Phase I randomized dose-ascending placebo-controlled trials of ferroquine - a candidate anti-malarial drug - in adults with asymptomatic Plasmodium falciparum infection

<p>Abstract</p> <p>Background</p> <p>The development and spread of drug resistant <it>Plasmodium falciparum </it>strains is a major concern and novel anti-malarial drugs are, therefore, needed. Ferroquine is a ferrocenic derivative of chloroquine with proven anti-malarial activity against chloroquine-resistant and -sensitive <it>P. falciparum </it>laboratory strains.</p> <p>Methods</p> <p>Adult young male aged 18 to 45 years, asymptomatic carriers of <it>P. falciparum</it>, were included in two-dose escalation, double-blind, randomized, placebo-controlled Phase I trials, a single dose study and a multiple dose study aiming to evaluate oral doses of ferroquine from 400 to 1,600 mg.</p> <p>Results</p> <p>Overall, 54/66 patients (40 and 26 treated in the single and multiple dose studies, respectively) experienced at least one adverse event, 15 were under placebo. Adverse events were mainly gastrointestinal symptoms such as abdominal pain (16), diarrhoea (5), nausea (13), and vomiting (9), but also headache (11), and dizziness (5). A few patients had slightly elevated liver parameters (10/66) including two patients under placebo. Moderate changes in QTc and morphological changes in T waves were observed in the course of the study. However, no adverse cardiac effects with clinical relevance were observed.</p> <p>Conclusions</p> <p>These phase I trials showed that clinically, ferroquine was generally well-tolerated up to 1,600 mg as single dose and up to 800 mg as repeated dose in asymptomatic young male with <it>P. falciparum </it>infection. Further clinical development of ferroquine, either alone or in combination with another anti-malarial, is highly warranted and currently underway.</p

Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres

BACKGROUND: Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. So far, CHMI is done by exposure of volunteers to bites of five mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a technique available in only a few centres worldwide. Mosquito-mediated CHMI is logistically complex, exact PfSPZ dosage is impossible and live mosquito-based interventions are not suitable for further clinical development. METHODS: An open-labelled, randomized, dose-finding study in 18-45 year old, healthy, malaria-naive volunteers was performed to assess if intravenous (IV) injection of 50 to 3,200 aseptic, purified, cryopreserved PfSPZ is safe and achieves infection kinetics comparable to published data of mosquito-mediated CHMI. An independent study site verified the fully infectious dose using direct venous inoculation of PfSPZ. Parasite kinetics were assessed by thick blood smear microscopy and quantitative real time PCR. RESULTS: IV inoculation with 50, 200, 800, or 3,200 PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers, respectively. The geometric mean pre-patent period (GMPPP) was 11.2 days (range 10.5-12.5) in the 3,200 PfSPZ IV group. Subsequently, six volunteers received 3,200 PfSPZ by direct venous inoculation at an independent investigational site. All six developed parasitaemia (GMPPP: 11.4 days, range: 10.4-12.3). Inoculation of PfSPZ was safe. Infection rate and pre-patent period depended on dose, and injection of 3,200 PfSPZ led to a GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The infectious dose of PfSPZ predicted dosage of radiation-attenuated PfSPZ required for successful vaccination. CONCLUSIONS: IV inoculation of PfSPZ is safe, well tolerated and highly reproducible. It shall further accelerate development of anti-malarial interventions through standardization and facilitation of CHMI. Beyond this, rational dose selection for whole PfSPZ-based immunization and complex study designs are now possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01624961 and NCT01771848

