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The public health measures instituted by governments to combat the coronavirus disease 2019 (COVID-19) may cause developmental and educational losses to adolescents. The impacts of the COVID-19 pandemic and its mitigation strategies on adolescents in sub-Saharan Africa are unclear. This study aimed to examine adolescents’ knowledge, perceptions, and practices related to COVID-19 and the impacts of the pandemic on the daily lives of adolescents in sub-Saharan Africa. The survey was conducted in Burkina Faso, Ethiopia, and Nigeria using computer-assisted telephone interviews to enable rapid and remote data collection. Two sites were included in each country, with approximately 300 adolescents per site and 1,795 adolescents in total. Variations across the six sites were noted for the proportions of the adolescents who could correctly identify all key COVID-19 symptoms (4–25%), transmission methods (16–59%), and prevention approaches (33–79%). Most (> 72%) of the adolescents were no longer going to school due to school closures. Many adolescents (23–81%) were not receiving any education during the pandemic. A considerable proportion of the adolescents (44–83%) self-assessed as having less ability to learn during the pandemic; many expected it to be very difficult to catch up on education after the pandemic. Decreases in the consumption of major food groups were common across sites. Urgent actions are needed in sub-Saharan Africa to address the inadequate knowledge of COVID-19 among adolescents and the impacts of the pandemic on adolescent education and nutrition.

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented public health crisis globally. Understanding healthcare providers’ (HCPs’) knowledge and perceptions of COVID-19 is crucial to identifying effective strategies to improve their ability to respond to the pandemic in sub-Saharan Africa. A phone-based survey of 900 HCPs in Burkina Faso, Ethiopia, and Nigeria (300 per country) was conducted to assess knowledge, perceptions, COVID-19 prevention measures, stigma, and mental health of HCPs. Modified Poisson regression models were used to evaluate predictors of knowledge, perceptions, and prevention measures; adjusted risk ratios (ARRs) and 95% confidence intervals (CIs) were calculated. Three-fourths of the HCPs had adequate knowledge, and over half had correct perceptions of risk and high levels of self-reported prevention measures. The majority of the HCPs (73.7%) reported self-perceived social stigma. There was relatively low prevalence of depression (6.6%), anxiety (6.6%), or psychological distress (18%). Compared with doctors, being a nurse was associated with lower levels of knowledge (ARR: 0.83; 95% CI: 0.77–0.90) and was also negatively associated with having correct perceptions toward COVID-19 (AOR: 0.82; 95% CI: 0.73–0.92). HCPs treating COVID-19 patients had higher likelihood of having high levels of prevention measures (AOR: 1.37; 95% CI: 1.23–1.53). Despite high levels of knowledge among HCPs in sub-Saharan Africa, there is a need to improve COVID-19 perceptions and compliance with prevention measures as well as address social stigma toward HCPs to better ensure their safety and prepare them to deliver health services.

Coronavirus disease 2019 (COVID-19) is a public health emergency affecting the lives of millions of people globally. Different measures and extraordinary steps are being taken to contain the transmission of the virus. The levels of knowledge and implementation of preventive practices related to COVID-19 in sub-Saharan African countries are unclear. Additionally, there is a lack of evidence regarding the impacts of the pandemic on mental health. This study aimed to describe knowledge and practices related to COVID-19 and to assess mental health status among adults in three sub-Saharan African countries: Burkina Faso, Ethiopia, and Nigeria. A total of 1,797 adults were included in the survey, and data were collected using computer-assisted telephone interviews. The proportions of adults who identified more than 80% of COVID-19 symptoms, transmission methods, and prevention mechanisms were 69.9%, 79.2%, and 90.7%, respectively. The practice of preventive measures was relatively lower for avoiding social gatherings and disinfecting contaminated surfaces. Better education, urban residence, and believing the pandemic is real were factors associated with good knowledge on COVID-19 symptoms, transmission methods, and preventive actions. Additionally, being male was associated with good knowledge on symptoms and transmission methods, whereas being in an older age group was associated with knowledge of transmission methods. Mild, moderate, and severe psychological distress was reported by 20.6%, 5.9%, and 1.1% of the participants, respectively. Although this study found high levels of knowledge regarding COVID-19, interventions are needed to increase the uptake of recommended preventive practices among adults in sub-Saharan Africa.

