Showing papers on "Toxicity published in 1998"
TL;DR: HE inhibited the growth and killed a S OD-null strain to a greater extent than the SOD-replete parental strain and these effects were much diminished under anaerobic conditions, indicating that E+ was responsible for the toxicity of HE.
487 citations
TL;DR: Based on a large data set, the toxicity profile of the two schedules of administration of 5-FU was confirmed and quantified and allowed the identification of clinical predictors of toxicity.
Abstract: PURPOSE Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.
454 citations
TL;DR: The synthesis of subcutaneous collagen in smokers is specifically impeded, indicating an impaired wound-healing process, and the view that patients should be advised to stop smoking before an operation is supported.
326 citations
TL;DR: The protection against APAP toxicity afforded by deletion of both CYP2E1 and CYP1A2 likely reflects greatly diminished production of the toxic electrophile, NAPQI.
287 citations
TL;DR: In this paper, the toxicity of silver (Ag+) was investigated in a bioassays with freshwater and seawater fish and it was concluded that present regulatory standards for silver can be much improved by taking into account the important geochemical modifiers of silver toxicity, including complexation of Ag+ by chloride, dissolved organic carbon, and sulfide.
Abstract: In its ionic form, silver (Ag+) is highly toxic to fish (96-h 50% lethal concentration [LC50]: low μg/L range). However, concentrations of Ag+ in aquatic environments are extremely low and other more common forms of silver show only low to moderate toxicities (e.g., 96-h LC50: silver thiosulfate >100,000 μg Ag/L; silver chlorides >100 μg Ag/L). In bioassays with freshwater fish, acute toxicity appears to be derived exclusively from the Ag+ ion concentration of the water. Some other forms of silver are bioavailable but do not show obvious contribution to acute toxicity. Complexation of Ag+ by chloride, dissolved organic carbon, and sulfide are important in reducing silver toxicity. The protective action of hardness (i.e. calcium) is modest. When added as the readily dissociating silver nitrate salt, the toxicity of silver is considerably lower in seawater (96-h LC50 range: 330–2,700 μg Ag/L) than in freshwater (96-h LC50 range: 5–70 μg Ag/L). Acute silver toxicity to fish is caused by failure of the organism to maintain constant Na+ and Cl− concentrations in the blood plasma. In freshwater fish, Ag+ exerts its toxic effects on the Na+ and Cl− transport across the gills, whereas the intestine has been indicated as the site of toxicity in seawater fish. Although there are still many gaps in our understanding of silver effects on fish, it can be concluded that present regulatory standards for silver can be much improved by taking into account the important geochemical modifiers of silver toxicity.
275 citations
Journal Article•
TL;DR: Four elements that have been implicated in free-radical-induced oxidative stress in Alzheimer's disease were measured by instrumental neutron activation analysis (INAA) in seven brain regions from 58 AD patients and 21 control subjects.
Abstract: Four elements that have been implicated in free-radical-induced oxidative stress in Alzheimer's disease (AD) were measured by instrumental neutron activation analysis (INAA) in seven brain regions from 58 AD patients and 21 control subjects A statistically significant elevation of iron and zinc was observed in multiple regions of AD brain, compared with controls Mercury was elevated in AD in most regions studied, but the high variability of mercury levels in both AD and control subjects prevented the AD-control difference from reaching significance Selenium, a protective agent against mercury toxicity, was significantly elevated only in AD amygdala The elevation of iron and zinc in AD brain has the potential ofaugmenting neuron degeneration through free radical processes
266 citations
TL;DR: In this paper, a NQO1-null mouse was produced using targeted gene disruption and showed increased toxicity when administered menadione compared with wild-type mice, which can be used to determine the role of this enzyme in sensitivity to toxicity and carcinogenesis.
255 citations
TL;DR: The discussion of clinical toxicity focuses on the nervous, cardiovascular, pulmonary, gastrointestinal, and renal systems, as well as on the teratogenic effects of mercury.
