A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science in Medicine in Epidemiology and Biostatistics Johannesburg, 2002. / To systematically evaluate the efficacy of double dose of sulfadoxine-pyremithamine (SP/SP) treatment in pregnancy in malaria endemic areas. Methods - The relevant articles were retrieved by a computerized search of Medline, Cochrane Review, Pub Med and Google with the following key words, sulfadoxine-pyrimethamine, intermittent, pregnancy, Quasi- experimental studies and Randomised Control Trials. Three reviewers identified only 2 papers meeting the inclusion criteria set for the study. Systematic quantitative review was performed. / IT2018

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

En 2016, 216 millions de cas et 445000 décès liés au paludisme ont été reportés par l'Organisation Mondiale de la Santé (OMS), 90 % de ces cas ont eu lieu sur le continent africain, très majoritairement causés par Plasmodium falciparum. Chez les femmes enceintes le paludisme peut avoir de lourdes conséquences en termes de morbidité et de mortalité aussi bien pour la mère que pour l'enfant à venir. Outre l'utilisation de moustiquaires imprégnées, l'OMS recommande l'utilisation d'un traitement préventif intermittent par sulfadoxine-pyriméthamine (SP) pour les femmes enceintes des zones endémiques d'Afrique sub-saharienne. La résistance du parasite à la SP est un réel problème en l'absence d'alternative thérapeutique et le niveau de résistance est déjà très élevé dans certaines régions d'Afrique. Cette résistance est causée par différents polymorphismes nucléotidiques simples (SNPs) sur les gènes codant pour DHPS et DHFR. Ces mutations modifient la structure 3D de ces enzymes, diminuant leur liaison à la SP. Ce travail s'est attaché à faire un état des lieux récent de la prévalence des mutations des gènes pfdhfr et pfdhps à travers 7 sites d'Afrique Centrale. Un octuple mutant combinant trois mutations sur le gène pfdhfr et cinq mutations sur le gène pfdhps (CirnI + vagKgs) a été découvert à Yaoundé en 2015 ; nous l'avons retrouvé au Nigeria et au Cameroun mais pour la première fois à un haut niveau de prévalence à Maroua (52,2%). Sur plusieurs sites d'Afrique Centrale, nous décrivons l'augmentation de la prévalence de la mutation K540E, typique des parasites résistants de l'Afrique de l'Est et sur laquelle se base l'implémentation de la SP par l'OMS. D'autre part, à partir d'un modèle d'homologie de pfDHPS, nous avons utilisé des techniques de dynamique moléculaire pour mieux comprendre les modifications de la structure 3D liées à différents haplotypes d'intérêts retrouvés en Afrique Centrale. Cette partie de l'étude propose une autre approche pour évaluer et visualiser l'effet structurel des mutations, élément supplémentaire à la compréhension de leur impact sur la résistance à la SP. / Malaria was responsible for 445 000 death and 216 million new cases worldwide in 2016, 90% of these cases occurred in Africa. Pregnant women are particularly susceptible to malaria, resulting in medical consequences on both mother and child. In the endemic countries of sub Saharan Africa, in addition to the use of insecticidal nets, the World Health Organization (WHO) recommends a preventive treatment against Plasmodium falciparum malaria in pregnancy using Sulfadoxine Pyrimethamine (SP). Resistance of the parasite to SP is a significant problem in the absence of alternative treatment and the level of resistance is very high in some regions of Africa. This resistance is mediated by several single nucleotide polymorphisms (SNPs) in the genes coding for DHPS and DHFR, changing the 3D structure of the two target proteins and decreasing drug binding. This study offers an updated view of the epidemiology of these mutations throughout Central Africa. We identified for the first time the octuple mutant combining 3 mutations on pfdhfr gene and 5 mutations on pfdhps gene (CirnI + vagKgs), discovered in 2015 in Yaoundé, as the major haplotype in Maroua, northern Cameroon (52,2%). On several Central-African sites, we describe the increase of the prevalence of the typically East-African K540E mutation on which is based the implementation of SP by the WHO. Knowledge of the prevalence of resistance markers is crucial for the adaptation of SP recommendation in Central Africa. This study also explores the changes occurring in the 3D structure of the most common mutated pfDHPS haplotypes identified in our epidemiology study, using molecular dynamics on a homology model of the protein. It offers a new vision of the effect of the mutations on the structure, a further step to understanding the impact of mutations in resistance.

