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.

Amyloid peptides are toxic via a common oxidative mechanism

Abstract: beta-Amyloid protein (A beta) is a member of a small group of proteins that accumulate as amyloid deposits in various tissues. It has recently been demonstrated that the toxicity of A beta toward some neural cells is caused by oxidative damage. Since all of the amyloid diseases are characterized by protein deposited in the antiparallel beta-sheet conformation, it was asked whether there is a common toxic mechanism. It is shown here that the protein components of other human amyloidoses, including amylin, calcitonin, and atrial natriuretic peptide, are all toxic to clonal and primary cells. The toxicity is mediated via a free radical pathway indistinguishable from that of A beta. Experiments with synthetic peptides suggest that it is the amphiphilic nature of the peptides generated by their beta structure rather than their beta structure per se that causes toxicity. These results tend to rule out the alternative that amyloid toxicity is exclusively mediated via specific cell surface receptors.

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).

Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics.

Abstract: We have determined the relationships between busulfan average concentration at steady-state and (1) rejection of graft, and (2) regimen-related toxicity, and have evaluated the dependence of busulfan clearance/F on body size and age. Patients received 16-30 mg/kg of busulfan followed by cyclophosphamide in doses of 120, 150, 174, or 200 mg/kg or 8 g/m2 in preparation for autologous, syngeneic or allogeneic grafts varying in compatibility from HLA-matched siblings to HLA-partially-matched unrelated donors. In a multivariate Cox time-to-rejection analysis, only busulfan concentration remained a significant determinant of rejection, P = 0.0154. An average concentration of busulfan at steady-state of at least 200 ng/ml was needed to avoid rejection of a matched-sibling graft, while 600 ng/ml was needed to avoid rejection of HLA-partially-matched related or HLA-matched unrelated donor grafts. The toxicity of the cytoreductive regimen correlated with busulfan average concentration at steady-state (rs = 0.717). Busulfan clearance/F expressed relative to body weight, ideal body weight or surface area declined with age during the first decade of life. Over the entire span of age, the coefficient of variation in clearance/F for all ages was similar when clearance/F was expressed in absolute terms (ml/min) and when adjusted for body surface area; the coefficient of variation was greater for clearance/F when expressed relative to total or ideal body weight. We conclude that busulfan concentration in plasma is an important determinant of graft survival and regimen-related toxicity, and that the variability of busulfan pharmacokinetics with age precludes the use of a fixed dose for all ages and indications.

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.

Sulfite sensitivity: significance in human health

Abstract: Endogenous sulfite is generated as a consequence of the body's normal processing of sulfur-containing amino acids. Sulfites occur as a consequence of fermentation and also occur naturally in a number of foods and beverages. As food additives, sulfiting agents were first used in 1664 and approved in the United States as long ago as the 1800s. With such long experience with their use, it is easy to understand why these substances have been regarded as safe. They are currently used for a variety of preservative properties, including controlling microbial growth, preventing browning and spoilage, and bleaching some foods. It is estimated that up to 500,000 (< .05% of the population) sulfite-sensitive individuals live in the United States. Sulfite sensitivity occurs most often in asthmatic adults--predominantly women; it is uncommonly reported in preschool children. Adverse reactions to sulfites in nonasthmatics are extremely rare. Asthmatics who are steroid-dependent or who have a higher degree of airway hyperreactivity may be at greater risk of experiencing a reaction to sulfite-containing foods. Even within this limited population, sulfite sensitivity reactions vary widely, ranging from no reaction to severe. The majority of reactions are mild. These manifestations may include dermatologic, respiratory, or gastrointestinal signs and symptoms. Severe nonspecific signs and symptoms occur less commonly. Broncho-constriction is the most common sensitivity response in asthmatics. The precise mechanisms of the sensitivity responses have not been completely elucidated. Inhalation of sulfur dioxide (SO2) generated in the stomach following ingestion of sulfite-containing foods or beverages, a deficiency in a mitochondrial enzyme, and an IgE-mediated immune response have all been implicated.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy

Abstract: In conjunction with rehydration, the bisphosphonates are the treatment of choice for hypercalcaemia of malignancy. Single infusions of either pamidronate or clodronate are usually effective, but a direct comparison of the two agents given at the highest doses commonly used has not been performed. Forty-one patients (15 breast, 12 squamous carcinomas, four lymphomas, four bladder, two prostate and four others) with hypercalcaemia of malignancy (corrected serum calcium > 2.7 mmol l-1) persisting after 48 h of saline rehydration were randomly allocated to receive a 4 h intravenous (i.v.) infusion of either pamidronate 90 mg or clodronate 1500 mg. No other systemic anti-cancer treatment was prescribed. There were no significant differences in the post-hydration serum calcium values (mean 3.17 mmol l-1 for pamidronate and 3.06 mmol l-1 for clodronate), tumour type or frequency of bone metastases between the two treatments. One patient on each treatment died within 2 days and was not assessable for response. A total of 19/19 (100%) patients achieved normocalcaemia following pamidronate and 16/20 (80%) with clodronate. The median time to achieve normocalcaemia was 4 days (range 2-14) for pamidronate and 3 days (range 2-6) with clodronate. The median duration of normocalcaemia was 28 days (range 10-28+ days) after pamidronate and 14 days after clodronate (range 7-21 days) (P 28 days respectively. Two patients experienced fever after pamidronate but no significant toxicity was observed with either treatment. We conclude that both agents are effective in the management of hypercalcaemia of malignancy. At the doses studied, the effects of pamidronate are more complete and longer lasting than those of clodronate.

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