Showing papers on "Toxicity published in 1995"

Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.

Abstract: The plasma pharmacokinetics of the antitumor antibiotic geldanamycin (GM; NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 μg/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 μg/ml within 3–4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The drug exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of GM was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the drug was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.

Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: Preclinical experience.

Abstract: Docetaxel is a taxoid which is currently in phase II/III clinical trials in Europe, the US and Japan. It was found to promote tubulin assembly in microtubules and to inhibit their depolymerization. In vitro, the docetaxel concentrations required to reduce murine and human cell survival by 50% ranged from 4 to 35 ng/ml and the cytotoxic effects were greater on proliferating than on non-proliferating cells. It was also found to be cytotoxic on fresh human tumor biopsies. In vivo, the drug was found to be schedule independent. A total of 13/14 murine transplantable tumors were found very sensitive to i.v. docetaxel and complete regressions of advanced stage tumors were obtained. Activity was also observed in 15/16 human tumor xenografts in nude mice at an advanced stage. In combination studies, synergism was observed in vivo with 5-fluorouracil, cyclophosphamide and etoposide. Pharmacokinetic evaluation revealed linear pharmacokinetics in tumor-bearing mice. There was a good tumor retention with a 22 h elimination half-life. Plasma protein binding ranged from 76 to 89%. Preclinical toxicology evaluation of docetaxel included single-dose toxicity in rats, mice and dogs, 5-day toxicity in mice and dogs, intermittent-dose toxicity in rats, dogs and monkeys, genetic and reproductive toxicity, as well as investigation of the irritation and sensitization potential. The principal toxicities were hematopoietic (all species), gastrointestinal (dog, monkey) and neuromotor (mice). Dogs appeared to be the most sensitive species. The clinical entry dose of 5 mg/m2 was based on one-third of the 'toxic dose low' in dogs (15 mg/m2).

Induction of apoptosis in catecholaminergic PC12 cells by L-DOPA. Implications for the treatment of Parkinson's disease.

Abstract: The hypothesis that L-DOPA therapy in Parkinson's disease may augment neuronal damage and thus accelerate the progression of the disease remains controversial. In this study, we demonstrate that L-DOPA induces death of catecholaminergic cells in vitro via an active program of apoptosis. Treatment of PC12 cells with clinically applicable concentrations of L-DOPA (25-100 microM) induced cell death via a mechanism which exhibited morphological and biochemical characteristics of apoptosis, including chromatin condensation, membrane blebbing, and internucleosomal DNA fragmentation. L-DOPA-induced apoptosis was cell and drug-type specific. Toxicity is an intrinsic property of the drug molecule since it was not suppressed by inhibiting conversion of L-DOPA to dopamine. However, L-DOPA toxicity was inhibited by antioxidants, suggesting that activation of apoptosis is mediated by oxygen radicals. Our finding that L-DOPA-induced cell death in vitro occurs via apoptosis explains the lack of evidence supporting its toxicity in vivo, since apoptotic neurons are rapidly phagocytosed in vivo without causing damage to surrounding tissue. Furthermore, since apoptosis is an active cellular program which can be modulated, we suggest clinical approaches for decreasing L-DOPA toxicity, thus preventing acceleration of neuronal damage in Parkinson's disease.

Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial

Abstract: Background. Cancer is most common in older age groups, but little information is available with regard to the impact of age on chemotherapy toxicity. This study was undertaken to determine if age is an independent risk factor for 5-fluorouracil (5-FU) toxicity. Methods. Toxicity data from a prospective, randomized, multiinstitution trial of 5-FU-based treatment for advanced colorectal cancer were analyzed. Toxicity for each organ system was graded. Individual organ toxicity proportions were compared using chi-square analysis. A logistic regression was performed using age (younger than 70 years vs. 70 years or older), sex, treatment arm, performance status, and length of therapy as model parameters to predict severe toxicity. Toxicity in 331 patients was analyzed. Results. Advanced age was significantly associated with the occurrence of any severe toxicity (58 vs. 36%, P < 0.001), leukopenia (24 vs. 10%, P < 0.005), diarrhea (24 vs. 14%, P = 0.01), vomiting (15 vs. 5%, P = 0.01), severe toxicity in more than 2 organ systems (10 vs. 3%, P = 0.02), and treatment mortality (9 vs. 2%, P = 0.01). By univariate analysis, age (P < 0.001) and sex (P < 0.0001) were independent predictors of severe toxicity. Twenty-two of 27 women age 70 years or older had severe toxicity. Conclusions. Age 70 years or older and sex are risk factors for severe toxicity from 5-FU-based chemotherapy. Advanced age does not contraindicate the use of this type of chemotherapy, but close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are required. Dosing decisions in older patients are difficult and must integrate assessments of organ function, comorbidities, overall physical status, and goals of treatment, in an effort to ensure the best possible outcome for these patients.