No description available.

Malaria infection is a major cause of morbidity and mortality in tropical countries, and particularly in Mozambique. Recently substantial resources have been used to reduce the burden of malaria in Mozambique. These include the distribution of insecticide treated bed-nets, indoor residual insecticide spraying, access to artemisinin-based combination treatment (ACT), and intermittent preventive treatment of pregnant women with sulfadoxine-pyrimetamine (SP-IPTp). The most important benefit of SP-IPTp in malaria endemic areas has been the increase in birth weight, thus increasing the probability of child survival. The SP-IPTp policy was based on evidence of its effectiveness in areas of high intensity malaria transmission. The effect of SP-IPTp has been less evident in the presence of high coverage with insecticide treated bed-nets. It is not know whether reducing the risk of malaria through effective vector control using indoor residual insecticide spraying and large-scale deployment of ACTs has a similar effect in reducing the impact of SP-IPTp on birth weight. At the same time, increasing resistance of SP could be compromising the effect of SP-IPTp on birth weight, as could co-infection with HIV. The aim of this study was to determine if the effect of SP-IPTp on reduction in risk of low birth weight is modified by Plasmodium falciparum malaria prevalence. This retrospective antenatal record review, analyzed 20867 antenatal records from 2005 to 2007 from public health facilities in Maputo and Gaza provinces, southern Mozambique. One or two doses of SP-IPTp does not have any effect on reducing the risk of low birth weight, while women who had at least three doses of SP-IPTp had a 15% lower risk of their babies being born with low birth weigh compared with fewer doses, (OR=0.85; 95% CI 0.73 – 1.00; p=0.053). The risk of babies being born with low birth weight was reduced by 28% when both malaria prevalence and dhfr / dhps mutation prevalence are low, (OR=0.72; 95% CI 0.51 – 1.00), but this effect was no longer significant with higher malaria prevalence and or mutation prevalence. SP-IPTp has an effect on reducing low birth weight with three or more doses, and in areas where malaria prevalence and mutation prevalence are low.  Copyright / Dissertation (MSc)--University of Pretoria, 2013. / Clinical Epidemiology / unrestricted

Magister Pharmaceuticae - MPharm / Malaria remains one of the top mortality causes in the sub-Saharan African region, especially among pregnant women and infants. Despite several measures being implemented within the affected areas such as the use of treated mosquito nets, sulfadoxine and pyrimethamine (SULPYR) as an intermittent preventive treatment (IPTp-SP) is still considered the standard prophylactic regimen for pregnant women. Recently, the WHO increased the regimen of IPTp- SP from three to four doses on a monthly interval, this recommendation poses a potential risk of toxicity and resistance to the drugs. An improvement towards this challenge is under clinical trial and consists of the inclusion of azithromycin (AZI), a macrolide antibiotic, to the current IPTp-SP treatment regimen. This will not only aid in the prophylaxis of malaria in pregnant women but will also assist in other pregnancy related infections. All three these drugs exhibit poor aqueous solubility; requiring high concentrations for oral administration to achieve therapeutic plasma concentrations. / 2024

Malaria is a disease affecting millions of people in 109 malarious countries and territories, causing approximately one million deaths annually. In 2004 one of the parasites causing human malaria, Plasmodium falciparum, was among the leading global causes of death from a single infectious agent, especially in Africa (WHO, 2008:23). Treatment of this disease with single active pharmaceutical ingredients has led to the emergence of resistant P. falciparum parasites, resulting in the most severe form of this illness. Alarmingly, the poor quality of commercially available antimalarial products, especially in Africa, has increasingly been