The coronavirus disease 2019 (COVID-19) pandemic has significant health and economic ramifications across sub-Saharan Africa (SSA). Data regarding its far-reaching impacts are severely lacking, thereby hindering the development of evidence-based strategies to mitigate its direct and indirect health consequences. To address this need, the Africa Research, Implementation Science, and Education (ARISE) Network established a mobile survey platform in SSA to generate longitudinal data regarding knowledge, attitudes, and practices (KAP) related to COVID-19 prevention and management and to evaluate the impact of COVID-19 on health and socioeconomic domains. We conducted a baseline survey of 900 healthcare workers, 1,795 adolescents 10 to 19 years of age, and 1,797 adults 20 years or older at six urban and rural sites in Burkina Faso, Ethiopia, and Nigeria. Households were selected using sampling frames of existing Health and Demographic Surveillance Systems or national surveys when possible. Healthcare providers in urban areas were sampled using lists from professional associations. Data were collected through computer-assisted telephone interviews from July to November 2020. Consenting participants responded to surveys assessing KAP and the impact of the pandemic on nutrition, food security, healthcare access and utilization, lifestyle, and mental health. We found that mobile telephone surveys can be a rapid and reliable strategy for data collection during emergencies, but challenges exist with response rates. Maintaining accurate databases of telephone numbers and conducting brief baseline in-person visits can improve response rates. The challenges and lessons learned from this effort can inform future survey efforts during COVID-19 and other emergencies, as well as remote data collection in SSA in general.

COVID-19 vaccine hesitancy among adolescents poses a challenge to the global effort to control the pandemic. This multi-country survey aimed to assess the levels and determinants of COVID-19 vaccine hesitancy among adolescents in sub-Saharan Africa between July and December 2021. The survey was conducted using computer-assisted telephone interviewing among adolescents in five sub-Saharan African countries, Burkina Faso, Ethiopia, Ghana, Nigeria, and Tanzania. A rural area and an urban area were included in each country (except Ghana, which only had a rural area), with approximately 300 adolescents in each area and 2803 in total. Sociodemographic characteristics and perceptions and attitudes on COVID-19 vaccines were measured. Vaccine hesitancy was defined as definitely not getting vaccinated or being undecided on whether to get vaccinated if a COVID-19 vaccine were available. Log-binomial models were used to calculate the adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) for associations between potential determinants and COVID-19 vaccine hesitancy. The percentage of COVID-19 vaccine hesitancy was 15% in rural Kersa, 24% in rural Ibadan, 31% in rural Nouna, 33% in urban Ouagadougou, 37% in urban Addis Ababa, 48% in rural Kintampo, 64% in urban Lagos, 76% in urban Dar es Salaam, and 88% in rural Dodoma. Perceived low necessity, concerns about vaccine safety, and concerns about vaccine effectiveness were the leading reasons for hesitancy. Healthcare workers, parents or family members, and schoolteachers had the greatest impacts on vaccine willingness. Perceived lack of safety (aPR: 3.61; 95% CI: 3.10, 4.22) and lack of effectiveness (aPR: 3.59; 95% CI: 3.09, 4.18) were associated with greater vaccine hesitancy. The levels of COVID-19 vaccine hesitancy among adolescents are alarmingly high across the five sub-Saharan African countries, especially in Tanzania. COVID-19 vaccination campaigns among sub-Saharan African adolescents should address their concerns and misconceptions about vaccine safety and effectiveness.

