Hemming Poulsen

Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine

Objectives: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine.Methods:The study was carried out as an in vivo single-dose study including 24 young, healthy men. All volunteers had been identified as sparteine- and mephenytoin-extensive metabolisers. The volunteers received in randomised order, at weekly intervals, increasing single oral doses of one of the four SSRIs, followed 3 h later by sparteine (CYP2D6), mephenytoin (CYP2C19) and caffeine (CYP1A2) tests. Fluoxetine was given at 3-week intervals because of the long half-life of fluoxetine and its metabolite norfluoxetine. Citalopram, fluoxetine and paroxetine were given in doses of 10, 20, 40 and 80 mg and fluvoxamine was given in doses of 25, 50, 100 and 200 mg.Results:With increasing doses, there was a statistically significant increase in the sparteine metabolic ratio (MR) (P < 0.01, Page’s test for trend) for all four SSRIs. The increase was modest after intake of citalopram and fluvoxamine, while the increase was more pronounced after fluoxetine intake, although no volunteers changed phenotype from extensive metabolisers to poor metabolisers. Three of the six volunteers changed phenotype from extensive metabolisers to poor metabolisers after intake of 40 or 80 mg paroxetine. There was a statistically significant increase in the mephenytoin S/R ratio (P < 0.01, Page’s test for trend) with increasing doses of fluoxetine and fluvoxamine, but not after citalopram and paroxetine. However, no volunteers changed phenotype from extensive to poor metabolisers of S-mephenytoin. After intake of fluvoxamine, the urinary excretion of the metabolites related to N3 demethylation of caffeine were below the limit of quantification, whereas there were no significant changes in the urinary caffeine metabolic ratios after intake of the other three SSRIs.Conclusion:This investigation confirms that paroxetine and fluoxetine are potent inhibitors of CYP2D6, that fluvoxamine and fluoxetine are moderate inhibitors of CYP2C19 and that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo. The clinical prediction of interaction from single-dose experiments may have to take the degree of accumulation during steady-state after multiple doses into account.

Aspects of the Natural History of Gastrointestinal Bleeding in Cirrhosis and the Effect of Prednisone

The natural history of gastrointestinal bleeding in cirrhosis has been studied using prospectively collected data of 532 patients included in a randomized clinical trial with a regular follow-up of up to 12 yr. Of the total 199 patients who experienced gastrointestinal bleeding, 95 (48%) bled from esophageal or gastric varices, 67 (34%) bled from peptic ulcer or gastritis, and 37 (18%) had either insufficient evidence of the source (33) or mixed sources (4). In the total group of patients the cumulative percentage of patients in whom varices had been demonstrated of patients in whom varices had been demonstrated by radiography increased from 12 to 90 in 10 yr, while that of bleeding from varices increased from 7 to 40. In 104 patients who bled for the first time during the trial period (trial bleeding patients) the median number of bleeding episodes was one (range 1-8). In these patients the fatality from bleeding from varices was 82%. The risk of rebleeding from varices was 81%, and 4 yr after the first bleeding the cumulative survival had decreased to less than 10%. Rebleeding was significantly less frequent and survival significantly higher in patients bleeding from sources other than varices. Prednisone reduced the occurrence rate of varices, bleeding from varices, and death from bleeding varices in nonalcoholic females without ascites, 40% of whom fulfilled the histologic criteria of chronic active hepatitis. Prednisone significantly increased the occurrence rate of varices inpatient with ascites and of bleeding from varices in alcoholic patients. Prednisone significantly increased the occurrence rate of peptic ulcer in males and in patients without chronic active hepatitis.