Abstract: This review is Part I of a two-part series focusing on heavy metal toxicity. Part I will cover arsenic and mercury toxicity. Acute and chronic arsenic toxicity, as well as arsine gas toxicity, will be reviewed. The clinical presentation, with focus on the nervous, cardiovascular, pulmonary, gastrointestinal, hepatic, renal, hematopoietic, and dermatologic systems, is delineated. Mercury exposure, including exposure to short chain alkyl mercury, elemental mercury, and acute inorganic salt, is reviewed. The discussion of clinical toxicity focuses on the nervous, cardiovascular, pulmonary, gastrointestinal, and renal systems, as well as on the teratogenic effects of mercury. Recommendations for diagnostic tests and management plans are discussed, including chelation regimens.
238 citations
TL;DR: It is reported that GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against β-cells, and was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection.
Abstract: In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both β-cell toxicity and T-cell- dependent immune reactions. The target molecule(s) of MLD-STZ-induced β-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLDSTZ-treated C57BL/6 male mice, whereas mRNA expression of β-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of β-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against β-cells.
226 citations
TL;DR: It is suggested that curcumin inhibits ADR cardiotoxicity and might serve as novel combination chemotherapeutic agent with ADR to limit free radical‐mediated organ injury.
Abstract: The protective effect of curcumin on acute adriamycin (ADR) myocardial toxicity was analysed in rats. ADR toxicity, induced by a single intraperitoneal injection (30 mg kg(-1)), was revealed by elevated serum creatine kinase (CK) and lactate dehydrogenase (LDH). The level of the lipid peroxidation products, conjugated dienes and malondialdehyde, was markedly elevated by ADR. ADR caused a decrease in myocardial glutathione content and glutathione peroxidase activity. In contrast, cardiac catalase activity was increased in ADR rats. Curcumin treatment (200 mg kg(-1), seven days before and two days following ADR) significantly ameliorated the early manifestation of cardiotoxicity (ST segment elevation and an increase in heart rate) and prevented the rise in serum CK and LDH exerted by ADR. ADR rats that received curcumin displayed a significant inhibition of lipid peroxidation and augmentation of endogenous antioxidants. These results suggest that curcumin inhibits ADR cardiotoxicity and might serve as novel combination chemotherapeutic agent with ADR to limit free radical-mediated organ injury.
226 citations
TL;DR: An update of the current knowledge of the mechanism of action of low-dose methotrexate (MTX) in the treatment of patients with rheumatoid arthritis (RA), with an emphasis on the mechanisms involved in toxicity.
TL;DR: It is indicated that GPX1 is the major, if not the only, metabolic form of body Se that protects mice against the lethal oxidative stress caused by high levels of paraquat; it seems less important, however, in protecting dogs against the moderate oxidative stress by the low level of paraaquat.
Abstract: The antioxidative role of Se-dependent cellular glutathione peroxidase (EC 1.11.1.9, GPX1) in vivo has not been established. Our objective was to determine the effects of GPX1 knockout or overexpression on the susceptibility of mice to paraquat toxicity and the contributions of GPX1, compared with other selenoproteins and vitamin E, to body defenses against such acute oxidative stress. Four experiments were conducted using 111 GPX1 knockout or overexpressing mice and the respective controls. Mice were fed diets supplemented with Se (as sodium selenite) at 0-0.4 mg/kg and/or all-rac-alpha-tocopheryl acetate at 0-75 mg/kg before intraperitoneal injections of 12.5, 50 or 125 mg paraquat/kg body weight. All mice that received 50 or 125 mg paraquat/kg died spontaneously, and the survival time of mice was (independent of dietary levels of Se per se or alpha-tocopheryl acetate) solely a function of tissue GPX1 activity (P < 0.001). Severe acute pulmonary interstitial necrosis was found only in the GPX1 overexpressing mice and the controls that had extended survival time. Thiobarbituric acid reacting substances in postmortem liver inversely correlated with the tissue GPX1 activity and dietary levels of Se and/or alpha-tocopheryl acetate. In contrast, all mice that received 12.5 mg paraquat/kg survived and were killed 2 wk after the injection for tissue collection. Compared with the saline injection, this low dose of paraquat resulted in greater (P < 0.001) liver and lung F2-isoprostanes in both the GPX1 knockout mice and the controls. However, there was no difference in plasma alanine transaminase (EC 2.6.1.2) activity or overt injuries in liver, lung and kidney in either group. Our data indicate that GPX1 is the major, if not the only, metabolic form of body Se that protects mice against the lethal oxidative stress caused by high levels of paraquat; it seems less important, however, in protecting mice against the moderate oxidative stress by the low level of paraquat.
