A Novel Topical PPARγ Agonist Induces PPARγ Activity in Ulcerative Colitis Mucosa and Prevents and Reverses Inflammation in Induced Colitis Models.

Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPARγ agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods: Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPARγ-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPARγ agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis. Results: AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-α, IL-1ß, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-α, IL-1ß, and IL-13 levels. Conclusions: AS002 triggers anti-inflammatory PPARγ activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.

Isolated hepatic perfusion for liver metastases of malignant melanoma.

The objective was to analyze the outcome of three treatment strategies using isolated hyperthermic liver perfusion (IHP) with melphalan for liver metastases of malignant melanoma. It was designed as an exploratory study. The setting was a single-center study in a university hospital. The study was carried out on 27 patients. IHP was used with modifications during three different time periods (IHP I, IHP II and IHP III), in technique and temperature (amount of melphalan: 0.5, 1.0 and 2 mg/kg body weight in the perfusate; 41, 40 and 40 degrees C). Tumor response was estimated according to WHO criteria with computed tomography or MRI. Mortality and morbidity were secondary measures. Six of 11 patients in the IHP I cohort experienced a partial response (PR). In the IHP II cohort, two patients of 11 experienced a complete response and five a PR. In the IHP III cohort, five of five patients experienced a PR. Six postoperative deaths were reported (27%) (three in the IHP I and three in the IHP II series), secondary to liver insufficiency and multiorgan failure. Treatment of liver metastases of malignant melanoma with isolated hyperthermic melphalan perfusion has shown an impressive tumor response rate, which seems to be higher than the response rates reported for other systemic chemotherapy regimens. The maximum tolerated dose for melphalan in the perfusate was surpassed with a 2 mg/kg body weight. By modifying the technique and restricting the allowed tumor burden, the response rate remained high and the mortality was reduced.