Phase I clinical and pharmacokinetic study of trimetrexate using a daily x5 schedule.

Trimetrexate (TMQ; NSC 352122) is a potent inhibitor of dihydrofolate reductase with good activity against murine i.p.-implanted B16 melanoma and colon 26 tumors. Preclinical antineoplastic activity, demonstrated schedule dependency, and data suggesting effectiveness against methotrexate-resistant cells prompted a Phase I clinical and pharmacokinetic study of trimetrexate using an i.v. daily x5 schedule. Forty-three good performance status patients were treated with 12 dose levels using daily doses varying from 0.5 to 15 mg/m2/d. Plasma and urine samples were obtained for pharmacokinetic analysis using a high-performance liquid chromatographic method. Myelosuppression was dose limiting and 15 mg/m2/d x5 was the maximum tolerated dose. White blood cell (WBC) and platelet toxicity were noted at doses of 1.6 mg/m2 and above. Median WBC and platelet nadirs occurred on approximately Days 11-12 with recovery by Days 15-18. Nonhematological toxicity included mucositis, nausea and vomiting, stomatitis, diarrhea, and rash. Evidence for antitumor activity was seen in seven patients. Trimetrexate elimination from plasma could be represented as either a bi- or triexponential process. Terminal elimination half-lives were in the range of 5-14 h in patients represented by a triexponential model. Approximately 10-20% of the dose administered was excreted in urine over a 24-h period. The recommended starting dose for patients in Phase II trials using the d x5 i.v. schedule is 8.0 mg/m2/d repeated every 21 days. Dose escalations may be possible depending on the extent of prior therapy and individual tolerance of the drug.

Fluoride toxicosis in wild ungulates.

To compare the occurrence of chronic fluoride toxicosis in wild and domestic animals in selected areas of Utah, Idaho, Montana, and Wyoming, deer, elk, and bison bones and teeth were collected for evaluation. Vegetation and drinking water samples also were collected, so that potential sources of fluoride could be evaluated. Deer, elk, and bison were found to be susceptible to the adverse effects of ingestion of excessive amounts of fluoride. Teeth and bones were primarily affected with characteristic lesions. Pathognomonic soft tissue changes were not observed. The animals had been exposed to a variety of sources of excessive fluoride, including water high in fluoride, forages contaminated by industrial effluents that were high in fluoride, vegetation contaminated with high fluoride-content soil by rain splash or wind, or a combination of these sources. Waters high in fluoride, especially from geothermal springs and wells, often contained appreciable amounts of various soluble salts. Evidence accumulated from specimens collected throughout the aforementioned states indicated that there are areas where chronic fluoride toxicosis is a problem for wildlife. These areas were where natural sources of fluorine (especially geothermal waters) provided amounts for ingestion that exceed species tolerance limits or were near certain industrial operations.

Effects of DDE, TDE, and PCBs on shell thickness of western grebe eggs, Bear River Migratory Bird Refuge, Utah--1973-74.

DDE, TDE, and polychlorinated biphenyls (PCBs) as Aroclors 1260 and 1254 were detected in low concentrations in eggs of western grebes (Aechmophorus occidentalis) from Bear River Migratory Bird Refuge, Utah. DDE was the only contaminant which was both negatively correlated with eggshell thickness and a significant variable in a multiple regression model for predicting eggshell thickness. The eggshell thickness index for western grebe decreased 2.3 percent from pre- to post-DDT-use periods. Incubation stage appeared to have no measurable correlation with eggshell thickness. The small amount of eggshell thinning seen in western grebe eggs at Bear River Migratory Bird Refuge appeared to have no detectable effect on reproduction.

Toxic, neurochemical and behavioral effects of dieldrin exposure in mallard ducks.

Toxic, neurochemical and behavioral alterations were evaluated in ducks fed various dietary levels of dieldrin. Increasing amounts of dieldrin in the diet caused an appreciable decrease in the levels of three biogenic amines in whole brain, i.e. serotonin, norepinephrine and dopamine. No effect was noted in whole brain gamma aminobutyric acid contents. Hepatic microsomal enzymes were assayed in these birds using p-nitroanisol and O-ethyl-O-p-nitrophenyl benzenethionophosphate as substrates. Sublethal amounts of dieldrin caused an increase in hepatic drug metabolizing enzymes. Similar alterations were noted in liver protein, deoxyribonucleic acid and ribonucleic acid contents. Studies involving encounters between mallard drakes indicated a decline in the tendency for dieldrin exposed drakes to take the initiative and establish rights of access in approach confrontations. Although many of these changes are compatible with life processes, their significance is not well understood, especially in terms of lifelong exposure to persistent pesticides. The possible relationship between neurochemical alterations and the mechanisms of insecticide neurotoxicity is discussed.

A phase I clinical trial of didemnin B.

Didemnin B is a depsipeptide extracted from the marine tunicate Trididemnin cyanophorum. This agent is a potent inhibitor of L1210 growth in vitro and has activity against murine B16 melanoma, P388 leukemia, and M5076 sarcoma in vivo. The results of preclinical toxicologic tests demonstrated abnormalities in clotting parameters thought to be secondary to drug-induced liver dysfunction. Thirty-five patients with advanced cancer received didemnin B according to a 5-day bolus schedule with dose levels ranging from 0.03 to 2.00 mg/m2/d. The dose-limiting toxicity was nausea and vomiting. Sporadic elevation of the hepatic enzyme level occurred but was not dose limiting. Two patients had anaphylactic symptoms possibly related to the 5% polyoxyethylated castor oil (Cremophor EL, BASF, Ludwigshafen, Germany) vehicle during the drug infusion. Clinical bleeding was not observed and myelosuppression was not significant. No partial or complete tumor responses were seen. The recommended Phase II dose for the 5-day schedule is 1.6 mg/m2/d.