TL;DR: It is concluded that low-dose NAC protects against LPS toxicity by scavenging H2O2, while higher doses may have the opposite effect.
Abstract: We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on oxidative stress, lung damage, and mortality induced by an endotoxin (lipopolysaccharide, or LPS) in the rat. Continuous intravenous infusion of 275 mg NAC/kg in 48 h, starting 24 h before LPS challenge, decreased hydrogen peroxide (H2O2) concentrations in whole blood (p < 0.01). This decrease was accompanied by fewer histologic abnormalities of the lung and decreased mortality (p < 0.025), compared with rats receiving LPS alone. N-Acetylserine, which has no sulfhydryl group, did not protect rats against LPS toxicity. Improved survival was not associated with an increase in pulmonary reduced glutathione, nor with inhibition of serum tumor necrosis factor (TNF) activity. In vitro, TNF production and DNA binding of nuclear factor kappa B (NF-kappaB) in human Mono Mac 6 cells was only inhibited at concentrations of NAC above 20 mM. High-dose NAC treatment (550 and 950 mg/kg in 48 h) decreased lung GSH (p < 0.05) and resulted in a significantly smaller number of surviving animals when compared with the low-dose NAC group (p < 0.025). In vitro, NAC increased hydroxyl radical generation in a system with Fe(III)-citrate and H2O2 by reducing ferric iron to its catalytic, active Fe2+ form. We conclude that low-dose NAC protects against LPS toxicity by scavenging H2O2, while higher doses may have the opposite effect.
TL;DR: It is concluded that cyclosporin A causes renal injury by mechanisms involving hypoxia-reoxygenation, effects which can be prevented effectively by dietary glycine.
Abstract: The major side effect of cyclosporin A is severe nephrotoxicity. It is likely that cyclosporin A causes vasoconstriction leading to hypoxia-reperfusion injury; therefore, these experiments were des...
TL;DR: Overexpression of Cat and Gpx, alone or in combination with SOD, by use of molecular biology techniques can protect insulin-producing cells against oxidative damage, which may represent a strategy to protect pancreatic beta-cells against destruction during the development of autoimmune diabetes.
Abstract: To determine the importance of different antioxidative enzymes for the defense status of insulin-producing cells, the effects of stable overexpression of glutathione peroxidase (Gpx), catalase (Cat), or Cu/Zn superoxide dismutase (SOD) in insulin-producing RINm5F cells on the cytotoxicity of hydrogen peroxide (H2O2), hypoxanthine/xanthine oxidase (H/XO), and menadione have been investigated. Single overexpression of Cat or Gpx provided less protection than the combined expression of Cat plus SOD or Cat plus Gpx, while single overexpression of SOD either had no effect on the toxicity of the test compounds or increased it. RINm5F cells were also susceptible to butylalloxan, a lipophilic alloxan derivative that is selectively toxic to pancreatic beta-cells. Overexpression of enzymes, both alone and in combination, did not protect against butylalloxan-induced toxicity while SOD overexpression increased it, as evident from a half maximally effective concentration (EC50) value. The addition of Cat to the culture medium completely prevented the toxic effects of H2O2 and H/XO but had no significant effect on the toxicity of menadione or butylalloxan. Extracellular SOD had no effect on the toxicity of any of the test compounds. The results of this study show the importance of a combination of antioxidant enzymes in protecting against the toxicity of reactive oxygen species. Thus, overexpression of Cat and Gpx, alone or in combination with SOD, by use of molecular biology techniques can protect insulin-producing cells against oxidative damage. This may represent a strategy to protect pancreatic beta-cells against destruction during the development of autoimmune diabetes and emphasizes the importance of optimal antioxidative enzyme equipment for protection against free radical-mediated diseases.
