Doxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60, 60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions.

1. The dispositions of two acetylcholinesterase reactivators, pyrimidoxime and HI6, labelled with 14C on the oxime group, have been studied in normal rats and rats poisoned by the organophosphates Soman and A4. 2. For both compounds, and for healthy and poisoned rats, radioactivity was eliminated essentially in the urine (85% dose in 24 h). Faecal elimination was low (4% in 72 h). 3. Both compounds were concentrated in kidney and mucopolysaccharide-containing tissues such as cartilage and intervertebral disc. Soman and A4 poisoning do not modify the kinetic parameters of pyrimidoxime, but A4 poisoning increases HI6 tissue concentration. 4. Chromatography of urine and plasma showed only unchanged pyrimidoxime in both healthy and poisoned animals. In contrast, HI6 in plasma and urine was strongly degraded by scission of the quaternary ammonium bond, and formation of 2-pyridine aldoxime.

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