reported as a major cause of resistance to antimalarials. In Pakistan it was found that a P. falciparum epidemic that initially was attributed to drug resistance, was actually caused by substandard sulfadoxine/pyrimethamine products, causing a 50 times higher incidence of malaria in these areas than elsewhere (Leslie et al., 2009:1758). Other results indicated that up to 10% of sulfadoxine/pyrimethamine tablets, sampled in six African countries, failed the assay test, whilst up to 40% failed the USP dissolution test. Furthermore, the World Health Organization (WHO) reported that 20 - 90% of products failed quality requirements during 1999 and 2000 in seven African countries (WHO, 2003:263). Cases like these have raised the awareness of the vast number of inferior products that are being distributed. The subsequent need for establishing mechanisms to proactively detect substandard medicines, specifically antimalarials, easily and effectively had indirectly led to the origin of this study, long before it was formally undertaken. Testing monographs for pharmaceutical products are developed to formalise, or standardise, the regulation of pharmaceutical dosage forms. Problems have, however, been reported with regards to the inadequacy of existing antimalarial monographs in assuring quality medicines, fit for their intended use. The WHO had requested the Research Institute for Industrial Pharmacy, incorporating the Centre for Quality Assurance of Medicines (RIIP®/CENQAM®), both operating at the Potchefstroom Campus of the North–West University, to develop monographs for three immediate–release antimalaria dosage forms, namely amodiaquine tablets, sulfadoxine/pyrimethamine fixed–dose combination tablets and mefloquine tablets. The undertaking of these projects, to develop specifications for the quality control of these pharmaceutical products, formed the object of this research study. Data had been accumulated since 2000, as a result of continuous requests by the WHO to help solve problems that had been experienced with analytical test methods, especially from manufacturers. These requests either led to the refinement of existing methods, or to the development of new ones. The success with which these outcomes were implemented worldwide, finally led to the decision to publish these research findings under the umbrella of this project. The proud product is a comprehensive package of tests for three commercial antimalarial products, the outcomes of which are hoped to contribute towards the combat against resistance formation to these important disease fighters. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Malaria is a disease affecting millions of people in 109 malarious countries and territories, causing approximately one million deaths annually. In 2004 one of the parasites causing human malaria, Plasmodium falciparum, was among the leading global causes of death from a single infectious agent, especially in Africa (WHO, 2008:23). Treatment of this disease with single active pharmaceutical ingredients has led to the emergence of resistant P. falciparum parasites, resulting in the most severe form of this illness. Alarmingly, the poor quality of commercially available antimalarial products, especially in Africa, has increasingly been reported as a major cause of resistance to antimalarials. In Pakistan it was found that a P. falciparum epidemic that initially was attributed to drug resistance, was actually caused by substandard sulfadoxine/pyrimethamine products, causing a 50 times higher incidence of malaria in these areas than elsewhere (Leslie et al., 2009:1758). Other results indicated that up to 10% of sulfadoxine/pyrimethamine tablets, sampled in six African countries, failed the assay test, whilst up to 40% failed the USP dissolution test. Furthermore, the World Health Organization (WHO) reported that 20 - 90% of products failed quality requirements during 1999 and 2000 in seven African countries (WHO, 2003:263). Cases like these have raised the awareness of the vast number of inferior products that are being distributed. The subsequent need for establishing