TL;DR: The protection from Aβ-induced neurotoxicity afforded by apoE3 treatment may result from clearance of the peptide by apOE3:Aβ complex formation and uptake by apolipoprotein E receptors.
Abstract: Although the genetic link between the e4 allele of apolipoprotein E (apoE) and Alzheimer’s disease is well established, the isoform-specific activity of apoE underlying this correlation remains unclear. To determine whether apoE influences the neurotoxic actions of β-amyloid (Aβ), we examined the effect of native preparations of apoE3 and E4 on Aβ-induced toxicity in primary cultures of rat hippocampal pyramidal neurons. The source of apoE was conditioned medium from HEK-293 cells stably transfected with human apoE3 or E4 cDNA. ApoE4 (10 μg/ml) alone was toxic to the cultures, whereas apoE3 had no effect. ApoE3 treatment prevented the toxicity induced by 10 μm Aβ(1–40) or Aβ(25–35). The apoE3 protective effect appears to be specific to Aβ-induced toxicity, because apoE3 did not protect against the cytotoxicity produced by NMDA or staurosporine, nor did apoE3 affect the increase in intracellular calcium induced by either NMDA or KCl. ApoE3 had no effect on the toxicity produced by Aβ in the presence of receptor-associated protein, an inhibitor of apoE receptors, particularly the LDL-receptor-related protein. Interaction with apoE receptors may not mediate the toxic actions of apoE4, because receptor-associated protein did not affect apoE4-induced neurotoxicity. Consistent with our previous biochemical experiments, analysis of the culture medium revealed that SDS-stable apoE3:Aβ complex is present in greater abundance than apoE4:Aβ complex. Thus, the protection from Aβ-induced neurotoxicity afforded by apoE3 treatment may result from clearance of the peptide by apoE3:Aβ complex formation and uptake by apoE receptors.
TL;DR: In vivo data show that hepatocyte injury and oxidant damage to mitochondria caused by i.v. taurochenodeoxycholic acid can be significantly reduced by pretreatment with the antioxidant vitamin E.
TL;DR: The conclusion is that the comet assay has more potential for use in an in vitro context for the screening of agents destined for release or disposal into the marine environment.
Abstract: The potential application of the comet assay for monitoring the effect of DNA damaging agents on the marine mussel, Mytilus edulis (an important pollution indicator organism), was explored. A detailed investigation of the baseline levels of single-strand breaks in isolated gill cells, and how they were affected by age/size of animal, time since collection, feeding regime, in vivo vs. in vitro exposure conditions, and by antioxidant supplementation was undertaken. The level of cometing in untreated controls was found to be highly variable over time (fluctuations between low and very high DNA damage occurred over just 14 days post collection). No difference was observed between age/size and feeding regime of the animals. On exposure to 0, 100, 500 and 1000 microM H2O2, it was observed that the in vitro exposure produced a markedly more homogeneous dose response compared to the in vivo studies (where gill cells were exposed as a tissue). An important finding of our research was the effect of prior supplementation of the animals' diet with 1 mg/ml alpha-tocopherol acetate (vitamin E compound), which resulted in a marked reduction in the levels of DNA damage expressed by the negative controls, without influencing the actual response to H2O2 (0, 5, 25, and 100 microM) and N-nitrosodimethylamine, NDMA (0, 5, 25, and 100 mM). The effect of vitamin E supplementation was to increase the sensitivity of the comet assay at the lower end of the dose range. This study demonstrated the potential application of the comet assay to the gill cells of the mussel, M. edulis. Although preliminary findings suggest that antioxidant supplementation can improve the sensitivity of the assay by lowering the baseline damage in untreated animals, our conclusion is that the assay has more potential for use in an in vitro context for the screening of agents destined for release or disposal into the marine environment.
TL;DR: Phycocyanin shows anti-inflammatory activity in four experimental models of inflammation and may contribute, at least in part, to its anti- inflammation activity.
