Inhibition of Nifedipine Metabolism in Dogs by Erythromycin: Difference between the Gut Wall and the Liver

The purpose of this study was to evaluate possible interaction of nifedipine with erythromycin or rokitamycin in the intestinal mucosa. Male beagle dogs were orally administered nifedipine (10 mg), with or without oral pre-medication with erythromycin (300 mg), and 300 mg erythromycin or rokitamycin twice a day for 3 days. The experiments were of randomized cross-over design with a two-week wash-out period between dosing regimens. Erythromycin pre-medication for 3 days resulted in a significant increase in the area under the serum nifedipine concentration-time curve (AUC), whereas the curve for one nifedipine metabolite (M-2) decreased significantly. When the effects of erythromycin on the metabolism of nifedipine were studied using dog liver microsomes it was found that erythromycin significantly inhibited formation of M-2 but not of the metabolite M-1. These results indicate that formation of M-2 from M-1 in the liver might be reduced by erythromycin premedication. To avoid possible metabolism in the gut, the dogs were then administered 8 mg nifedipine into the peritoneal cavity, with or without multiple dose pre-treatment with erythromycin for 3 days. After intraperitoneal administration of nifedipine, the maximum concentration (C_max) of nifedipine increased significantly. After pre-administration of erythromycin the relative bioavailability of nifedipine after oral administration was increased compared with injection into the peritoneal cavity. In-vitro study using rat intestinal microsomes and the in-vivo rat intestinal loop technique also showed that pre-administration of erythromycin inhibits nifedipine metabolism in the small intestine.     

Long-Lasting Immune Response Induced by Recombinant Bacillus Calmette–Guérin (BCG) Secretion System

The recombinant bacillus Calmette–Guérin (rBCG) secretion system utilizing an extracellular α antigen of Mycobacterium kansasii (α-K) was characterized biochemically and immunologically. The human immunodeficiency virus type1 (HIV-1) p17 ^gag B cell epitope fused to α-K was secreted in extremely large amounts. At least three mice out of seven inoculated with rBCG generated high titres of antibody to the epitope. The long-lasting antibody production persisted more than 14 months.     

Reliability of the Japanese version of the Inventory to Diagnose Depression

Abstract The reliability of the Japanese version of the Inventory to Diagnose Depression (IDD) which is a self-report to diagnose major depressive disorders (MDD) of DSM-III-R, was investigated in 30 cases with MDD and 30 control subjects. On test-retest reliability, the agreement of diagnostic performance was substantial ( K = 0.64, P < 0.001) for 60 subjects, and scores of total and individual items correlated significantly ( P < 0.001) between test and retest except for decreased energy, decreased interest, and decreased concentration. The average score of the total IDD severity at test (38.4) was significantly higher than that at retest (28.0; P < 0.01). However, excluding the recovered 10 cases, there was no significant difference seen on the average total score between test and retest (38.8, 30.1, respectively). Internal consistency (Cronbach's a = 0.80) and split-half reliability (0.79) were sufficient, and item-total correlations of the IDD were significant ( P < 0.01) except for weight gain. The IDD might be useful as a screening tool and for clinical evaluation of subjects in Japan; however, it is necessary to examine the validity of this instrument.     

Cavum septum pellucidum in schizophrenia: A magnetic resonance imaging study

Abstract In order to determine if cavum septum pellucidum (CSP) is more prevalent in schizophrenic patients, we studied 72 Japanese patients who fulfilled the DSM-III-R criteria for schizophrenia and 41 normal controls. Sagittal, 1 mm thick magnetic resonance imaging slices of the entire cranium were obtained using a gradient-echo pulse sequence, and coronal and axial images were reconstructed for assessment. A CSP was observed in 34 patients (47.2%) and in 16 controls (38.0%). Although the CSP appeared to be more prevalent in schizophrenic patients, this difference was not statistically significant. However, schizophrenic patients with a history of long-term institutionalization had a higher incidence of CSP compared with patients who had not been admitted to hospital for more than 3 years (68.2 vs 38.0%). These results suggest that the CSP may be a pathophysiology that characterizes schizophrenic patients with poor prognoses.     

Spontaneous Termination of Reentry Ventricular Tachycardia in the Late Myocardial Infarction Period: An Experimental Study in the Dog

Forty episodes of induced ventricular tachycardia in the late myocardial infarction period (4-6 days old) were analyzed in 12 dogs in an attempt to identify the possible mechanisms for the termination of reentry tachycardia. Multiple epicardial and endocardial composite electrograms were recorded in and around the central ischemic zone of the infarction. During tachycardia, the earliest site of activation was identified in the epicardial surface of the border or normal zone immediately adjacent to the ischemic zone in 36 of the 40 episodes, suggesting efferent epicardial spread from the site of the activity. In four instances, the efferent pathways were directed to the endocardial surface. Four distinct patterns of activation sequences were observed during spontaneous termination: (a) a shift of the efferent pathways from epicardial to endocardial site (19 instances); (b) a change of the efferent pathways within the endocardium (4 instances); (c) a shift of the earliest site of activation between the left and right ventricles (9 instances); and (d) no apparent change in the epicardial efferent pathways (4 instances). In four other instances, ventricular tachycardia deteriorated into ventricular fibrillation. In patterns (a) and (c), a shift of the efferent pathways resulted in a more rapid and homogeneous activation of the border and normal zone epicardium. These changes were associated with cessation of delayed or continuous activity in the ischemic zone epicardium, resulting in termination of tachycardia.     

A tumor necrosis factor (TNF) receptor fragment attenuates TNF-α- and muramyl dipeptide-induced sleep and fever in rabbits

It is hypothesized that tumour necrosis factor (TNF) is an endogenous substance involved in sleep responses occurring during bacterial infection. If this hypothesis is correct, then blocking endogenous TNF, using a TNF inhibitor, should attenuate the bacterial cell wall-derived, muramyl dipeptide (MDP)-induced sleep. To test this hypothesis, the effects of intracerebroventricular (i.c.v.) injection of a TNF inhibitor, a biologically active fragment of the soluble TNF 55 kDa receptor (TNFRF), on TNF-α- and MDP-induced sleep were determined in rabbits. I.c.v. injection of 250 ng human recombinant TNF-α- or 150 pmol MDP increased non-rapid-eye-movement sleep (NREMS), decreased rapid-eye-movement sleep (REMS), enhanced electroencephalogram slow-wave activity (SWA) during NREMS and induced fever. Pretreatment of rabbits with 25 μg of the TNFRF significantly inhibited TNF-α- and MDP-induced sleep and fever responses. Finally, intravenously (i.v.) injected MDP enhanced NREMS, suppressed REMS, enhanced SWA, and induced fever; pretreatment of animals with the TNFRF injected centrally attenuated i.v. MDP-induced sleep responses but not fever. These results suggest that the TNFRF acts as a TNF-α antagonist in vivo and support the hypothesis that MDP-induced sleep is partially mediated via brain TNF-α.