mechanisms to proactively detect substandard medicines, specifically antimalarials, easily and effectively had indirectly led to the origin of this study, long before it was formally undertaken. Testing monographs for pharmaceutical products are developed to formalise, or standardise, the regulation of pharmaceutical dosage forms. Problems have, however, been reported with regards to the inadequacy of existing antimalarial monographs in assuring quality medicines, fit for their intended use. The WHO had requested the Research Institute for Industrial Pharmacy, incorporating the Centre for Quality Assurance of Medicines (RIIP®/CENQAM®), both operating at the Potchefstroom Campus of the North–West University, to develop monographs for three immediate–release antimalaria dosage forms, namely amodiaquine tablets, sulfadoxine/pyrimethamine fixed–dose combination tablets and mefloquine tablets. The undertaking of these projects, to develop specifications for the quality control of these pharmaceutical products, formed the object of this research study. Data had been accumulated since 2000, as a result of continuous requests by the WHO to help solve problems that had been experienced with analytical test methods, especially from manufacturers. These requests either led to the refinement of existing methods, or to the development of new ones. The success with which these outcomes were implemented worldwide, finally led to the decision to publish these research findings under the umbrella of this project. The proud product is a comprehensive package of tests for three commercial antimalarial products, the outcomes of which are hoped to contribute towards the combat against resistance formation to these important disease fighters. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Le paludisme est l’une des maladies infectieuses la plus fréquente au monde avec 40% de la population mondiale exposée. En dépit des stratégies actuelles de lutte notamment la prise en charge rapide des cas, l’utilisation de matériaux imprégnés et la pulvérisation intra domiciliaire d’insecticide, le paludisme reste une des premières causes de morbidité et de mortalité notamment en Afrique subsaharienne. Cette partie du monde totalise à elle seule plus de 90% des cas de décès par paludisme dont 88% chez les enfants de moins de moins de 5 ans. En absence de vaccin utilisable en santé publique, il y a donc un besoin urgent de trouver une stratégie efficiente et simple de contrôle du paludisme. Le traitement préventif intermittent (TPI) définie comme l’administration d’un antipaludique à dose curative à des intervalles de temps prédéfinis réduit l’incidence du paludisme et apparaît aujourd’hui comme une des stratégies les plus prometteuses. Cette stratégie couplée au Programme Elargi de Vaccination (PEV) chez les enfants de moins de 1 an réduit l’incidence du paludisme de 30%. Des résultats plus importants sont obtenus chez les enfants de 0 à 5 ans voire de 0 à 10 ans lorsque la stratégie est appliquée en ciblant la saison de transmission. Nos travaux de recherche au Mali ont porté sur :- l’impact de la mise en œuvre du TPI couplé à la vaccination du PEV (TPin) sur i) la résistance P. falciparum à la Sulfadoxine pyrimethamine (SP), ii) la couverture des vaccins du PEV, iii) le taux de mortalité des enfants âgés de 4 à 18 mois.- l’efficacité du TPI chez les enfants ciblant la saison de transmission (TPIe) dans un contexte de faible et de forte couverture en des Moustiquaires Imprégnés d’Insecticides (MII). Nos résultats ont montré qu’après une année de mise en œuvre à l’échelle du district sanitaire, le TPIn a entrainé une augmentation de la couverture des vaccins du PEV. Cette couverture était de 53% en zone de non-intervention contre 69.5% en zone d’intervention (p<0.01). Il y a eu une réduction de la mortalité globale de 27% (RR= 0,73, IC95% : 0,55-0,97, p=0,029) chez les enfants âgés de 4 à 18 mois. Les fréquences des marqueurs moléculaires de la résistance de P. falciparum à SP en début et en fin la mise en œuvre et entre la zone d’intervention et la zone de non –intervention après une année