No abstract

The ascomycin macrolactam pimecrolimus is a novel inflammatory cytokine release inhibitor that so far has not been administered systemically to humans. In this phase I/II randomized double-blind, placebo-controlled, multiple rising dose proof of concept study psoriasis patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation but no changes in gene expression linked to drug-related side-effects. A steady state of pimecrolimus was reached after 5-10 d, Cmax, and area under the curve (0-24) was 54.5 ng per ml and 589.9 ng h per ml, respectively, at steady state at the highest dose. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a reduction of Psoriasis Area and Severity Index by 60% and 75%, respectively. Histopatho logically and immunopathologically there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. We conclude that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated and this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases.

Enterocutaneous fistulas (ECFs) are a complex topic in terms of classification. ECF-related morbidity and mortality can be high due to fluid loss and electrolyte imbalance, sepsis, and malnutrition. Most prognostic factors influencing the outcome of ECF are now well-known. ECF treatment is complex; and, based on various situations, it can be surgical or conservative/ medical. Depending on fistula site and nutritional status, clinicians have to decide whether total parenteral or enteral nutrition should be established. In cases where total parenteral nutrition alone for 7 days has failed to influence the high output fistulas, overall data support the use of adjuvant drug, somatostatin, or its synthetic analogue, octreotide. Somatostatin 250 microg/d and octreotide 300-600 microg/d have been tried along with total parenteral nutrition to decrease the healing time of ECFs and to reduce the number of complications.