To examine knowledge of menstruation, HIV and STIs other than HIV across eight sites in SSA to develop effective programmatic interventions enabling adolescents to achieve positive SRH as their transition to adulthood.We combine data from eight Health and Demographic Surveillance Sites across sub-Saharan Africa, from an adolescent-specific survey that included 7116 males and females age 10-19 years old. We provide pooled and site-specific estimates from multiple analytic models examining the how year-specific age, school attendance and work correlate with knowledge of menstruation, HIV knowledge and knowledge of sexually transmitted infections (STIs) other than HIV.Many adolescents lack knowledge of menstruation (37.3%, 95% CI 31.8, 43.1 do not know of menstruation) and STIs other than HIV (55.9%, 95% CI 50.4, 61.3 do not know of other STIs). In multivariate analysis, older age, being in school and wealth are significant positive correlates of STI knowledge. Older adolescent age, female sex and being in school are significant positive correlates of knowledge of menstruation. Knowledge of HIV is high (89.7%, 95% CI 8.3, 12.7 know of HIV) and relatively similar across adolescent age, sex, wealth and school and work attendance.Knowledge of HIV is widespread across adolescents in these communities in sub-Saharan Africa, but knowledge of other dimensions of sexual and reproductive health - menstruation and other STIs in this study - is lacking especially for early adolescents (10- to 14-year olds). The dissemination of more comprehensive sexual and reproductive health information is needed within these and similar communities in SSA to help adolescents gain insight on how to make their own decisions towards positive adolescent sexual and reproductive health and protect them from risks.Examiner les connaissances sur la menstruation, le VIH et les IST autres que le VIH dans huit sites d’Afrique subsaharienne (ASS) afin d’élaborer des programmes d’interventions efficaces permettant aux adolescents d’obtenir une santé sexuelle et reproductive (SSR) positive lorsqu’ils passent à l’âge adulte. MÉTHODES: Nous combinons ici les données de huit sites de Surveillance Démographique et de Santé en Afrique subsaharienne, à partir d'une enquête spécifique réalisée auprès d'adolescents et comprenant 7.116 hommes et femmes âgés de 10 à 19 ans. Nous fournissons des estimations poolées et spécifiques à chaque site à partir de plusieurs modèles analytiques examinant la corrélation entre l'âge, la fréquentation scolaire et le travail, avec les connaissances sur la menstruation, sur le VIH et sur les IST autres que le VIH. RÉSULTATS: Beaucoup d'adolescents manquaient de connaissance sur les menstruations (37,3% ; IC95%: 31,8-43,1 ne connaissaient pas les menstruations) et les IST autres que le VIH (55,9% ; IC95%: 50,4-61,3 ne connaissent pas d'autres IST). Dans l'analyse multivariée, l'âge plus avancé, la fréquentation scolaire et la richesse sont des corrélats positifs significatifs des connaissances sur les IST. L’âge adolescent plus avancé, le sexe féminin et le fait d’être à l’école sont des corrélats positifs significatifs pour les connaissances sur la menstruation. Les connaissances sur le VIH sont élevées (89,7%, IC95%: 8,3-12,7 sont au courant du VIH) et relativement similaires selon les âges des adolescents, le sexe, la richesse et la fréquentation scolaire et le travail.Les connaissances sur le VIH semblent être répandues parmi les adolescents de ces communautés en Afrique subsaharienne, mais les connaissances sur les autres aspects de la santé sexuelle et reproductive - menstruations et autres IST dans cette étude - semblent faire défaut, en particulier chez les jeunes adolescents (âgés de 10 à 14 ans). La dissémination de telles informations plus complètes est nécessaire au sein de ces communautés et de communautés similaires en ASS afin d’aider les adolescents à comprendre comment prendre leurs propres décisions en matière de santé sexuelle et reproductive et de les protéger contre les risques.

