3 days. Metronidazole was non-toxic for all cell types at 810 micrograms/ml, whether as the parent compound or after attempted rat liver microsomal activation. QMIT data, integrated as time-concentration effects, showed all cell responses to either emetine or chloroquine to be parallel (P less than 0.05), and their order of susceptibility to be: E greater than M greater than F cells. Although morphologic signs of injury and changes in beating are not readily evaluated statistically, there was a general parallelism between these indices of injury and those of QMIT. As judged by QMIT emetine was more toxic than chloroquine. However, at equivalent QMIT grades chloroquine produced greater effects on morphology and beating. Toxic concentration-50 values for chloroquine with the QMIT were similar to reported human toxic and lethal blood concentrations.

Animals↗
PubMed1984

A model system for measuring comparative toxicities of cardiotoxic drugs for cultured rat heart myocytes, endothelial cells and fibroblasts. II. Doxorubicin, 5-fluorouracil and cyclophosphamide.

Separate cultures of beating myocytes (M cells), endothelial cells (E cells) and fibroblasts (F cells) from neonatal rat hearts were compared for their susceptibilities to the toxic effects of doxorubicin, 5-fluorouracil and cyclophosphamide. Toxic injury was measured as inhibition of metabolism and changes in morphology for all cell types, and changes in beating of myocytes. Cells were exposed to the anti-tumor agents for 3 days with myocytes and 7 days for endothelial cells and fibroblasts. All measures of injury were made several times the first day and daily thereafter, with the same cultures used throughout. Toxic effects of DOX and 5-FU were greater for E and F cells than for M cells, and all measures of toxicity were generally parallel. Cyclophosphamide, whether activated by liver microsomes or unactivated, was less toxic in general than the other agents, but it was more toxic for M cells than for E cells or F cells.

Animals↗
PubMed1987

Cytotoxic properties of glutamate and aspartate in rat peripheral nerves: histological findings.

Two excitatory neurotransmitters, L-glutamate and L-aspartate, known for their neurotoxic properties in the central nervous system were injected in rat sciatic nerve. The morphological results are compared with sodium chloride injections in sciatic nerve on the other side. Rats were sacrificed 24 h to 1 month after the administration of compounds. Marked endoneural edema with global axonal loss of myelinated fibers were observed in animals injected either with glutamate or aspartate. A demyelinating process was also associated with axonal damages. Sodium chloride did not induce similar morphological abnormalities. This model of toxic neuropathy may be mediated by the excitotoxic properties of L-aspartate and L-glutamate.

Animals↗