Thirty dogs with spontaneously occurring malignant neoplasms were treated monthly with carboplatin (CBDCA) given as a 30-minute intravenous infusion in a dose escalation study. Twenty-eight dogs were considered evaluable for toxicity. The maximally tolerated dose of CBDCA was conceptually defined as that dose, determined by logistic regression analyses of toxicity data, resulting in a 50% incidence of moderate toxicity (MOD,) or a 5% incidence of severe toxicity (SEV,). Each designated maximally tolerated dose was calculated for the first course of treatment only and for the first and second courses of treatment combined to estimate cumulative drug toxicity. The MOD, and SEV, for the first treatment course were 340 and 278 mg/MZ, respectively. MOD, and SEV, values for the first plus second treatment courses were 327 and 231 mg/MZ, respectively. The nadir of neutrophil and platelet counts occurred approximately 14 days after treatment. The mean neutrophil and platelet values for all dogs experiencing myelosuppression during the first two treatment courses were 1541 /pL and 62,600/& respectively. Nonparametric pharmacokinetic analysis of plasma CBDCA values suggested that half-life (T,,2), area-under-the-curve and total body clearance (CL,) were not dose dependent. Volume of distribution (VD,) significantly increased with dose only between 100 and 150 mg/M2, not between 150 and 300 mg/M2. Dose-independent serum CBDCA pharmacokinetic disposition indicates that detailed investigation of tissue CBDCA distribution would be warranted and may identify novel dosing strategies that could improve the therapeutic index of CBDCA by minimizing toxicity. IN PEOPLE, cis-diammine-1,1 -cyclobutane dicarboxylate platinum (11) carboplatin* (CBDCA, JM-8) is a second generation platinum compound that differs from cisplatin (CDDP) in its pharmacological properties and pattern of toxicity without reduction in clinical efficacy.
The protein binding of timegadine to albumin, serum, plasma and plasma enriched with the acute phase reactants alpha 1‐acid glycoprotein, alpha 1‐anti‐trypsin and C‐reactive protein was determined by equilibrium dialysis. The effects of other analgesic and anti‐ inflammatories (indomethacin, ketoprofen, paracetamol and sodium salicylate) and other basic drugs (disopyramide, lignocaine, propranolol and quinidine) on the binding of timegadine were also determined. Timegadine binding was concentration‐dependent up to 0.5 micrograms/ml, but independent above this level up to 10.0 micrograms/ml, the mean and standard error being 93.8 +/‐ 0.5%. Albumin accounted for only 32.4% of timegadine bound to plasma. Plasma enrichment with the acute phase reactants led to significant increases in timegadine binding. Simultaneous dialysis with other drugs caused significant decreases in timegadine binding.
A 250 mg tablet of timegadine was given twice daily for 15 days to 13 healthy volunteers. On Day 16 a single morning dose of timegadine was supplemented by two 200 mg tablets of a proprietary brand of ibuprofen. Serum concentrations of timegadine were measured by high pressure liquid chromatography, and steady state was achieved between Days 5 and 8. Serum concentrations of two metabolites of timegadine, MI and MII were measured by thin layer chromatography by Leo Pharmaceutical Products, Denmark. Ibuprofen did not significantly affect the serum half-time of timegadine, but did reduce the maximum measured serum timegadine concentration, the area under the serum concentration versus time curve and the time to achieve maximum measured serum concentration. Serum liver enzymes remained within the normal ranges and there were no changes in hepatic microsomal enzyme activity as assessed by urinary excretion of D-glucaric acid.
The effects of food ingestion on the absorption of timegadine, a recently synthesised non‐steroidal anti‐inflammatory drug, was studied in ten healthy volunteers. It was found that food enhanced the absorption of timegadine as shown by increased peak plasma concentrations (Cmax), decreased time taken to achieve these concentrations (tmax), and increased area under the plasma concentration time curve (AUC).
The effects of metolazone on the protein binding of glibenclamide were studied. It was found that increasing metolazone concentrations up to 100 ng/ml had no significant effect on the protein binding of glibenclamide studied at 10 micrograms/ml. Metolazone is unlikely to cause a clinically significant increase in the free fraction of glibenclamide in patients receiving both drugs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.