To measure health-related behaviours and risk factors among sub-Saharan African adolescents.Cross-sectional study in nine communities in Burkina Faso, Ethiopia, Eswatini, Ghana, Nigeria, Tanzania and Uganda between 2015 and 2017. Community-representative samples of males and females 10-19 years of age were selected. All communities used a uniform questionnaire that was adapted from the WHO Global School-based Student Health Survey. Weighted prevalence estimates and 95% confidence intervals were calculated for each indicator and stratified by age and sex using SAS version 9.4. All prevalence estimates were pooled across communities through random-effects meta-analyses in Stata version 14.A total of 8075 adolescents participated in the study. We observed a high prevalence of inadequate fruit consumption (57-63%) and low physical activity (82-90%); a moderate prevalence of inadequate vegetable consumption (21-31%), unprotected last sex (38-45%), age at first sex15 years (21-28%) and bullying and physical fighting (12-35%); and a low prevalence of mental health risk factors (1-11%) and alcohol and substance use risk factors (0-6%). We observed a moderate to high prevalence of daily soft drink consumption (21-31%) for all adolescents. Among sexually active adolescents 15-19 years, 37% of females reported ever being pregnant and 8% of males reported to have ever made someone pregnant. Bullying (23%) and physical fighting (35%) were more common among younger male adolescents . The prevalence of low mood was generally higher among older (15-19 years) than younger adolescents (10-14 years). The proportion of adolescents reporting alcohol, drug or cigarette use was very small, with the exception of khat use in Ethiopia.Overall, diet and physical activity, violence, sexual and reproductive health, and depression are important risk factors for these sub-Saharan African communities. These findings suggest that more evidence is needed including novel efforts for the collection of sensitive information, as well as a need to move towards community-tailored interventions to reach adolescent populations with varying needs.Mesurer les comportements liés à la santé et les facteurs de risque chez les adolescents africains subsahariens. MÉTHODES: Etude transversale dans neuf communautés au Burkina Faso, en Ethiopie, à Eswatini, au Ghana, au Nigéria, en Tanzanie et en Ouganda entre 2015 et 2017. Des échantillons représentatifs de la communauté composés d'hommes et de femmes âgés de 10 à 19 ans ont été sélectionnés. Toutes les communautés ont utilisé un questionnaire uniforme adapté de l'Enquête Mondiale sur la Santé des Elèves de l'OMS. Les estimations de prévalence pondérée et les intervalles de confiance à 95% ont été calculés pour chaque indicateur et stratifiées par âge et sexe à l'aide de la version 9.4 de SAS. Toutes les estimations de prévalence ont été poolées dans les communautés via des méta-analyses à effets aléatoires dans Stata, version 14. RÉSULTATS: 8.075 adolescents ont participé à l'étude. Nous avons observé une prévalence élevée de consommation insuffisante de fruits (57-63%) et de faible activité physique (82-90%); une prévalence modérée de consommation insuffisante de légumes (21-31%), du dernier rapport sexuel non protégé (38-45%), du premier rapport sexuel à moins de 15 ans (21-28%) et de l'intimidation et des combats physiques (12-35%), une faible prévalence de facteurs de risque pour la santé mentale (1-11%) et de facteurs de risque pour la consommation d'alcool et de substances (0-6%). Nous avons observé une prévalence modérée à élevée de consommation quotidienne de boissons gazeuses (21-31%) chez tous les adolescents. Parmi les adolescents sexuellement actifs âgées de 15 à 19 ans, 37,0% des femmes ont déclaré avoir déjà été enceintes et 8,0% des hommes ont rapporté avoir déjà enceinté une femme. L'intimidation (23%) et les combats physiques étaient plus fréquents chez les adolescents plus jeunes (35%). La prévalence de la mauvaise humeur était généralement plus élevée chez les adolescents d’âge plus élevé (de 15 à 19 ans) que chez les plus jeunes (de 10 à 14 ans). La proportion d'adolescents déclarant avoir consommé de l'alcool, des drogues ou des cigarettes était très faible, à l'exception de la consommation de khat en Ethiopie.Dans l’ensemble, le régime alimentaire et l’activité physique, la violence, la santé sexuelle et reproductive et la dépression sont des facteurs de risque importants pour ces communautés d’Afrique subsaharienne. Ces résultats suggèrent que davantage de données sont nécessaires, notamment de nouveaux efforts pour la collecte d'informations sensibles, ainsi que la nécessité de passer à des interventions adaptées aux communautés pour atteindre les populations adolescentes avec des besoins variés.