The influence of salinity on the toxicity of various classes of chemicals to aquatic biota.

Abstract: The objective of this study was to review all available aquatic toxicity literature regarding the effects of salinity on the toxicity of various classes of inorganic and organic chemicals. Toxicity data for studies in which toxicity was assessed at various salinities were organized by chemical classes and trophic groups. Seventy percent of the studies were conducted with either crustaceans or fish. The other 30% were with mollusks, annelids, zooplankton, bacteria, phytoplankton, or fungi. Results from 173 data entries showed that negative correlations (toxicity increasing with decreasing salinity) were reported most frequently (55%), followed by no correlations (27%) and positive correlations (18%). The toxicity of most metals such as cadmium, chromium, copper, mercury, nickel, and zinc was reported to increase with decreasing salinity. This finding is likely related to the greater bioavailability of the free metal ion (toxic form) at lower salinity conditions. There was generally no consistent trend for the toxicity of most organic chemicals with salinity. The one exception to this was reported with organophosphate insecticides, the toxicity of which appeared to increase with increasing salinity. Physiological characteristics of the various test species were important in determining the toxicity of the various classes of chemicals at a range of salinities. Results from various studies showed that euryhaline species were more resistant to toxic conditions at isosmotic salinities due to minimization of osmotic stress. Specific examples showed that fish were more resistant to toxic chemicals at middle salinities when compared with either lower or higher extremes. Life history and ecology of test species were important factors to consider when interpreting salinity/contaminant interaction data.

Influence of developmental stage, salts and food presence on various end points using Caenorhabditis Elegans for aquatic toxicity testing

Abstract: This study used a randomized block design to investigate the importance of several variables in using the free-living soil nematode, Caenorhabditis elegans, for aquatic toxicity testing. Concentration-response data were obtained on nematodes of various developmental stages exposed to four metals (Cd, Pb, Cu, and Hg) and a water-soluble organic toxicant, sodium pentachlorophenate (PCP), under conditions of varied solvent medium (with or without salts and with or without a bacterial food source). The end points measured were 24- and 96-h mortality LC50 value, as well as development of larval stages to adulthood and evidence of reproduction. The results suggest that nematodes of various ages respond similarity to a given toxicant for all end points measured, although adults cultured from eggs appeared more sensitive than adults cultured from dauer larvae. The most important environmental variable in determining toxicity was the medium in which the tests were conducted. The presence of potassium and sodium salts in the medium significantly (p < 0.05) reduced the toxicity of many test samples. The presence of bacteria had little effect on 24-h tests with salts, but was important in 96-h survival and development. Based on sensitivity and ease of handling, adults cultured from eggs are recommended inmore » both 24h and 96-h tests.« less

Role for circulating lipoproteins in protection from endotoxin toxicity.

