Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21-28 days. Thirteen patients have received a total of 24 courses (median 2; range 1-3). At the starting dose of 40 mg/m2 doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 1/5 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 mg/m2 DOXeq. Hepatotoxicity was noted in 5/5 patients (1 x WHO grade IV, 1 x WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 x WHO grade IV, 2 x WHO grade III). At 12.5 mg/m2 DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 micrograms/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83-80.21 micrograms/ml*h with dose-dependent elimination half lives (t1/2 alpha: 0.02-0.87 h; t1/2 beta: 2.69-11.58 h; t1/2 gamma: 41.44-136.58 h).(ABSTRACT TRUNCATED AT 250 WORDS)

A 22-year-old man attempted to commit suicide by swallowing an unknown amount of barium carbonate dissolved in hydrochloric acid. Shortly after ingestion, he developed crampy abdominal pain and generalized muscle weakness. About 2 h later, respiratory failure ensued necessitating orotracheal intubation and mechanical ventilation. Concomitantly, life-threatening arrhythmias including ventricular fibrillation occurred, and he had to be resuscitated for 45 min. After correction of severe hypokalemia (serum potassium 1.5 mmol/l), cardiac rhythm stabilized. In an attempt to accelerate removal of barium from the circulation hemodialysis was begun. During hemodialysis muscle strength returned. Pharmacokinetic analysis of serum barium levels suggest that hemodialysis shortened the serum half-life of barium. Subsequently, the patient made a complete and uneventful recovery. Our case demonstrates that severe barium poisoning can be survived provided that early aggressive therapeutic measures are undertaken. Hemodialysis seems to be efficacious in the therapy of barium intoxication.

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