Abstract: Objective: To examine the effects of C-phyco- cyanin, a pigment found in blue-green algae which acts as an antioxidant in vitro and in vivo, in different animal models of inflammation. Material: Male Sprague Dawley rats and OF1 mice were used. Treatments: Oedema was induced by: a) AA (0.5 mg/ear) or TPA (4 mg/ear) in the mouse ear b) carrageenan injection (0.1 mL of 1% suspension) in the rat paw (6 adrenalectomy) and c) cotton pellet implantation in the rat axilla. Phyco- cyanin (50-300 mg/kg, p.o.) or indomethacin (1 mg/ear or 3-10 mg/kg, p.o.) as control were tested in the four animal models. Methods: Measurement of the increase in the weight (mg) of 6 mm ear punch biopsies from treated ears were made in comparison to control ears, together with myeloperoxidase (MPO) activity as an index of neutrophil infiltration. The increase in the paw thickness (mm) was measured with a dial caliper. Cotton pellet was implanted and seven days afterwards the granuloma was removed and the dry weight was determined. Acute toxicity was studied in mice and rats. Statistics were performed using one-way analysis of variance with the Duncan Multirange test. Results: Phycocyanin reduced significantly (p < 0.05) and in a dose-dependent manner ear oedema induced by AA and TPA in mice as well as carrageenan-induced rat paw oedema (both in intact and adrenalectomized animals). In the TPA test, phycocyanin also reduced MPO content. Phycocyanin also exerted an inhibitory effect in the cotton pellet granuloma test. In the acute toxicity test in rats and mice, even at the highest dose tested (3 000 mg/kg, p.o.), no toxicity was found. Conclusions: Phycocyanin shows anti-inflammatory activity in four experimental models of inflammation. Its anti- oxidative and oxygen free radical scavenging properties may contribute, at least in part, to its anti-inflammatory activity.
Journal Article•
TL;DR: The infusion of cryopreserved peripheral blood progenitor cells transplanted in 22 patients receiving high dose chemotherapy and stem cells transplantation for malignancy caused minor to moderate toxicity in most cases and side effects were observed only during infusion.
Abstract: Background: We evaluated the infusion-related toxicity of cryopreserved autologous circulating progenitor cells transplanted in 22 patients receiving high dose chemotherapy and stem cells transplantation for malignancy. Materials and Methods: Progenitor cells were collected following mobilization with chemotherapy plus filgrastim and stored in liquid nitrogen in the presence of 10% dimethylsulfoxide (DMSO). Before infusion of the graft, patients were medicated with mannitol, hydrocortisone and clorphenamine. The amount of DMSO infused as well as the number of dead and damaged cells were evaluated as possible cause of toxicity. Results: Eleven patients (50%) experienced symptoms related to graft infusion, nausea and vomiting being the most common adverse events. Hypotension was documented in 3 patients (one of them developing transient bradycardia resolved with atropin administration) and one had hypertension with tachycardia. Other observed side effects were: chest tightness (2 pts), fever and chills (3 pts), associated with abdominal cramps (2 pts). 7 out of 8 (88%) patients infused with greater than 30 mL volume of DMSO experienced side-effects, the grade of toxicity being significantly less in those receiving lower amount ( 10×10 9 ) developed toxicity. Conclusions: In our exeperience the infusion of cryopreserved peripheral blood progenitors caused minor to moderate toxicity in most cases and, when present, side effects were observed only during infusion. The amount of DMSO present in the graft is related to the grade of toxicity.
TL;DR: Paclitaxel is active in drug-resistant SCLC; further investigation in combination with other active agents in this poor prognosis group is appropriate.