de mise en œuvre étaient similaires. Deux doses de SP données en TPI à 8 semaines d’ intervalle durant la saison de transmission réduit le taux d’incidence du paludisme pendant la saison de transmission de 69,4% chez les enfants de moins de 5 ans et de 63,4% chez les enfants de 5-10 ans dans un contexte de très faible utilisation de MII (<5%). Dans une autre étude que nous avons menée, le TPI avec SP + Amodiaquine (AQ) donné en 3 occasions à un mois d’ intervalle pendant la saison de transmission a réduit le taux d’ incidence du paludisme clinique non compliqué de 82% (IC à 95%: 78%– 85%; P<0.001) et les formes graves de paludisme de 87% (IC à 95% 42% – 99%, P=0.001) chez les enfants âgés de 3 à 59 mois en dépit un taux d’utilisation des MII de plus de 99%. Nous n’avons pas documenté d’événement indésirable grave lié à l’utilisation de la SP ou de la SP + AQ en TPI durant ces deux études. Nos résultats étayent la recommandation du TPI, ciblant la saison de transmission ou couplée au PEV, pour la lutte antipaludique chez les enfants. / Malaria is one of the most common infectious diseases in the world and 40% of the world population is exposed to malaria. Despite the current control strategies such as rapid diagnosis and treatment of disease cases, use of insecticide impregnated materials and indoor residuals spraying with insecticides, malaria remained a main cause of morbidity and mortality particularly in sub Saharan Africa. More than 90% of the deaths due to malaria occurred in this region and 88% of these deaths occurred in children aged less than 5 years of age. In absence of vaccine that can be used in public health, there is an urgent need for a simple and efficient control strategy. Malaria intermittent preventive treatment (IPT) defined as the administration of curative dose of anti-malarial drug at predefined time intervals, appears as one of the most promising strategies. Given through the Expanded Program of Immunization (EPI), the strategy reduced the incidence of malaria by 30%. More drastic reductions were obtained in children aged 0-5 years and even 0-10 years when the malaria transmission season was targeted for the administration of the strategy. Our research work in Mali has assessed the following:- The impact of implementation of IPT administrated through EPI (IPTi) on: i) the resistance of P. falciparum to Sulfadoxine pyrimethamine (SP); ii) EPI vaccine coverage, and iii) mortality of children of 4-18 months of age. - The efficacy of IPT in children targeting the malaria transmission season (IPTe) in a context of low and high coverage of insecticide impregnated nets (ITN).We have found that the implementation of IPTi at the district level has resulted in an augmentation of the EPI vaccine coverage. The EPI vaccine coverage was 53% in the non-intervention zone compared to 69.5% in the intervention zone (p<0,01). There was a reduction in all cause mortality of 27% (RR= 0.73, 95% CI : 0.55-0.97, p=0.029) in children aged 4-18 months. The frequencies of molecular markers of the resistance of P. falciparum to SP were similar at the beginning and the end of the one year implementation period and between the intervention and non-intervention zones.Two doses of SP given at 8 weeks interval during the transmission season, reduced the incidence of malaria episodes during the transmission season by 69.4% in children aged less than 5 years and by 63.4% in children aged 5-10 years in a context of very low ITN use (<5%). In another study that we have conducted, IPT with SP + Amodiaquine (AQ) given at three occasions at one month interval during the transmission season reduced the incidence rate of clinical malaria by 82% (95% CI: 78%– 85%; P<0.001), and the incidence of severe and complicated malaria by 87% (95% IC 42% – 99%, P=0.001) in children aged 3 to 59 months of age despite an ITN use of greater than 99%.There was no serious adverse event related to the use of SP or SP+AQ in IPT during the two studies. Our results support the recommendation of IPT targeting the transmission season and IPT given through the EPI for malaria control in children.

