No abstract

Silibinin, the main constituent of silymarin, a flavonoid drug from silybum marianum used in liver disease, was tested for inhibition of human cytochrome P-450 enzymes. Metabolic activities were determined in liver microsomes from two donors using selective substrates. With each substrate, incubations were carried out with and without silibinin (concentrations 3.7-300 mM) at 37ae in 0.1 M KH 2 PO 4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by HPLC or direct spectroscopy. First, silibinin IC 50 values were determined for each substrate at respective K M concentrations. Silibinin had little effect (IC 50 Ͼ200 mM) on the metabolism of erythromycin (CYP3A4), chlorzoxazone (CYP2E1), S(π)-mephenytoin (CYP2C19), caffeine (CYP1A2) or coumarin (CYP2A6). A moderate effect was observed for high affinity dextromethorphan metabolism (CYP2D6) in one of the microsomes samples tested only (IC 50 Ω173 mM). Clear inhibition was found for denitronifedipine oxidation (CYP3A4; IC 50 Ω29 mM and 46 mM) and S(ª)-warfarin 7-hydroxylation (CYP2C9; IC 50 Ω43 mM and 45 mM). When additional substrate concentrations were tested to assess enzyme kinetics, silibinin was a potent competitive inhibitor of dextromethorphan metabolism at the low affinity site, which is not CYP2D6 (K i,c Ω2.3 mM and 2.4 mM). Inhibition was competitive for S(ª)-warfarin 7-hydroxylation (K i,c Ω18 mM and 19 mM) and mainly non-competitive for denitronifedipine oxidation (K i,n Ω9 mM and 12 mM). With therapeutic silibinin peak plasma concentrations of 0.6 mM and biliary concentrations up to 200 mM, metabolic interactions with xenobiotics metabolised by CYP3A4 or CYP2C9 cannot be excluded.

The surgical results of transthoracic en bloc esophagectomy and high intrathoracic esophagogastrostomy performed on 109 consecutive patients are presented. Adenocarcinoma was present in 59 patients, squamous cell carcinoma in 45 patients, and other neoplastic lesions of the esophagus in 5 patients: 29.5% of the patients received neoadjuvant radiochemotherapy or chemotherapy alone. In 35% of the patients, the preoperative risk was classified as normal, whereas in 42% and 23% of the patients the preoperative status was compromised or severely impaired, respectively. On average 33 lymph nodes were dissected from each specimen. The postoperative course was uneventful in 60% of the patients and prolonged or severe in 40% of the patients. The hospital mortality was 5.5% (six patients). Nine patients (8.2%) developed anastomotic leakage. Six of these nine patients were discharged after rethoracotomy and reanastomosis ( n=3) or endoscopic treatment with fibrin glue ( n=3). Three patients died despite rethoracotomy and reanastomosis. Only 2 of 103 discharged patients (1.9%) underwent postoperative endoscopic bougienage two or three times because of an anastomotic stenosis. High intrathoracic esophagogastrostomy is a safe anastomosis, which nevertheless requires diligent postoperative management.

Infiltration of lymph nodes in the hepatoduodenal ligament is the most important prognostic factor following R0 resection of colorectal liver metastases.