The NTCP-inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics.

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.

A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions.

The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001-3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and C(max) increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000-fold concentration range, and therefore that nano- and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.

The epidemiological consequences of leprosy-tuberculosis co-infection.

While in antiquity both leprosy and tuberculosis were prevalent in Europe, leprosy declined thereafter and, simultaneously, tuberculosis prevalence increased. Since both diseases are caused by mycobacterial infections, it has been suggested that there might be a causal relationship between both epidemics. Chaussinand observed the inverse prevalence of leprosy and tuberculosis and suggested that individuals with a latent tuberculosis infection are protected from acquiring leprosy. His cross-immunity hypothesis has been countered more recently by a co-infection hypothesis. The latter suggestion, proposed by Donoghue, states that people being infected with multi-bacillary leprosy are more susceptible to tuberculosis, which leads to increased mortality from the disease. This study utilizes mathematical modeling to explore the epidemiological consequences of the co-infection hypothesis for realistically confined parameter values. While the co-infection hypothesis appears plausible at first glance, a second thought reveals that it comprises also substantial consequences for tuberculosis epidemics: if co-infection raises the mortality rate above that of purely tuberculosis infected persons, then tuberculosis might as well be eradicated by leprosy. It is the specific interplay of both increased susceptibility towards tuberculosis and increased death rate when co-infected that determines the epidemiological fate. As a result of this analysis, it is shown that there is a large parameter region where the eventual disappearance of leprosy could indeed be explained by co-infection. This parameter region is considerably larger than that predicted by the cross-immunity hypothesis. This shows that the co-infection hypothesis should be considered a significant alternative to the cross-immunity hypothesis. The time scales at which the effects of co-infection are observed depend critically on the spatial distribution of the individuals but reach epidemiologically realistic values for rather immobile individuals with local interaction.

[Working memory in healthy subjects and schizophrenics: studies using BOLD fMRT]. / Das Arbeitsgedächtnis bei Gesunden und bei Schizophrenen: Untersuchungen mit BOLD-fMRT.

Functional magnetic resonance imaging uses the blood oxygen level-dependent effect (BOLD MRI) for noninvasive display of cerebral correlatives of cognitive function. The importance for the understanding of physiological and pathological processes is demonstrated by investigations of working memory in schizophrenics and healthy controls. Working memory is involved in processing rather than storage of information and therefore is linked to complex processes such as learning and problem solving. In schizophrenic psychosis, these functions are clearly restricted. Training effects in the working memory task follow an inverse U-shape function, suggesting that cerebral activation reaches a peak before economics of the brain find a more efficient method and activation decreases.