This study demonstrates that local colonic application of tacrolimus 2-4 mg daily in patients with refractory distal colitis is feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial.

The effects of quinidine on oxidative routes of drug metabolism mediated by different forms of cytochrome P450 were investigated in 10 healthy subjects. Each subject was studied on three different occasions and separately received oral administration of (1) a "cocktail" of nifedipine (5 mg), sparteine sulfate (90 mg), and mephenytoin (100 mg), (2) quinidine sulfate (200 mg), and (3) quinidine sulfate followed by the "cocktail" 1 hour later. Quinidine pretreatment significantly inhibited the aromatization of nifedipine to its major first-pass pyridine metabolite (M-0) and prolonged the elimination half-life of the calcium channel antagonist, both by about 40%. More marked inhibition of metabolism was observed with sparteine, and the formation of dehydrosparteine was abolished. A significant correlation was found between the 0-8-hour urinary ratio and the plasma concentration ratio of sparteine to dehydrosparteine obtained 4 hours after drug administration. No quinidine-induced changes were observed in the 4-hydroxylation of mephenytoin. The interaction between quinidine and nifedipine supports the involvement of a common P450 (P450IIIA4) in the metabolism of the two drugs. (CLIN PHARMACOL THER The rate of drug oxidation in humans often exhibits pronounced interindividual variability that is related to the activities of various cytochrome P450 enzymes. In recent years, a number of different forms of this monooxygenase have been purified and characterized at the biochemical and molecular levels.' However, a major problem exists in vivo, namely, the identification of which specific form(s) of P450 is involved in the metabolism of a particular drug and the relative contribution of each in the overall process. Several approaches have been taken to resolve this problem, including the use of model substrates administered either individually or as a "cocktail" containing several

Terminally ill patients suffering from intractable cancer pain are treated in our hospital on an outpatient basis with a percutaneous intrathecal (i.t.) catheter and a portable pump delivering morphine continuously. In a patient showing an increased demand of morphine the dose was raised from 1.5 to 2 mg/h, but pain intensity did not decrease. Subsequently a 1.5 ml dose of 5% lidocaine was administered; however, no motor or sensory block was observed. After controlling the catheter position and passage through the catheter, a sample of cerebrospinal fluid (CSF) was taken and the pH was measured. It was found to be outside the physiological range of 7.19 (normal range: 7.27-7.37), possibly explaining the decreased activity of the local anesthetic. The purpose of this study was to determine the influence of morphine, with or without sodium metabisulfite, on pH in vitro, using artificial CSF (ACSF) and on pH in vivo during i.t. administration of morphine. An in vitro model was used to measure pH changes by adding a morphine solution (concentrations of 0.5, 2, 5 and 10 mg/ml) with and without sodium metabisulfite to ACSF solutions (Elliott B). Fourteen patients were consecutively selected for continuous administration of morphine. An i.t. catheter was inserted, tunnelled and connected with an external pump (Provider 5500, Abbott, Chicago, IL). CSF was aspirated and pH was measured with a blood-gas system (Ciba-Corning 288, Medfield, USA). In vitro, morphine solutions with or without sodium metabisulfite added to an Elliott B solution (pH = 7.47, 37 degrees C) caused a concentration-related decrease in pH.(ABSTRACT TRUNCATED AT 250 WORDS)

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