Background The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria. Methods At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009–2010 and 2014–2015 and at 2-year interval in 2009–2010 and 2012–2015, respectively after deployment in 2005. Results Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009–2010 to 2014–2015 (P = 0.002 and P 75 000 μl− 1, haematocrit > 27% 1 day post-treatment initiation, treatment with artemether-lumefantrine and enrolment in 2014–2015 independently predicted APPD1. In parallel, Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P = 0.005) and from 9 to 15% (P = 0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3 h within 2 years (P

The coronavirus disease 2019 (COVID-19) pandemic may have short-term and long-term impacts on health services across sub-Saharan African countries. A telephone survey in Burkina Faso, Ethiopia, and Nigeria was conducted to assess the effects of the pandemic on healthcare services from the perspectives of healthcare providers (HCPs) and community members. A total of 900 HCPs (300 from each country) and 1,797 adult community members (approximately 600 from each country) participated in the study. Adjusted risk ratios (ARRs) and 95% confidence intervals (CIs) were computed using modified Poisson regression. According to the HCPs, more than half (56%) of essential health services were affected. Child health services and HIV/surgical/other services had a slightly higher percentage of interruption (33%) compared with maternal health services (31%). A total of 21.8%, 19.3%, and 7.7% of the community members reported that their family members and themselves had difficulty accessing childcare services, maternal health, and other health services, respectively. Nurses had a lower risk of reporting high service interruptions than physicians (ARR, 0.85; 95% CI, 0.56–0.95). HCPs at private facilities (ARR, 0.71; 95% CI, 0.59–0.84) had a lower risk of reporting high service interruptions than those at governmental facilities. Health services in Nigeria were more likely to be interrupted than those in Burkina Faso (ARR, 1.38; 95% CI, 1.19–1.59). Health authorities should work with multiple stakeholders to ensure routine health services and identify novel and adaptive approaches to recover referral services, medical care, maternal and child health, family planning, immunization and health promotion, and prevention during the COVID-19 era.

Objectives COVID-19 has far-reaching consequences for developing countries through the combined effects of infection and mortality and unintended consequences from mitigation measures. COVID-19 can adversely impact food systems and dietary diversity for populations. This cross-sectional study evaluated, using a mobile platform, the effect of COVID-19 on food prices and dietary diversity and quality, among 1797 households in Nouna and Ouagadougou (Burkina Faso), Addis Ababa and Kersa (Ethiopia), and Lagos and Ibadan (Nigeria). Methods Dietary intake was assessed as the frequency of consumption of 20 food groups over the previous 7 days. Dietary diversity scores (DDS; range: 0–10) and Prime Diet Quality Score (PDQS; range: 0–40) assessed dietary diversity and quality. Linear regression models were used to evaluate associations between changes in the prices of staples, pulses, vegetables, fruits, and animal source foods (ASF) with DDS and PDQS during COVID-19. Results Most households reported increases in prices of staples, pulses, fruits, vegetables and ASF, and ≥40% reported decreased consumption of staples, legumes, ASF, other vitamin A rich vegetables, other vegetables and other fruits, and lower DDS and PDQS compared to the period before the COVID-19 emergency. Increases in pulse prices were associated with lower DDS (estimate − 0.35, 95% CI: −0.61, −0.09). Lower crop production (estimate − 0.70, 95% CI: −1.02, −0.37), and skipping meals (estimate − 0.39, 95% CI: −0.56, −0.21) or not eating for a whole day (estimate − 0.23, 95% CI: −0.43, −0.03) were also associated with lower DDS. Conclusions The price increases and worsening dietary diversity and quality call for social protection and other strategies to increase the availability and affordability of nutrient-rich foods during the COVID-19 pandemic and other public health emergencies. Funding Sources The Bill and Melinda Gates Foundation Grant as well as institutional support from the Heidelberg Institute of Global Health, Germany and the Harvard T.H. Chan School of Public Health, USA, supported this work.

