Phase I clinical and pharmacokinetic study of zeniplatin, a new platinum complex.

Forty-six patients with refractory solid malignancies received the new platinum complex [2,2-bis(aminomethyl)-1,3-propanediol-N-N'] [1,1-cyclobutanedicarboxylato] [(2-)0,0')] platinum (zeniplatin). Zeniplatin was given, without hydration or mannitol, as a 60- to 90-min i.v. infusion every 3 weeks at doses ranging from 8 to 145 mg/m2. The maximum tolerated dose of zeniplatin was 145 mg/m2. The dose-limiting toxicity of zeniplatin was dose-related leukopenia and neutropenia, with the nadir usually observed between 1 and 2 weeks after therapy and recovery usually occurring by 3 weeks after therapy. Thrombocytopenia was rare. The most prominent non-hematological side-effect of zeniplatin was nausea and vomiting. Other non-hematological side-effects were mild or absent. Zeniplatin did not induce significant neurological or auditory toxicity. Zeniplatin was not nephrotoxic at doses less than or equal to 120 mg/m2. At 145 mg/m2, the clearance decreased by a mean of 40% after 2 cycles of therapy. Two patients, one with malignant melanoma and one with renal cell cancer, achieved a partial response. Pharmacokinetics of free (plasma ultrafiltrates) and total platinum in plasma were determined in 5 patients. An in vitro study of the rate and extent of zeniplatin binding to protein in human plasma was also performed. Free and total platinum were measured by flameless atomic absorption spectrometry; free zeniplatin was measured in ultrafiltrate by HPLC. Total and free plasma platinum concentrations were co-modelled using the information from the in vitro study.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine and codeine are endogenous components of human cerebrospinal fluid.

We have examined cerebrospinal fluid (CSF) from twelve patients who were not on any medication and found them to contain both morphine and codeine in concentrations of 2 to 339 fmol/ml. These are comparable to the concentration of opioid peptides in spinal fluid. Both morphine and codeine are present mainly in conjugated form from which the free alkaloids can be released by acid hydrolysis.

Serum protein binding of a new oral cephalosporin, CL 284,635, in various species.

CL 284,635 is a new third generation oral cephalosporin. Its serum protein binding was investigated in the human, monkey, dog, rat, and rabbit. This study was performed by using an equilibrium dialysis and ultrafiltration method, using radiolabeled and cold CL 284,635. In humans, CL 284,635 was found to have a mean free fraction [fu = concentration of unbound (free) drug divided by total concentration of unbound plus bound to serum proteins] of 31.3 +/- 3.3% with no serum concentration dependency in a range of 0.5 to 26 micrograms/ml. The drug was mainly bound to albumin. In rabbits and monkeys the protein binding profile of CL 284,635 was found to be 36.1 +/- 2.3% and 33.9 +/- 1.5% with no serum concentration dependency. In rats and dogs a non-concentration-dependent fu was observed at serum concentrations ranging from 0.5 to 30 micrograms/ml. A gradual increase in fu values was observed at higher serum concentrations of CL 284,635. Overall, the protein binding profile of CL 284,635 was found to be different in the five investigated species. The protein binding of CL 284,635 in monkeys and rabbits was most similar to that in humans. These species differences in protein binding may have an impact on the disposition of the drug in different species.

Isolation of morphine from toad skin.

A nonpeptide opioid was found in toad skin and purified to homogeneity by using HPLC with electrochemical detection. A nonpeptide opioid also was detected in bovine brain and adrenals as well as rabbit and rat skin, by reversed-phase HPLC following Sephadex G-15 column chromatography. The material in toad skin was identical to morphine by immunological, pharmacological, and physical chemical criteria.

Presence of endogenous morphine in toad skin.

Morphine was identified by immunological, pharmacological and physical criteria to be present in the skin of toad, rat and rabbit.