Abstract: The purpose of the study was to delineate the efficacy and toxicity of paclitaxel (Taxol, Bristol Myers Squibb) in the treatment of drug resistant small-cell lung cancer (SCLC). Patients with SCLC relapsing within 3 months of cytotoxic therapy received paclitaxel 175 mg m(-2) intravenously over 3 h every 3 weeks. The dose of paclitaxel was adjusted to the toxicity encountered in the previous cycle. Of 24 patients entered into the study, 24 and 21 were assessable for response and toxicity respectively. There were two early deaths and two toxic deaths. No complete and seven partial responses (29%) (95%CI 12-51%) were observed and five patients had disease stabilization. The median survival (n = 21) was 100 days. Life-threatening toxicity occurred in four patients; in others (non)-haematological toxicity was manageable. Paclitaxel is active in drug-resistant SCLC. Further investigation in combination with other active agents in this poor prognosis group is appropriate.
TL;DR: It is concluded that S(-)-bupivacaine has similar local anaesthetic characteristics to RS-bupvacaine when used for extradural anaesthesia.
Abstract: Bupivacaine has a chiral centre and is currently available as a racemic mixture of its two enantiomers: R(+)-bupivacaine and S(-)-bupivacaine. Preclinical studies have demonstrated that there is enantiomer selectivity of action with the bulk of central nervous system and cardiovascular toxicity residing with the R(+) isomer. The aim of this study was to compare the clinical efficacy and safety of S(-)-bupivacaine with racemic RS-bupivacaine for extradural anaesthesia. We studied 88 patients undergoing elective lower limb surgery under lumbar extradural anaesthesia who received 15 ml of 0.5% or 0.75% S(-)-bupivacaine, or 0.5% RS-bupivacaine in a randomized, double-blind study. There was no difference in onset time, maximum spread of sensory block or intensity of motor block between the three groups. Duration of sensory block was significantly longer for 0.75% S(-)-bupivacaine. We conclude that S(-)-bupivacaine has similar local anaesthetic characteristics to RS-bupivacaine when used for extradural anaesthesia.
TL;DR: Dietary fumonisin B1 levels of 250 and 500 mg FB1/kg increased the level of thiobarbituric acid reactive substances (TBARS) significantly in the liver of rats fed FB1 over 21 days, suggesting that lipid peroxidation is likely to contribute to the cytotoxic effect of FB1.
TL;DR: The battery of mutagenicity studies shows no evidence of a genotoxic risk to man, and the toxicological characteristic of this compound is demonstrated.
TL;DR: Decitabine is a well tolerated regimen with modest clinical activity against hormone-independent prostate cancer recurrent after total androgen blockade and flutamide withdrawal and in patients of African-American origin.
Abstract: Aims and BackgroundDecitabine (5-aza-2′-deoxycytidine) is an S-phase-specific pyrimidine analog with hypomethylation properties. In laboratory models of prostate cancer (PC-3 and DU-145), decitabine induces cellular differentiation and enhanced expression of genes involved in tumor suppression, immunogenicity, and programmed cell death.MethodsWe conducted a phase II study of decitabine in 14 men with progressive, metastatic prostate cancer recurrent after total androgen blockade and flutamide withdrawal. Decitabine was administered at a dose of 75 mg/m2/dose IV as a 1 hour infusion every 8 hours for three doses. Cycles of therapy were repeated every 5 to 8 weeks to allow for resolution of toxicity.ResultsTwo of 12 patients evaluable for response had stable disease with a time to progression of more than 10 weeks. This activity was seen in 2 of 3 African-American patients. Toxicity was similar to previously reported experience. No significant changes in urinary concentrations of the angiogenic factor bFGF,...
TL;DR: In an effort to improve predictability, two-parameter QSAR, or response surface, analyses were performed to develop quantitative structure-activity relationships (QSARs), and no high-quality relationship was observed between toxicity and hydrophobicity, or Elumo, individually.
Abstract: Toxicity data for the 50% growth inhibitory concentration against Tetrahymena pyriformis (log (IGC50-1)) for 42 alkyl- and halogen-substituted nitro- and dinitrobenzenes were obtained experimentally. Log (IGC50-1) along with the hydrophobicity, the logarithm of the 1-octanol/water partition coefficient (log Kow), and the molecular orbital properties, the lowest unoccupied molecular orbital energy (Elumo) and maximum acceptor superdelocalizability (Amax), were used to develop quantitative structure−activity relationships (QSARs). All the nitroaromatic compounds tested had toxicity in excess of baseline, nonpolar narcosis. The nitrobenzenes were thought to elicit their toxic response through multiple (and mixed) mechanisms. No high-quality relationship was observed between toxicity and hydrophobicity, or Elumo, individually. However, a strong relationship {log (IGC50-1) = 16.4(Amax) − 4.64; n = 42, r2 = 0.847, s = 0.279, F = 229} was obtained. In an effort to improve predictability, two-parameter QSAR, or r...
