Longitudinal study based on a safety registry for malaria patients treated with artenimol-piperaquine in six European countries.

BACKGROUND: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. METHODS: Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. RESULTS: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). CONCLUSIONS: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942.

Propionyl-L-carnitine improves postischemic blood flow recovery and arteriogenetic revascularization and reduces endothelial NADPH-oxidase 4-mediated superoxide production.

OBJECTIVE: The beneficial effect of the natural compound propionyl-l-carnitine (PLC) on intermittent claudication in patients with peripheral arterial disease is attributed to its anaplerotic function in ischemic tissues, but inadequate information is available concerning action on the vasculature. METHODS AND RESULTS: We investigated the effects of PLC in rabbit hind limb collateral vessels after femoral artery excision, mouse dorsal air pouch, chicken chorioallantoic membrane, and vascular cells by angiographic, Doppler flow, and histomorphometrical and biomolecular analyses. PLC injection accelerated hind limb blood flow recovery after 4 days (P<0.05) and increased angiographic quadriceps collateral vascularization after 7 days (P<0.001) Histomorphometry confirmed the increased vascular area (P<0.05), with unchanged intramuscular capillary density. PLC-induced dilatative adaptation, and growth was found associated with increased inducible nitric oxide synthase and reduced arterial vascular endothelial growth factor and intracellular adhesion molecule-1 expression. PLC also increased vascularization in air pouch and chorioallantoic membrane (P<0.05), particularly in large vessels. PLC increased endothelial and human umbilical vascular endothelial cell proliferation and rapidly reduced inducible nitric oxide synthase and NADPH-oxidase 4-mediated reactive oxygen species production in human umbilical vascular endothelial cells; NADPH-oxidase 4 also regulated NF-kappaB-independent intracellular adhesion molecule-1 expression. CONCLUSIONS: Our results provided strong evidence that PLC improves postischemic flow recovery and revascularization and reduces endothelial NADPH-oxidase-related superoxide production. We recommend that PLC should be included among therapeutic interventions that target endothelial function.

Chronic istaroxime improves cardiac function and heart rate variability in cardiomyopathic hamsters.

PURPOSE: Istaroxime is a new luso-inotropic compound. It exerts inotropic action by reducing Na+/K+-ATPase activity, and simultaneously it stimulates sarcoplasmic reticulum Ca(2+)-ATPase function, thus also inducing lusitropic action. The aim of present study is to assess the effect of chronic istaroxime treatment on cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure. METHODS: Bio TO.2 hamsters were daily treated, from 12 to 28 weeks of age, with 30 mg/kg/day oral istaroxime. Age-matched Bio TO.2 and Bio F1B hamsters were treated with vehicle and used as diseased and healthy controls. At the end of treatment, hearts function and autonomic cardiac control were evaluated. RESULTS: Hearts from vehicle-treated Bio TO.2 when compared with hearts from Bio F1B showed higher heart/body weight ratio, and lower left ventricular systolic pressure (LVSP), positive and negative derivative of LV pressure (dP/dT), coronary flow rate (CFR). Hearts from istaroxime-treated when compared with those of vehicle-treated hamsters, showed the reduction of heart/body weight ratio, and the increase of LVSP, of both positive and negative dP/dT, and of CFR. Autonomic cardiac control, evaluated by HRV analysis, indicated in vehicle-treated Bio TO.2 hamsters, when compared to healthy, a shift towards increased sympathetic and decreased parasympathetic activities. Istaroxime-treatment preserved parasympathetic activity. CONCLUSIONS: Chronic istaroxime improves cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.

Sympathomimetic inefficiency in restoring contractility in the acute or chronic beta-blocker-treated ischaemic heart: comparison with a new agent.

BACKGROUND: Adequate pharmacologic cardiac support in acute myocardial infarction (MI), as well as in chronic MI patients under beta-blocker therapy, is problematic due to the impaired cardiac response to beta-adrenergic agonists. New therapeutic approaches could resolve this problem. Istaroxime (ISTA) is a new Na(+),K(+)-ATPase inhibitor and SERCA(2) agonist. AIMS: To evaluate: 1) the effects of dobutamine (DOB) on left ventricular function in early (48-72 h) and late (14 days) phases of a post-MI canine model, compared to ISTA, and 2) the efficacy of DOB in chronic left ventricular dysfunction (6 months post-MI) in dogs pre-treated or not with a beta-blocker, compared with ISTA and milrinone (MIL). RESULTS: When compared to the effects in healthy animals, DOB increased contractility only slightly in the first 48-72 h post-MI, whereas its efficacy recovered partially by day 14 and fully by 6 months after MI. ISTA had a greater effect on contractility than DOB and improved relaxation, while DOB did not. Moreover, beta-adrenergic blockade inhibited the inotropic action of DOB, without altering the effect of ISTA. Surprisingly, beta-adrenergic blockade blunted the effects of MIL. CONCLUSION: ISTA may represent a novel strategy for enhancing left ventricular performance even in the context of acute MI and/or concomitant beta-adrenergic blockade.

Istaroxime: a new luso-inotropic agent for heart failure.

Istaroxime is a new luso-inotropic compound selected for the treatment of acute heart failure syndromes, which reduces sodium-potassium adenosine triphosphatase (ATPase) activity and stimulates the sarcoplasmic calcium ATPase isoform 2 reuptake function. The aim of this study was to evaluate the safety profile of istaroxime. For this purpose, istaroxime was administered during a 24-hour infusion to conscious dogs with chronic heart failure and to genetically cardiomyopathic BIO TO.2 hamsters for 34 weeks orally. The parameters recorded were arrhythmic events and hemodynamic effects in dogs and mortality in hamsters. In dogs, istaroxime at 1, 3, and 4 microg/kg per min did not trigger arrhythmic events or magnify preexisting events. It increased left ventricular (LV) dP/dtmax (about 50% at 3 microg/kg per min) and LV-dP/dtmax (about 20% at 3 microg/kg per min) without changing heart rate, blood pressure, or double product. At 4 microg/kg per min, istaroxime increased dP/dtmax>100% but induced intense emesis in all animals. In cardiomyopathic hamsters, the dose of 30 mg/kg prolonged the survival rate to 32%. In conclusion, istaroxime seems to be a promising and safe new drug for improving cardiac performance in the failing heart.