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.     

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.     

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     

Experimental determination of the kinetics of calcium-binding with chondroitin sulphate and the effects of uric acid on this process

Summary The calcium-binding kinetics of chondroitin sulphate C (CS) have been determined using equilibrium analysis including ⁴⁵Ca. There is a linear relationship between the extent of the Ca binding and the concentration of CS present. 1 mol CS disaccharide unit binds 0.757 mol Ca. Scatchard plots of the data have revealed a single constant of dissociation (K _D =1429). In the presence of urate ions, and dependent on the pH value, the ability of CS to bind Ca may be impaired by as much as 31%. These measurements have supported the theory that urate ions interact with the GAGs in urine.     

Interactions between the putative calcium entry promotor Bay k 8644 and pressor responses produced by α-1 and α2-adrenocepter agonists in the pithed normotensive rat

Summary Interactions between the putative calcium entry promotor Bay k 8644 and both -₁ and ₁-adrenocepter mediated increases in diastolic pressure were studied in the pithed normotensive rat. The ₁-adrenocepter mediated pressor responses elicited by B-HT920, TL-99, DP-6,7-ADTN and B-HT958 were potentiated by Bay k 8644, reflected by a leftward shift and an increase in the maximum of the log dose-pressor respinse curves. The -₁-adrenocepter effects elicited by cirazoline, methoxamine, (–)-amidephrine, St 587, (–)-phenylephrine and Sgd 101/75 were less enhanced by Bay k 8644. Only a leftward shift of the dose-response curves was observed, which was most pronounced for (–)-phenylephrine and Sgd 101/75. The -₁ and ₂-adrenocepter pressor components of (–)-noradrenaline were similarly distinguished by Bay k 8644 as observed for the selective -₁ or ₂-adrenocepter agonists.Effects of Bay k 8644 on the increase in diastolic pressure mediated by B-HT 920, St 587 and cirazoline were also studied after pretreatment with the calcium entry blocker nifedipine. After additional pretreatment with nifedipine the potentiation by Bay k 8644 observed for B-HT 920 and St 587 was more pronounced. The presence of nifedipine had no effect on the interaction between Bay k 8644 and cirazoline.It is concluded that Bay k 8644 behaves as a mirror image of nifedipine. The observation that Bay k 8644 enhances ₂-adrenocepter mediated pressor effects more effectively than ₁-adrenocepter increases in diastolic pressure is in accordance with the hypothesis of the more pronounced calcium dependency of ₂-adrenocepter mediated pressor responses. The data obtained for ceptor mediated pressor responses. The data obtained for St 587 and (–)-phenylephrine are in apparent contradiction to the finding that the pressor responses to the former drug are more markedly inhibited by calcium entry blockade than those of the latter. It is suggested that St 587 employs calcium channels which are already maximally modulated and that (–)-phenylephrine makes use of calcium channels which are in a rather inactive state. The hypothesis is put forward that the intrinsic activity of ₂-adrenocepter agonists reflects their ability to bring calcium channels in an active state.