TL;DR: Inulin has been shown to modulate serum lipids, therefore, the effect of consuming three servings per day of inulin-containing foods, compared to similar foods without inulin, on serum lipid profiles among hypercholesterolemic men and women as discussed by the authors.
Journal Article•
TL;DR: Copper-64-TETA-octreotide is a promising radiopharmaceutical for targeted radiotherapy of somatostatin receptor-positive tumors in Lewis rats and data indicate that radiotherapy with 64Cu-tetraacetic acid (TETA) in humans would be feasible.
Abstract: UNLABELLED The efficacy of 64Cu [T1/2 = 12.7 hr; beta+ (0.655 MeV; 19%); beta- (0.573 MeV; 40%)] as a radioisotope for radiotherapy has been recently established. Here we demonstrate that 64Cu-1,4,8,11 -tetraazacyclotetradecane-N,N',N",N'''-tetraacetic acid (TETA)-octreotide, a somatostatin receptor ligand, inhibits the growth of CA20948 rat pancreatic tumors in Lewis rats at doses that cause minimal toxicity. METHODS Tumor-bearing rats were administered a single 15 mCi (555 MBq) dose, a fractionated dose of 15 mCi given in 2-3 doses over 2-8 days, or control agents of buffer, unlabeled octreotide or 64Cu-labeled TETA. In certain experiments, blood was removed at times from 4-23 days post-treatment, and a complete blood count along with blood chemistry analyses were obtained. RESULTS Tumor-growth inhibition was significantly greater in rats injected with a single 15 mCi dose than in rats injected with control agents (p < 0.05). Dose fractionation in two doses, either 1 or 2 days apart, induced significantly increased tumor-growth inhibition compared with rats given a single dose (p < 0.05). The only toxicity observed in treated rats was a decrease in the white blood cell count. This drop was more pronounced in rats treated with a single dose compared with those treated with a fractionated dose. Human absorbed doses of 64Cu-TETA-octreotide to normal organs were estimated from biodistribution data in Lewis rats, and these data indicate that radiotherapy with 64Cu-TETA-octreotide in humans would be feasible. CONCLUSION Copper-64-TETA-octreotide is a promising radiopharmaceutical for targeted radiotherapy of somatostatin receptor-positive tumors.
TL;DR: The phagolysosomal nephropathy was detected in rats after acute exposure as well as in the surviving rats following 1 intraperitoneal injection of 500 mg/kg or intravenous injection of 100mg/kg, and may serve as a biological marker in toxicity screening tests for this class of compound.
Abstract: Polyalkylsulfonated C60, or FC4S, a highly water-soluble caged fullerene derivative, is believed to be a free radical remover or an antioxidant in biological systems. A 50 mg/ml aqueous solution was prepared as a master solution and administered to female Sprague-Dawley CD(Crl:CDR (SD)BR) rats in a single-dose acute toxicity study or a 12-day subacute toxicity study where rats were given the solution daily. In a study of the median lethal dose (LD50), no rats died after oral administration, and thus FC4S was considered to nontoxic if administered orally. In an LD50 intraperitoneal injection study, rats died within 30 hr after injection; the LD50 was determined to be approximately 600 mg per kilogram of body weight. Rats injected with the compound intraperitoneally or intravenously immediately eliminated the compound through the kidney; the kidney appeared to be the primary target organ. The compound induced a distinct lysosome-overload nephrosis, a phagolysosomal nephropathy characterized by a tinctorial ...
TL;DR: It can be concluded that the use of ADMUL WOL brand of PGPR in tin-greasing emulsions or in chocolate couverture does not constitute a human health hazard.