Anorectal Malformation with Rectovestibular Fistula and Vaginal Agenesis: Usage of Rectovestibular Fistula as a Neovagina Followed by PSARP with Preservation of the Anal Sphincter.

Anorectal malformation with rectovestibular fistula associated with vaginal agenesis is rare. We report on a child in whom this combination was diagnosed at the age of 1 year. After creation of a divided descending colostomy, we chose to leave the rectum-rectovestibular fistula to function as a neovagina, while the sigmoid colon was relocated via modified posterior sagittal anorectoplasty. The colostomy was closed 6 months after the main surgery. After a follow-up of 3 years, the patient is continent for stool and urine. The introitus of the neovagina appears wide and easy to explore. We conclude that our surgical approach may be a good option for these children.

Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK).

Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26pmol/mg protein.