Abstract: Previous studies have shown that endotoxin (lipopolysaccharide [LPS])-induced death can be prevented by preincubating LPS with lipoproteins in vitro or by infusing large quantities of lipids into animals prior to LPS administration. In the present study we determined whether physiological levels of lipids also provide protection. Serum lipid levels were decreased by two different mechanisms: administration of 4-aminopyrolo-(3,4-D)pyrimide, which prevents the hepatic secretion of lipoproteins, and administration of pharmacological doses of estradiol, which increases the number of hepatic low-density lipoprotein receptors, leading to increased lipoprotein clearance. In both hypolipidemic models, LPS-induced mortality is markedly increased compared with that of controls with normal serum lipid levels. In both hypolipidemic models, administration of exogenous lipoproteins, which increase levels of serum lipids into the physiological range, reduces the increased mortality to levels similar to that seen in normal animals. In normal lipidemic animals, 63% of 125I-LPS in plasma is associated with lipoproteins, where it would not be capable of stimulating cytokine production. In contrast, in hypolipidemic animals, very little LPS (12 to 17%) is associated with lipoproteins. Rather, more LPS is in the lipoprotein-free plasma compartment, where it could exert biological effects. In both hypolipidemic models, LPS produces a greater increase in serum tumor necrosis factor levels than it does in controls (three- to fivefold increase), and administration of exogenous lipoproteins prevents this increase. Cytokines, in particular tumor necrosis factor, are responsible for most of the toxic effects of LPS. These data provide evidence that physiological levels of serum lipids protect animals from LPS toxicity. Thus, lipoproteins, in addition to playing a role in lipid transport, may have protective functions. Moreover, as part of the immune response, cytokine-induced increases in serum lipid levels may play a role in host defense by decreasing the toxicities of biological and chemical agents.

Evaluation of soil toxicity at joliet army ammunition plant

Abstract: Environmental toxicity testing and chemical analyses of soil were performed as part of an ecological risk assessment at the Joliet Army Ammunition Plant (JAAP), Johet, Illinois Soils were collected from an area where munitions were loaded, assembled, and packed (area L7, group 1), and from an area where waste explosives were burned on unprotected soil (area L2) Control samples were collected from an adjacent field Soil toxicity was determined using early seedling growth and vigor tests, earthworm survival and growth tests, and Microtox® assays Relative toxicity of soils was determined within each area based on statistical significance (p = 0 05) of plant and earthworm growth and survival, and the effective concentration at which luminescence of the bacterium Photobacterium phosphoreum was reduced by 50% (EC50) in the Microtox assay Samples were designated as having high, moderate, or no significant toxicity Soil that had significant toxicity according to at least one test, and representative samples showing no toxicity, were analyzed for munitions via HPLC Chemical residues found in soils were 2,4,6 trinitrotoluene (TNT), 1,3,5 trinitrobenzene (TNB), 2,4 dinitrotoluene (2,4-DNT), 2,6 dinitrotoluene, 2 amino-4,6-DNT, 4-ammo-2,6 DNT, 1,3,5 trinitro 1,3,5 triazine (RDX), and octahydro-1,3,5,7 tetramtro-l,3,5,7-tetrazocme (HMX) All soils with no significant toxicity were void of these chemicals However, some soils void of munitions still showed toxicity that may have been caused by elevated levels of heavy metals Linear regressions of toxicity test results vs chemical concentrations showed that TNT and TNB accounted for most of the soil toxicity Lowest observable-effect concentrations (LOEC) of TNT were de termined from these data This study presents a simple, relatively inexpensive methodology for assessing toxicity of soils containing TNT, RDX, and other contaminants related to munitions production

Phase I study of phenylacetate administered twice daily to patients with cancer

Abstract: Background The growth-inhibiting and differentiating effects of sodium phenylacetate against hematopoietic and solid tumor cell lines has aroused clinical interest in its use as an anticancer drug In an earlier Phase I trial of phenylacetate aimed at maintaining serum drug concentrations in the range that proved active in vitro (>250 μg/ml) for 2 consecutive weeks, infusion rates approached the maximum velocity of drug elimination and commonly resulted in drug accumulation and reversible dose-limiting neurologic toxicity In this study, the authors described the nonlinear pharmacokinetics, metabolism, toxicity, and clinical activity of phenylacetate Methods The treatment regimen of this Phase I study was designed to expose patients intermittently to drug concentrations exceeding 250 μg/ml and to allow time for drug elimination to occur between doses to minimize accumulation Sodium phenylacetate was administered as a 1-hour infusion twice daily (8 am, 5 pm) at two dose levels of 125 and 150 mg/kg for a 2-week period Therapy was repeated at 4-week intervals for patients who did not experience dose-limiting toxicity or disease progression Results Eighteen patients (4 of whom previously were treated with phenylacetate by continuous intravenous infusion) received 27 cycles of therapy Detailed pharmacokinetic studies for eight patients indicated that phenylacetate induced its own clearance by a factor of 27% in a 2-week period Dose-limiting toxicity, consisting of reversible central nervous system depression, was observed for three patients at the second dose level One patient with refractory malignant glioma had a partial response, and one with hormone-independent prostate cancer achieved a 50% decline in prostate specific antigen level, which was maintained for 1 month Conclusions Phenylacetate administered at a dose of 125 mg/kg twice daily for 2 consecutive weeks is well tolerated High grade gliomas and advanced prostate cancer are reasonable targets for Phase II clinical trials Cancer 1995;75:2932–8

