Buffering the stomach content enhances the absorption of diflunisal in man

Diflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p less than 0.05) shortened the time to reach peak plasma concentration (tmax greater than 15 per cent), raised maximum plasma concentration slightly (Cmax 6 per cent) and increased the area under the plasma concentration-time curve (AUC greater than 8 per cent). Other pharmacokinetic parameters, including terminal half-life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine. In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half-life of 12.8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89.5 per cent.     

Inter-study differences: How should they influence the interpretation and analysis of results?

In determining the role inter-study variation should play in an overview analysis, it is important to consider three factors: which question one is trying to answer; the degree of similarity or dissimilarity of design, and the degree to which heterogeneity of outcomes can be explained. Three questions one might be interested in are: whether treatment can be effective in some circumstances; whether treatment is effective on average, and whether treatment was effective on average in the trials at hand. Under the assumption of no qualitative interaction, the answers to these questions coincide. The O-E analysis most directly answers the third question. Other analyses are suggested when the first question is of interest, using the aspirin post-MI studies as an example.     

Alteration of cytochrome P-450 by prolonged administration of imipramine and/or lithium to rats

Summary The aim of this study was to investigate imipramine-induced alterations of cytochrome P-450 and to determine whether prolonged concomitant administration of imipramine and lithium results in a pharmacokinetic interaction.Male Wistar rats received imipramine (10 mg/kg i. p.) at 12 h intervals or lithium chloride (100 mg/kg in drinking water) or they were treated with the combination of these drugs for 2 weeks. The long term treatment with imipramine produced a very complex alteration of cytochrome P-450: imipramine increased the level of the cytochrome, but it decreased the rate of its own aromatic hydroxylation in position 2. The rate of N-demethylation in the side chain was not changed. Consequently, in the case of both hydroxylation and demethylation, calculated molecular activities were decreased to 48% and 70% respectively. This differential change in activities corresponded well to the observed decrease of absorption in difference spectra (type I) produced in microsomes by imipramine. Carbamazepine-induced type I difference spectra were also decreased by imipramine pretreatment, but to a lesser extent. In contrast, hexobarbital type I binding was increased by imipramine treatment while type II difference spectra produced by metyrapone were not affected. The preliminary SDS-PAGE analysis of cytochrome P-450 isoenzymes of control and imipramine treated rats showed that the investigated antidepressant markedly intensified a protein band at 50.11 kD while bands at 51.28 kD, 56.20 kD and 56.88 kD were less intensive. These results indicate that the alteration of cytochrome P-450 by imipramine treatment is not only of quantitative but also of qualitative character. Lithium alone given to rats affected neither the concentration of cytochrome P-450 in microsomal protein nor the rate of imipramine metabolism in vitro. Lithium given jointly with imipramine reduced imipramine-induced elevation of cytochrome P-450. This, however, did not cause any change in the rate of imipramine metabolism in vitro and accordingly in imipramine pharmacokinetics in vivo. The concentration of lithium in the blood plasma tended to increase by concurrent administration of imipramine.Send offprint requests to K. J. Netter at the above address     

Elevation of carbamazepine plasma levels by diltiazem in rabbits: a potentially important drug interaction

The effect of diltiazem on the plasma level of carbamazepine (CBZ) was investigated in rabbits. The animals were given either CBZ alone or in combination with diltiazem and plasma samples were collected at different time intervals. The concentration of CBZ was detected using an HPLC method. Diltiazem significantly increased the area under the curve (AUC), the maximum plasma concentration (Cmax), and the elimination half-life (t1/2) of CBZ (p less than 0.05). These results suggest that a potentially harmful drug-drug interaction may occur if CBZ and diltiazem are administered concurrently.     

The interaction of cocaine and alcohol on schedule-controlled responding

 Within a number of physiological preparations, the effects of alcohol and cocaine in combination are reported to be greater than the effects of either drug given alone. Little has been reported, however, on the behavioral effects of the interaction. The present study investigated this issue by assessing the effects of cocaine and alcohol (alone and in combination) on schedule-controlled responding. Specifically, rats were trained to respond on an FR20 schedule for a water reinforcer. They were then administered cumulative doses of cocaine or alcohol. Following this, subjects were administered ineffective doses of alcohol prior to further dose-response assessments with cocaine and with ineffective doses of cocaine prior to further dose-response assessments with alcohol. Cocaine and alcohol alone produced dose-related decreases in responding. Furthermore, the dose-response function for cocaine was shifted to the left by alcohol and the dose-response function for alcohol was shifted to the left by cocaine. An isobolographic analysis revealed that the interaction between cocaine and alcohol was additive in nature. The possible bases for the interaction (e.g., changes in cocaine pharmacokinetics by alcohol and the formation of cocaethylene following co-administration of cocaine and alcohol) were discussed. Received: 22 February 1996 / Final version: 23 August 1996     

