Dose-Related Hemodynamic and Electrocardiographic Effects of the Calcium Promoter BAY y 5959 in the Presence or Absence of Congestive Heart Failure

Objectives. The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure.

Background. There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes.

Methods. Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 μg/kg body weight per min.

Results. In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 μg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 μg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 μg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 μg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses.

Conclusions. BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response— combining bradycardia, reduced preload and improved cardiac output—appeared to be achieved at a dose of 2.0 μg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.     

Variations in Digestive Physiology of Rats After Short Duration Flights Aboard the US Space Shuttle

The purpose of this work was to assess the influence of microgravity on several endogenous and microbial parameters of digestive physiology. On the occasion of two Spacelab Life Sciences missions, SLS-1 (a 9-day space flight) and SLS-2 (a 14-day space flight), Sprague-Dawley rats flown aboard the US space shuttle were compared to age-matched ground-based controls. In both flights, exposure to microgravity modified cecal fermentation: concentration and profile of short-chain fatty acids were altered, whereas urea and ammonia remained unchanged. Only in SLS-1 was there an induction of intestinal glutathione-S-transferase. Additional analyses in SLS-2 showed a decrease of hepatic CYP450 and of colonic goblet cells containing neutral mucin. After a postflight recovery period equal to the mission length, only modifications of the hepatic and intestinal xenobiotic metabolizing enzymes still persisted. These findings should help to predict the alterations of digestive physiology and detoxification potential likely to occur in astronauts. Their possible influence on health is discussed.     

Hepatitis G and C Viruses Respond to Interferon-α with Different Virologic Kinetics

The aim of this work was to specify the timecourse of response to interferon (IFN) of hepatitis Gvirus (HGV) and hepatitis C virus (HCV) in coinfectedindividuals. A group of 33 patients, undergoing 12 months of IFN therapy for chronic hepatitis C,was screened for the presence of both HGV and HCV RNAsto select seven coinfected patients. Spontaneousrecovery from HGV infection was excluded through the detection of antibodies to the envelope-2protein of HGV and HCV isolates were genotyped. Withinthree months of treatment, we found that HGV RNA wastransiently cleared in 6/7 patients, but the rate of long-term favorable response was very low(1/7). In addition, considering the same individualsseparately, it was shown that HGV and HCV responded toIFN with different kinetics in 5/7 patients. Takentogether, these results underscore the importance of thevirological basis of the resistance to IFNtreatment.     

POLLAR: Impact of air POLLution on Asthma and Rhinitis; a European Institute of Innovation and Technology Health (EIT Health) project

Allergic rhinitis (AR) is impacted by allergens and air pollution but interactions between air pollution, sleep and allergic diseases are insufficiently understood. POLLAR (Impact of air POLLution on sleep, Asthma and Rhinitis) is a project of the European Institute of Innovation and Technology (EIT Health). It will use a freely-existing application for AR monitoring that has been tested in 23 countries (the Allergy Diary, iOS and Android, 17,000 users, TLR8). The Allergy Diary will be combined with a new tool allowing queries on allergen, pollen (TLR2), sleep quality and disorders (TRL2) as well as existing longitudinal and geolocalized pollution data. Machine learning will be used to assess the relationship between air pollution, sleep and AR comparing polluted and non-polluted areas in 6 EU countries. Data generated in 2018 will be confirmed in 2019 and extended by the individual prospective assessment of pollution (portable sensor, TLR7) in AR. Sleep apnea patients will be used as a demonstrator of sleep disorder that can be modulated in terms of symptoms and severity by air pollution and AR. The geographic information system GIS will map the results. Consequences on quality of life (EQ-5D), asthma, school, work and sleep will be monitored and disseminated towards the population. The impacts of POLLAR will be (1) to propose novel care pathways integrating pollution, sleep and patients’ literacy, (2) to study sleep consequences of pollution and its impact on frequent chronic diseases, (3) to improve work productivity, (4) to propose the basis for a sentinel network at the EU level for pollution and allergy, (5) to assess the societal implications of the interaction. MASK paper N°32.     

PBPK modeling of irbesartan: incorporation of hepatic uptake

Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp^®. The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF_1B1 using estrone‐3‐sulfate and pitavastatine clearances, and RAF_1B3 using cholecystokinine octapeptide (CCK‐8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REF_HH) or tissues (REF_tissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp® simulator. Pharmacokinetic simulation using REF_HH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling. Copyright © 2015 John Wiley & Sons, Ltd.