The ARISE Network Adolescent Health Study is an exploratory, community-based survey of 8075 adolescents aged 10-19 in 9 communities in 7 countries: Burkina Faso, Eswatini, Ethiopia, Ghana, Nigeria, Tanzania and Uganda. Communities were selected opportunistically and existing population cohorts maintained by health and demographic surveillance systems (HDSSs). The study is intended to serve as a first round of data collection for African adolescent cohorts, with the overarching goal of generating community-based data on health-related behaviours and associated risk factors in adolescents, to identify disease burdens and health intervention opportunities. Household-based sampling frames were used in each community to randomly select eligible adolescents (aged 10-19 years). Data were collected between July 2015 and December 2017. Consenting participants completed face-to-face interviews with trained research assistants using a standardised questionnaire, which covered physical activity, cigarette and tobacco use, substance and drug use, mental health, sexual behaviours and practices, sexually transmitted infections, pregnancy, food security and food diversity, teeth cleaning and hand washing, feelings and friendship, school and home activities, physical attacks and injuries, health care, health status assessment and life satisfaction, as well as media and cell phone use and socio-demographic and economic background characteristics. Results from this multi-community study serve to identify major adolescent health risks and disease burdens, as well as opportunities for interventions and improvements through policy changes.L’étude ARISE du réseau sur la santé des adolescents est une étude exploratoire de surveillance basée sur la communauté portant sur 8.075 adolescents âgés de 10 à 19 ans dans 9 communautés de 7 pays: Burkina Faso, Eswatini, Ethiopie, Ghana, Nigéria, Tanzanie et Ouganda. Les communautés ont été sélectionnés de manière opportuniste et les cohortes de population existantes maintenues par des systèmes de surveillance de la santé et démographique (SSSD). L'étude est destinée à servir comme premier cycle de collecte de données pour les cohortes d’adolescents africains, dans le but primordial de générer des données communautaires sur les comportements liés à la santé et les facteurs de risque associés chez les adolescents, afin d'identifier la charge de morbidité et les opportunités d'intervention en matière de santé. Des cadres d'échantillonnage basés sur le ménage ont été utilisés dans chaque communauté pour sélectionner au hasard les adolescents admissibles (âgés de 10-19 ans). Les données ont été collectées entre juillet 2015 et décembre 2017. Les participants consentants ont participé à des entretiens de face à face avec des assistants de recherche formés, à l'aide d'un questionnaire standardisé couvrant l'activité physique, l’usage de la cigarette ou la consommation de tabac, l'usage de drogues et autres substances, la santé mentale, les comportements et pratiques sexuels, les infections sexuellement transmissibles, la grossesse, la sécurité et la diversité alimentaire, le nettoyage des dents et le lavage des mains, les sentiments et les amitiés, les activités scolaires et à domicile, les attaques et les blessures physiques, les soins de santé, l’évaluation de l’état de santé et la satisfaction à l’égard de la vie, l’utilisation des médias et du téléphone portable ainsi que les caractéristiques sociodémographiques et économiques. Les résultats de cette étude portant sur plusieurs communautés permettent d'identifier les principaux risques pour la santé des adolescents et les charges de morbidité, ainsi que les opportunités d'interventions et d'amélioration par le biais de changements de politiques.

Resistance in Plasmodium falciparum to amodiaquine (AQ) can be reversed in vitro with with antihistaminic and tricyclic antidepressant compounds, but its significance in vivo is unclear. The present report presents the enhancement of the antimalarial efficacy of AQ by chlorpheniramine, an H1 receptor antagonist that reverses chloroquine (CQ) resistance in vitro and enhances its efficacy in vivo, in five children who failed CQ and/or AQ treatment, and who were subsequently retreated and cured with a combination of AQ plus CP, despite the fact that parasites infecting the children harboured mutant pfcrtT76 and pfmdr1Y86 alleles associated with AQ resistance. This suggests a potential clinical application of the reversal phenomenon.

