Parenteral formulation and thermal degradation pathways of a potent rebeccamycin based indolocarbazole topoisomerase I inhibitor.

The development of a practical and pharmaceutically acceptable parenteral dosage form of 1 is described. A cosolvent formulation strategy was selected to achieve the necessary human dose of 1 for administration via intravenous infusion. The final market formulation of 1 chosen for commercial development and Phase II clinical supplies was the topoisomerase inhibitor dissolved in a 50% aqueous propylene glycol solution vehicle with 50mM citrate buffered to pH 4. The thermal degradation pathways of 1 in this aqueous propylene glycol vehicle in the pH range of 3-5 were determined by relative kinetics and degradation product identification using LC/MS, LC/MS/MS, and NMR analysis. The primary mode of degradation of 1 in this aqueous cosolvent formulation is hydrolysis affording the anhydride 2 (in equilibrium with the dicarboxylic acid 3) and release of the hydrazine diol side chain 11. Subsequent oxidative degradation of 11 occurs in several chemical steps which yield a complicated mixture of secondary reaction products that have been structurally identified.

Management of mandibular osteoradionecrosis corresponding to the severity of osteoradionecrosis and the method of radiotherapy.

PURPOSE: : To demonstrate appropriate treatment methods for mandibular osteoradionecrosis (ORN) by evaluating previous results. METHODS: : The relationship between the time interval after radiation therapy (RT) and the severity of ORN was examined. Eighty-seven patients were classified according to the extent of the lesion (grades), and the cure rates were calculated according to the RT modality, the grade, and the treatment method for ORN. RESULTS: : The later ORN developed and the higher the dose of irradiation, particularly among the patients who received external RT, the more it progressed. The initial cure rates for conservative management, marginal, and segmental mandibulectomy were 39.7%, 50%, and 86.7%, respectively. CONCLUSIONS: : Conservative management should be limited to early-onset ORN after brachytherapy with or without a low dose of external irradiation. Marginal mandibulectomy is appropriate for the late-onset ORN after brachytherapy with or without low-dose external irradiation. Segmental mandibulectomy is required for late-onset ORN after a high dose of external irradiation.