New biodegradable networks of poly(N-vinylpyrrolidinone) designed for controlled nonburst degradation in the vitreous body.

Polymers of N-vinylpyrrolidinone (NVP) are known to have excellent biocompatibility when implanted in the vitreous body or used as a vitreous substitute. Although poly(NVP) is capable of absorbing relatively large amounts of water, it is not prone to hydrolysis. Yet intraocular degradation of several crosslinked poly(NVP) hydrogels has been reported recently, but some ambiguity remains about the exact mechanism of degradation of these materials. To date there is no biomaterial that combines the excellent intraocular biocompatibility on the one hand and controlled kinetics of degradation on the other hand. We attempted to design and prepare such materials through the chemical synthesis of a novel dimethacrylate crosslinker molecule. The essential feature of this molecule is that its core contains two carbonate groups, which are evidently susceptible to hydrolytic scission. We studied a series of 3-dimensional networks of poly(NVP), which were crosslinked by this molecule. This approach offers several advantages: the hydrolysis of the carbonate groups in the crosslinks leads to liberation of poly(NVP) and/or oligo(NVP) chains that can probably be cleared from the eye via phagocytosis; hydrolysis generates two alcohols and CO(2) (i.e., there is no catalytic burst effect); when these materials are implanted in dry form, swelling and degradation will progress from the exterior of the material toward its interior. Therefore, these materials can be designed such that surface degradation rather than bulk degradation occurs; the hydrolysis rate can be controlled via the crosslink density or through synthesis of other crosslink molecules with either more (>2) or less (1) carbonate groups or alternatively with one or more other labile groups. We report on the chemical synthesis of the crosslinker molecule, as well as the preparation and degradation of a series of poly(NVP)-based hydrogels in vitro and in vivo (rabbit eyes). We found that these materials indeed displayed excellent biocompatibility in the rabbit eye. Further, the experiments confirmed that degradation occurs without the burst effect. The results are in line with the idea that the rate of intraocular swelling and degradation depends on the crosslink density, but this is only a preliminary conclusion that must be strengthened by much more experimental work. Nonetheless, we foresee several applications of these or related materials in ophthalmology, for example, as biodegradable matrix materials for controlled drug delivery of ganciclovir in the vitreous body.

Phase II study of elsamitrucin in non-small cell lung cancer.

Elsamitrucin (BMY-28090) a novel fermentation product has demonstrated pre-clinical anti-tumour activity against a number of cell lines. The dose limiting toxicity in phase I studies was a reversible increase in hepatic transaminase. This study was initiated to determine the activity of elsamitrucin in patients with previously untreated, bi-dimensionally measurable, cytologically or histologically proven, non-small cell lung cancer who were not curable by surgery. Elsamitrucin at a dose of 25 mg/m2 was administered intravenously over 5-10 min weekly for a minimum of 6 weeks. Seventeen patients were entered on study, 15 were evaluable for toxicity and 14 evaluable for response. No responses were documented in the 14 patients evaluable for response. Both hematological and non-hematological toxicities were mild to moderate in severity. The commonest being nausea, vomiting, lethargy and local skin reactions at the site of the infusion. These results indicate that elsamitrucin when given in this dose and schedule to patients with surgically incurable non-small cell lung cancer has no activity.