Resistance to chloroquine (CQ) in Plasmodium falciparum has reached unacceptably high levels in many endemic countries. The pre-treatment factors that identify the children who are at risk of treatment failure after being given CQ were evaluated in 385 children with acute, uncomplicated, Plasmodium falciparum malaria. These children each took part in one of six antimalarial drug trials conducted, between July 1996 and July 2004, in a hyper-endemic area of south-western Nigeria. Following treatment with CQ, 149 (39%) of the children failed treatment by day 7 or 14. In a multivariate analysis, an age ofor =7 years [giving an adjusted odds ratio (AOR) of 2.17, with a 95% confidence interval (CI) of 1.19-3.85; P = 0.01], an asexual parasitaemia ofor =100,000/microl (AOR = 2.17; CI = 1.08-4.35; P = 0.03), the presence of gametocytaemia (AOR = 2.08; CI = 1.14-3.85; P = 0.02) and enrolment4 years after commencement of the study (i.e. after 2000; AOR = 2.13; CI = 1.3-4.0; P = 0.003) were found to be independent predictors at presentation of the subsequent failure of treatment with CQ. Compared with the other children, those who failed to clear their parasitaemias within 3 days and those who still had fever 1-2 days after commencing treatment were more likely to be treatment failures. Together, these findings may have implications for malaria-control efforts in all areas of sub-Saharan Africa where treatment of malaria depends almost entirely on antimalarial monotherapy.

Resistance to chloroquine in Plasmodium falciparum can be reversed, both in vitro and in vivo, by chlorpheniramine, a histamine H(1) receptor antagonist. This reversal raises the possibility of using chlorpheniramine to prolong the clinical usefulness of chloroquine in resource-poor communities. The factors that identify children at risk of treatment failure after being given chloroquine plus chlorpheniramine have now been evaluated in 281 children with uncomplicated, P. falciparum malaria. The children, who had taken part in six trials of antimalarial drugs between February 1996 and September 1999, in a hyper-endemic area of south-western Nigeria, were enrolled prospectively for the present study. Following treatment with chloroquine plus chlorpheniramine, 13 (5%) of the children failed treatment by day 7 or 14. In a multivariate analysis, an age ofor =3 years (adjusted odds ratio = 11.1; 95% confidence interval = 2.2-55.3; P = 0.003) and a parasitaemia that took3 days to clear (adjusted odds ratio=7.9; 95% confidence interval = 1.3-49.4; P = 0.027) were found to be independent predictors of treatment failure. In addition, compared with the children who had a lower axillary temperature then, the children who had an axillary temperature ofor =38 degrees C 2 days after commencing treatment were significantly more likely to be treatment failures. In resource-poor communities using chloroquine plus chlorpheniramine, the easily identifiable predictors of treatment failure might be used to identify children requiring alternative antimalarial drugs.

Seven methanol extracts of seven plants from seven plant families were screened for antimalarial properties. The plants were identified and selected from Gboko and Kastina-Ala local government areas in the Tivland ethnobotany in the Middle Belt Zone of Nigeria. Methanol plant extracts were evaluated for in vitro. antimalarial properties using the lactate dehydrogenase technique, with a multiresistant strain of Plasmodium falciparum. K1. Quantification of activity was by estimation of the concentration of extracts that inhibited 50% growth of parasite (IC50) in µg/ml. Of the seven plants screened, Erythrina senegalensis. DC (Leguminosae), Pericopsis elata. Harms (Papilionaceae), and Bridelia micrantha. Benth (Fabaceae) had IC50 values of 99.7, 124.8, and 158.7 µg/ml, respectively. Nauclea latifolia. SM (Rubiaceae) extract exhibited the least activity in the assay with an IC50 value of 478.9 µg/ml.