Perceived occupational stress,affective, and physical well-being among telecommunication employees in Greece

The present study examined four potential roles of work-related negative affectivity on the associations between self-reported occupational stress and physical well-being among telecommunication employees in Greece. Participants (764, predominantly male) completed a battery of self-report measures on perceived occupational stress, negative affectivity, and illness symptoms. In line with previous research, negative affectivity exerted a nuisance effect, by inflating the association between reported stressors and illness symptoms, and significantly predicted illness symptoms, over and above the effects of stressors. In addition, negative affectivity influenced reported illness symptom indirectly, through the effects of stressors, and moderated the relationship between interpersonal conflict at work and illness symptoms. The findings suggest that negative affectivity can largely explain and influence in different ways the associations between self-reported stress and physical strain. It is recommended that future studies of occupational stress should control for the effects of negative affectivity, and that health professionals should be cautious of its effects when interpreting relationships between self-reported occupational stress and physical well-being.     

膳食纤维与不同蛋白质联用对大鼠胆固醇代谢的影响

观察４种膳食纤维在两种蛋白来源下，对高脂血症大鼠生长、血脂、肝胆固醇、粪类固醇及胆汁成分的影响。结果表明：①四种膳食纤维均可降低大鼠血清ＴＣ水平，尤以豆胶效果显著。②豆胶显著升高ＨＤＬ－Ｃ／ＬＤＬ－Ｃ。膳食蛋白为大豆蛋白时，豆胶、沙棘皮可显著升高血清ＨＤＬ－Ｃ、ＨＤＬ－Ｃ／ＴＣ。③豆胶显著减少肝胆固醇累积，两种沙棘皮与大豆蛋白联用降脂强于与酪蛋白共用。④蛋白来源显著影响粪类固醇的排出，纤维类型可影响中性固醇排出并与蛋白质有交互作用。提示：蛋白质与膳食纤维之间的交互作用是探讨营养素与脂质代谢不可忽视的因素。     

An association of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and common carotid atherosclerosis

Plasma homocysteine (Hcy) concentration has been shown to be influenced by a mutation in the gene coding methylenetetrahydrofolate reductase (MTHFR). Although plasma Hcy is related to atherosclerotic disorders, conflicting results have been reported about the association between MTHFR gene polymorphism and sclerotic lesions of the common carotid arteries. The effect of age–gene interaction on carotid arterial remodeling was investigated in elderly subjects with several risk factors for atherosclerosis. We evaluated sclerotic lesions of the common carotid arteries by ultrasonography in 326 patients (mean age ± standard deviation, 73 ± 12 years) and studied relations among the known risk factors for atherosclerosis, including MTHFR gene polymorphism and its interactions with age and sex. Of the 326 subjects studied, 136 had MTHFR genotype CC, 136 genotype CT, and 54 genotype TT. The three groups did not differ with respect to background factors such as age, history of cigarette smoking, blood pressure, lipids or uric acid, or in the incidence of atherosclerotic diseases. Spearman's rank correlation revealed a significant relationship between gender, age, Brinkman index, systolic blood pressure, triglycerides, HDL-cholesterol (HDL-C), uric acid, and MTHFR gene polymorphism. Multiple regression analysis using intima-media complex thickness (IMT) as a criterion variable and risk factors, including MTHFR gene polymorphism as explanatory variables showed that MTHFR gene polymorphism (P = 0.039) was a significant independent explanatory variable for IMT, along with gender (male) (P < 0.001), age (P < 0.001), systolic blood pressure (SBP) (P = 0.047), total cholesterol (T-C) (P < 0.001), and HDL-C (P < 0.001). Furthermore, a general linear model analysis revealed that interaction between age and MTHFR gene polymorphism was significantly associated with IMT, independently of age, SBP, T-C, and HDL-C in male subjects. However, age–gene interaction was not observed in female subjects. The findings of the present study confirm an association between MTHFR gene polymorphism and common carotid atherosclerosis in the Japanese population and further support the role of risk factor–gene interaction in common carotid atherosclerosis. Received: May 14, 2001 / Accepted: June 8, 2001