Updating Prognosis and Therapeutic Effect Evaluation in Cirrhosis with Cox's Multiple Regression Model for Time-Dependent Variables

A multivariate Cox regression analysis with time-dependent variables has been performed on the data of 415 patients with cirrhosis included in a controlled clinical trial of 10-15 mg prednisone daily versus placebo. The analysis showed that a poor prognosis was associated with a low prothrombin index, marked ascites, GI bleeding, high age, high daily alcohol consumption, high bilirubin and alkaline phosphatase and low albumin values, little liver connective tissue inflammation, and poor nutritional status. Prothrombin index and ascites showed significant interaction with the treatment in such a manner that high prothrombin index and absence of ascites were associated with a beneficial effect of prednisone, whereas low prothrombin index and presence of ascites were associated with a harmful effect of prednisone treatment. The final model was validated in independent patients by comparing their actual survival with that predicted from the model, using a split-sample testing technique. The prognostic factors were combined with an index that can be used to update prognosis whenever changes occur in the clinical status of a patient during the course of the disease. The probability of surviving the next 3 or 6 months can be estimated from the prognostic index at any time during the course. The index may be of value for the correct timing of special therapeutic procedures such as liver transplantation.

Main causes of death in cirrhosis.

The main causes of 436 deaths among 532 patients with cirrhosis followed up for up to 16 years constituted liver failure (24%), liver failure with gastrointestinal bleeding (13%), gastrointestinal bleeding (14%), primary liver cell carcinoma (4%), other liver-related causes (2%), infections (7%), cardiovascular diseases (22%), extrahepatic malignancies (9%), and other non-liver-related causes (5%). Totally, 57% died of liver-related causes. A high frequency of liver-related death was found among patients with a short observation time, high biochemical activity, pronounced change in liver architecture, ascites, and other signs of a poor prognosis at the time of diagnosis. The findings favoured the hypothesis that cirrhosis of the liver is a disease with an initial active and a subsequent inactive phase. Half of the patients were treated with prednisone, but this had no detectable influence on the distribution of causes of or on the frequency of single causes of death as infections or gastrointestinal bleeding. The group of patients responding favourably to prednisone treatment with regard to survival (non-alcoholic women without ascites) showed causes of death not different from those of the total material.

Nitrate tolerance in vivo is not associated with depletion of arterial or venous thiol levels.

Results from in vitro experiments suggest that development of nitrate tolerance is due to a depletion of vascular thiol compounds (ie, cysteine and glutathione [GSH]) necessary for the bioconversion of organic nitrates. However, it is unknown whether in vivo tolerance development is associated with changes in thiol levels. This study measures plasma and vessel tissue GSH and cysteine levels in nontolerant rats, nitrate-tolerant rats, and rats treated with the two characteristically different thiol donors N-acetyl-L-cysteine and L-2-oxothiazolidine-4-carboxylic acid (OXO). Chronically catheterized conscious rats received an intravenous infusion of either nitroglycerin (NTG, 0.2 mg/h) or matching placebo for 3 days. At day 3, the hypotensive effect of 2.5 mg NTG/kg was decreased by 74 +/- 6% (mean +/- SEM, P < .05) in the NTG-treated group (n = 7), indicating the development of tolerance. No change in the hypotensive effect of NTG was seen in the placebo group (n = 6, P > .05). Hemodynamic tolerance is not associated with changes in aorta cysteine or GSH levels as compared with the placebo group (cysteine, 77 +/- 14 versus 57 +/- 11 [mean + SEM] nmol/g; GSH, 414 +/- 62 versus 399 +/- 89 nmol/g; P > .05). However, the increase in vascular thiol levels seen after OXO treatment in nontolerant rats is completely absent in nitrate-tolerant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal bile duct epithelium in chronic aggressive hepatitis and cirrhosis: A review of morphology and clinical, biochemical, and immunologic features

Abstract This paper describes the so-called abnormal bile duct epithelium seen in chronic aggressive hepatitis and cirrhosis as well as associated histologic changes. The epithelial changes are characteristic and easily recognized when one is familiar with them. The changes affect the bile ducts of medium size that are centrally located in the connective tissue. This type of abnormal bile duct epithelium differs from other previously described types of abnormal epithelium in bile ducts of the same size. The bile duct changes are probably of viral origin, possibly with a superimposed immunologic component. Patients with chronic aggressive hepatitis with abnormal bile duct epithelium develop cirrhosis more quickly and more frequently than do similar patients without it.