A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon

<p>Abstract</p> <p>Background</p> <p>Chloroquine resistance (CR) decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR) conferring mutant <it>pfcrt </it>allele and its associated chromosomal haplotype were determined before and after the change in Gabonese national treatment guidelines from chloroquine (CQ) to artesunate plus amodiaquine (AQ) in 2003.</p> <p>Methods</p> <p>The prevalence of the wild type <it>pfcrt </it>allele was assessed in 144 isolates from the years 2005 - 07 by PCR fragment restriction digest and direct sequencing. For haplotype analysis of the chromosomal regions flanking the <it>pfcrt </it>locus, microsatellite analysis was done on a total of 145 isolates obtained in 1995/96 (43 isolates), 2002 (47 isolates) and 2005 - 07 (55 isolates).</p> <p>Results</p> <p>The prevalence of the mutant <it>pfcrt </it>allele decreased from 100% in the years 1995/96 and 2002 to 97% in 2005 - 07. Haplotype analysis showed that in 1995/96 79% of the isolates carried the same microsatellite alleles in a chromosomal fragment spanning 39 kb surrounding the <it>pfcrt </it>locus. In 2002 and 2005 - 07 the prevalence of this haplotype was 62% and 58%, respectively. <it>Pfcrt </it>haplotype analysis showed that all wild type alleles were CVMNK.</p> <p>Conclusion</p> <p>Four years after the withdrawal of CQ from national treatment guidelines the prevalence of the mutant <it>pfcrt </it>allele remains at 97%. The data suggest that the combination of artesunate plus AQ may result in continued selection for the mutant <it>pfcrt </it>haplotype even after discontinuance of CQ usage.</p

Modelování volatility devizových kurzů

Import 22/07/2015The aim of this Diploma thesis is modelling and in-sample forecasting volatility of selected exchange rates using linear and nonlinear conditional heteroskedasticity models. The main aim of the thesis is supported by two partial aims. The first partial aim is to compare whether linear or nonlinear models are more efficient for modelling conditional heteroskedasticity for exchange rates. The second partial aim is to assess the suitability of estimated models to predict volatility. Tested data are time series of daily exchange rates modified to time series of daily logarithmic returns of Slovenian tolar, Cyprus pound, Slovakian koruna and Latvian lat against Euro. Observed period is divided into three parts in order to model volatility of all exchange rates in different relations of domestic countries to European Union. Thesis is divided into six parts including Introduction and Conclusion. Second and third chapter is theoretical and methodological, while the fourth and fifth chapter is practical and empirical.Cílem Diplomové práce je modelování volatility a ve výběru provedená predikce vybraných měnových kurzů za využití lineárních a nelineárních modelů podmíněné heteroskedasticity. Hlavní cíl práce je dále rozdělen na dva dílčí cíle. První z dílčích cílů se věnuje otázce, zda jsou k modelování měnových kurzů podmíněné heteroskedasticity vhodnější lineární nebo nelineární modely. Druhý dílčí cíl zohledňuje, zda jsou odhadnuté modely vhodné k predikování volatility. Testovaná data jsou časové řady denních měnových kurzů upravené na časové řady denních logaritmovaných výnosů Slovinského tolaru, Kyperské libry, Slovenské koruny a Lotyšského latu vůči Euru. Sledovaná časová perioda je rozdělena na tři části za účelem modelovat volatilitu všech měnových kurzů při různém vztahu domácí země vůči Evropské Unii. Práce je rozdělena na šest částí včetně úvodu a závěru. Druhá a třetí kapitola jsou teoretické a metodologické, zatímco čtvrtá a pátá kapitola jsou praktické a empirické.154 - Katedra financívýborn

Education, Demographics, and the Economy

This paper deals with two issues concerning the effects of population aging on education decisions in the presence of a PAYG pension system: We first analyze the effects of an aging population per se on individual skill choices and continuous education and the production structure. Second, we study the implications of postponed retirement, which is often proposed as a measure to cope with the economic challenges of increased longevity. Our study uses a dynamic general equilibrium framework with overlapping generations and probabilistic aging. Themodel allows for capital-skill complementarity in the production of final output. As a response to population aging, in a small open economy with a fixed interest rate, our first simulation shows that GDP is depressed due to an adverse effect on skill choice and labor supply. We then introduce postponed retirement as a potentially dampening policy measure due to its encouragement of human capital formation. However, since there is less private saving in this scenario, the overall effect on GDP is even worse than in the pure aging scenario