Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers.

Orlistat, an inhibitor of gastrointestinal lipases, limits the absorption of ingested fat and could become a potential treatment for obesity. This analysis was performed to elucidate the relationship between orlistat dose and intensity of inhibition of dietary fat absorption (assessed by measuring fecal fat excretion). In 11 phase I double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or matching placebo three times a day for 9 to 10 days. The results of the daily mean fecal fat excretion percentage (relative to ingested fat) were correlated to the orlistat daily dose. A simple maximum-effect model that included a basal value was used to fit the dose-response relationship for all evaluable subjects. The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration. The orlistat daily dose that produced 50% of the maximum effect was 98 mg/day. The model-fitting suggests the existence of a steep portion of the dose-response curve up to approximately 400 mg/day, with a subsequent tendency to plateau at higher doses. Such an analysis was instrumental in identifying appropriate doses to be used in therapeutic trials for weight loss in obese patients.

Nephropathy-gonadal dysgenesis, type 2: renal failure in three siblings with XY dysgenesis in one.

The nephropathy-XY gonadal dysgenesis syndrome in a 17-year-old phenotypical female with focal glomerulosclerosis was associated with renal failure in two sisters, one with crescentic glomerulonephritis at 27 months, and one with membranoproliferative glomerulonephritis at 10 years. Neither the propositus or the siblings had the distinctive mesangial sclerosis of nephropathy-XY dysgenesis, type 1 (Drash syndrome). The association of nephropathy-XY dysgenesis with familial nephritis of heterogeneous pathology suggests that nephropathy-XY dysgenesis, type 2, may relate to separate genetic loci for XY dysgenesis and glomerulopathy or reflect a loss of protection against familial renal disease when the Y chromosome is absent or defective.