Malignant melanoma. Changing trends in factors influencing metastasis-free survival from 1964 to 1982

Seven hundred fourteen patients with cutaneous melanoma in clinical Stage I treated between 1964 and 1982 were included in this study. In an analysis of metastasis‐free survival, thickness of the tumor, ulceration, gender, epithelioid cells as predominant cells in the tumor, and localization of the tumor were found to be independent prognostic factors. In a time trends analysis, the distributions of three of the prognostic factors (thickness of the tumor, ulceration, and inflammatory cell infiltrate) were found to shift during the last decade in the direction of improved prognosis, indicating that tumors are detected earlier than before. The distributions of two other factors (cell type and location of the tumors) shifted in the direction of deteriorated prognosis, suggesting partly that the biologic nature of the disease may have changed and partly that other behavioral factors may have played a role.

Interaction of smoking, uptake of polycyclic aromatic hydrocarbons, and cytochrome P450IA2 activity among foundry workers.

An increased lung cancer risk has been described among foundry workers. Polycyclic aromatic hydrocarbons (PAHs) and silica are possible aetiological factors. This study describes a urinary PAH metabolite, 1-hydroxypyrene (hpU), as well as the degree of cytochrome P450IA2 activity/induction as reflected by the urinary caffeine ratio (IA2) in 45 foundry workers and 52 controls; IA2 was defined as the ratio of paraxanthine 7-demethylation products to a paraxanthine 8-hydroxylation product (1,7-dimethyluric acid). Mean exposure concentrations for foundry workers were defined by breathing zone hygienic samples (respirable dust 1.2 to 3.52 mg/m3 (93 samples)) and as total PAH (0.46 micrograms/m3) and pyrene concentrations (0.28 micrograms/m3) (six samples). Non-smoking controls and foundry workers had similar IA2 ratios (5.63, 95% confidence interval (95% CI) 4.56-6.70 and 4.40, 95% CI 3.56-5.24). The same was true for smoking controls and foundry workers (9.10, 95% CI 8.00-10.20 and 8.69, 95% CI 7.37-10.01). Both smoking groups had raised IA2 ratios compared with non-smokers (p less than 0.01). Non-smoking controls and foundry workers had similar hpU concentrations (0.16, 95% CI 0.10-0.22 and 0.11, 95% CI 0.09-0.13 mumol/mol creatinine). Smoking foundry workers had raised hpU concentrations (0.42, 95% CI 0.25-0.59) compared with smoking controls (0.26, 95% CI 0.18-0.34) (p less than 0.01). A small subgroup of smoking foundry workers with the highest exposures to both silica and PAH also had the highest hpU concentrations (0.70, 95% CI - 0.07-1.47 mumol/mol creatinine) (p less than 0.04). Increased hpU concentrations in smoking foundry workers suggest a more than additive effect from smoking and foundry exposures resulting in increased PAH uptake. Increased P450IA2 enzyme activity was only found in smokers and no additional effect of foundry exposures was seen. These data suggest that smoking as well as work related PAH exposure may be casually related to increased risk of lung cancer in foundry workers.

Influence of dose and route of administration on disposition of metronidazole and its major metabolites

SummaryThe influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p<0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.

The hepatic glutathione content in liver diseases

We measured the total glutathione content in 38 liver biopsies from patients undergoing diagnostic liver biopsy to study whether liver diseases result in decreased glutathione content making the liver more sensitive to different toxic damages. The glutathione concentrations ranged from 20.2 to 41.0 mumol/g hepatic protein in six biopsies without light microscopic pathological changes (mean +/- SD = 26.9 = +/- 8.1). The mean concentrations +/- SD in patients with toxic hepatitis (n = 3), viral hepatitis (n = 4), chronic active hepatitis (n = 4), cirrhosis (n = 14) and steatosis (n = 7) were 62.5 +/- 27.2, 47.4 +/- 25.9, 38.3 +/- 17.0, 29.1 +/- 15.7 and 21.0 +/- 9.6, respectively. The hepatic glutathione content is not decreased in patients with moderate hepatic impairment.