Malaria ist noch immer die häufigste parasitäre Erkrankung in den Tropen. Vor allem afrikanische Kinder < 5 Jahren sind betroffen. Die steigende Chloroquinresistenz ist für einen deutlichen Anstieg der Kindersterblichkeit verantwortlich. Mehrere Studien belegen, dass die Kombination von Chloroquin (CQ) mit Sulfadoxin-Pyrimethamin (SP) in Afrika bei niedriggradiger CQ-Resistenz die therapeutische Wirksamkeit erhöht und damit auch die Resistenzentwicklung gegenüber beiden Medikamenten verzögern kann. Bei 315 Kindern im Alter von 6-59 Monaten wurde von Nov. 2000 bis Nov. 2001 eine Studie zur Epidemiologie der Malaria und zum Therapieausgang von CQ und SP in Tamale/Nord-Ghana durchgeführt. Bei Vorliegen einer Malaria wurde mit CQ und SP behandelt und der Therapieausgang gemäß eines modifizierten WHO-Protokolls von 1996 ermittelt. Die Gesamtzahl der Malaria-Episoden im Zeitraum betrug 836. In der Regenzeit erkrankte mit 23,7% ein signifikant höherer Anteil der Kinder an Malaria als in der Trockenzeit mit 9,4%. Ein frühes Therapieversagen (ETF) wurde in 5% der Fälle beobachtet, ein spätes Therapieversagen (LTF) in 19,5% der Fälle. 211 Fälle (68,7%) hatten einen klinischen Therapieerfolg (ACR). Alter < 3 Jahren war ein unabhängiger Einflussfaktor für ETF und Gesamttherapieversagen. Eine hohe Parasitendichte war ein unabhängiger Einflussfaktor für LTF und Gesamttherapieversagen. Das Risiko, ein Gesamttherapieversagen (ETF + LTF) zu entwickeln, war in der Regenzeit um das 6-fache gegenüber der Trockenzeit erhöht. Bei allen erstmalig mit CQ und SP behandelten Fällen (n = 206) war der ACR (72,3%) statistisch grenzwertig höher als bei zweiter oder mehrfacher Behandlung (61,4%; n = 101). Bei den mehrfach therapierten Fällen bestand mit 27% gegenüber 16% bei den erstmalig therapierten Fällen ein signifikant höheres Risiko, ein LTF zu entwickeln. Die Erholung des Hb-Gehalts bei den erfolgreich therapierten Fällen betrug 0,6 g/dl und unterschied sich signifikant vom Hb-Anstieg (0,4 g/dl) bei Fällen mit LTF. Ein Vergleich des ACR der beschriebenen Studie mit einer zuvor durchgeführten CQ-Studie ergab keinen signifikanten Unterschied. Die Ergebnisse dieser Studie legen die Schlussfolgerung nahe, dass sich die Therapie aus CQ und SP wegen der hohen CQ-Resistenz und der sich rasch entwickelnden SP-Resistenz zumindest in Nordghana nicht eignet. / Malaria remains the most frequent parasite disease in the tropics. Especially African children under 5 years are at risk. The rising chloroquine resistance is the cause for a significant increase in childhood mortality. Several studies indicate that the combination of chloroquin (CQ) and sulfadoxine-pyrimethamine (SP) in Africa with low-grade CQ resistance increases the therapeutic efficacy and can thus slow down the development of resistance to both drugs. The epidemiology of malaria and the therapeutic outcome of CQ and SP was assessed in a cohort study of 315 children aged 6-59 months from November 2000-November 2001 in Tamale/Northern Ghana. In the case of malaria a combination therapy of CQ and SP was given and the therapeutic outcome was assessed in a modified WHO protocol. The total number of all malaria episodes in the observation period was 836. In the rainy season, the amount of the children with malaria was significantly higher than in the dry season (23,7% vs. 9,4%). Early treatment failure (ETF) was observed in 5% of the cases and late treatment failure (LTF) in 19,5%. 211 cases (68,7%) fulfilled the criteria for adequate clinical response (ACR). Age under 3 years was an independent predictor for ETF and overall therapeutic failure. High initial parasite density was an independent predictor for LTF and overall therapeutic failure. The risk of developing an overall therapeutic failure (ETF + LTF) was 6 times greater in the rainy season than in the dry sason. In all cases with the first treatment of CQ and SP (n = 206), the percentage of ACR (72,3%) was significantly greater than in cases treated twice or more (61,4%, n = 101). Cases with 2 or more treatments were at a significantly higher risk of developing a LTF than cases with one treatment (27% vs. 16%). The recovery of the hb levels in cases with successful treatment was 0,6 g/dl and was significantly different from the haemoglobin increase in cases with LTF. A comparison between the therapeutic success of CQ and SP with CQ alone did not show a significant difference. The results of this study indicate that the combination therapy of CQ and SP is no longer useful for treatment of uncomplicated malaria in Northern Ghana because of the high CQ resistance and the increasing resistance of SP.