Serum Levels of Free 1,25-Dihydroxyvitamin D in Vitamin D Toxicity

Abstract: Objective: To determine the serum level of free 1,25-dihydroxyvitamin D (1,25-[OH]2D) in patients with vitamin D toxicity and to assess the in vitro effect of differing concentrations of vitamin D ...

Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine.

Abstract: Objective Myocardial depression from verapamil toxicity may result from alterations in carbohydrate metabolism as well as calcium-channel antagonism. We hypothesized that pharmacologic doses of insulin may be effective in reversing both of these deficits.Design Randomized, controlled, prospective st

Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Australian Leukaemia Study Group

Abstract: All-trans retinoic acid (ATRA) induces complete remission (CR) in most cases of acute promyelocytic leukemia (APL) but its use is associated with potentially fatal pulmonary toxicity in approximately 25% of APL patients in the setting of a rapidly rising peripheral blood white cell count (WBC). The efficacy of oral corticosteroid for prophylaxis against pulmonary toxicity has been investigated in a prospective multi-center study. ATRA was administered at 45 mg/m2/day as single agent therapy throughout induction treatment in 19 patients with an initial WBC < 10 x 10(9)/l, and prednisolone 75 mg/day was added in those 12 patients in whom the WBC rose above 10 x 10(9)/l. Combination chemotherapy plus prednisolone was added to ATRA in six other patients on the basis of criteria specified in the protocol. All 19 patients who received ATRA without chemotherapy achieved CR without signs of pulmonary toxicity despite a rise in WBC to peak values as high as 112 x 10(9)/l. Pulmonary toxicity developed in two patients commenced on ATRA in association with an unusually rapid increment in WBC of 7.5 x 10(9)/l and 32.5 x 10(9)/l in the first 2 days; both were subsequently treated with chemotherapy. The low incidence of pulmonary toxicity in this study compared with that in previous trials suggests that prednisolone prophylaxis increases safety of ATRA therapy in APL irrespective of the peak WBC.

Protective Effects of Kampo Medicines and Baicalin against Intestinal Toxicity of a New Anticancer Camptothecin Derivative, Irinotecan Hydrochloride (CPT-11), in Rats

Abstract: In clinical use, irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(piperidino)-1-piperidino]carbonyloxycamptothecin), a novel antitumor agent, causes a relatively high incidence of severe forms of diarrhea We investigated whether baicalin, an inhibitor of beta-glucuronidase, which deconjugates the glucuronide of the active metabolite of CPT-11, SN-38 (7-ethyl-10-hydorxycamptothecin), and Japanese herbal medicines (Kampo medicines) which contain baicalin can ameliorate CPT-11-induced intestinal toxicity in rats CPT-11 (60 mg/kg iv once daily for 4 consecutive days) induced intestinal toxicity characterized by diarrhea, loss of body weight, anorexia and disruption of intestinal epithelium Treatment with baicalin (25 mg/kg po twice daily) or Kampo medicines (TJ-14 and TJ-114; 1 g/kg po twice daily) from the day before to 4 or 10 days after the start of CPT-11 administration resulted in significantly decreased weight loss, improved anorexia and delayed onset of diarrheal symptoms Histological examination revealed that Kampo medicine-treated animals had less damage to the intestinal epithelium and that damage was repaired more rapidly than in control rats These results suggest that the prophylactic use of Kampo medicines (TJ-14 and TJ-114) may be of value against CPT-11-induced intestinal toxicity