The ethnographic study was conducted in two communities in Oyo State in Southwestern Nigeria. The study sites consisted of a rural and an urban local government area located in the tropical rain forest zone of Nigeria. The study was designed to obtain information on febrile illnesses and herbal remedies for treatment with the aim of identifying potential antimalarial drugs. The study revealed that fever is a general term for describing illnesses associated with elevated body temperature. The indigenous Yoruba ethnic population has categorized fever based on symptoms and causes. The present communication is the result of focus group discussion and semi-structured questionnaire administered to traditional healers, herb sellers, elders and mothers. This was on types of fevers, symptoms and causes of febrile illnesses. The investigation also included use of traditional herbs in the prevention and treatment of the illnesses in the two communities.A total of 514 respondents were interviewed. This was made up of 266 (51.8%) from Atiba local government area (LGA), an urban centre while 248 (48.2%) respondents were interviewed from Itesiwaju LGA, a rural community. The LGAs are located in Oyo State of Nigeria. The respondents proffered 12 types of febrile illnesses in a multiple response answering system in Yoruba language. The most common ones (direct translation into English) were: yellow fever (39.1%), typhoid (34.8%), ordinary (28.8%), rainy season (20.8%) and headache (10.5%) fevers, respectively. Perceived causes of each of the febrile illnesses included stress, mosquito bites, unclean water, rains and over exposure to the sun. Methods of fever prevention were mainly with the use of herbal decoctions, powdered herbs, orthodox medications and maintenance of proper hygiene. Of a total of 112 different herbal remedies used in the treatment of the febrile illnesses compiled from the study, 25 recipes are presented. Recipes consisted of 2-7 ingredients. Oral decoctions (84%), oral powders (63%), use as soaps and creams (40%) in a multiple response system, were the most prevalent routes of administration of prepared herbs used in the treatment of the fevers. Boiling in water or alcohol was the most common method used in the preparation of the remedies. The four most frequently mentioned (multiple response system) plants in the Southwest ethnobotany for fevers were Azadirachta indica (87.5%), Mangifera indica (75.0%), Morinda lucida (68.8%) and Citrus medica (68.8%).

The efficacy of chloroquine and chloroquine plus chloropheniramine, a histamine H1 receptor blocker which reverses chloroquine insensitivity in Plasmodium falciparum in vitro, was studied in 96 children with acute symptomatic uncomplicated falciparum malaria. The chloroquine/chloropheniramine combination produced a significantly higher cure rate than chloroquine alone and cured 77% of children with chloroquine treatment failures. Children with chloroquine treatment failure had mean plasma chloroquine concentrations above the minimum therapeutic concentration for the area. Chloroquine concentrations in plasma and red blood cells and ratio of red cell to plasma chloroquine concentrations on days 3 and 7 after initiation of therapy were not significantly different in the two groups. Chloroquine/chloropheniramine produces a higher cure rate than chloroquine alone and reverses chloroquine insensitivity in Plasmodium falciparum in vivo. It may be a useful way of optimising the antimalarial effect of chloroquine.

Drug resistance inPlasmodium falciparumrequires that new drugs must be developed. Plants are a potential source for drug discovery and development. Two plants that used to treat febrile illnesses in Nigeria were tested forin vitroandin vivoantimalarial activity and cytotoxicity in cancer cell lines. Methanol, hexane, and ethyl acetate leaf extracts ofFicus thonningiiandLophira alatawere active inin vitroassays againstP. falciparumNF54 (sensitive) and K1 (multiresistant) strains. Hexane extracts ofF. thonningiiandL. alatawere the most effective extracts inin vitroassays with IC50of2.7±1.6 μg/mL and2.5±0.3 μg/mL for NF54 and10.4±1.6 μg/mL and2.5±2.1 μg/mL for K1 strain. All extracts were nontoxic in cytotoxicity assays against KB human cell line with IC50of over 20 μg/mL, demonstrating selectivity againstP. falciparum.In vivoanalysis shows that hexane extracts of both plants reduced parasitaemia. At the maximum dose tested,L. alatahad a 74.4% reduction of parasitaemia whileF. thonningiihad a reduction of 84.5%, both extracts prolonged animal survival in mice infected withP. bergheiNK65 when compared with vehicle treated controls. The antiplasmodial activity observed justifies the use of both plants in treating febrile conditions.

The Plasmodium falciparum erythrocyte binding antigen-175 gene (eba-175) has highly divergent allelic segments (Cseg and Fseg) in one part of the gene (region III), but only a small number of single nucleotide polymorphisms (SNPs) in the rest of the sequence. Here, evidence for the possible importance of the Cseg/Fseg dimorphism was sought in a molecular population genetic analysis of the gene. First, allele frequency distributions were determined for the Cseg/Fseg dimorphism and five SNPs in a sample of five populations in Africa. The inter-population variance in frequencies was higher for Cseg/Fseg (F(ST)=0.18) than for the SNPs (F(ST) values from 0.03 to 0.10), but these values were entirely dependent on the inclusion of one particularly divergent population (Sudan). Second, linkage disequilibrium was measured among the intragenic loci. There was the expected trend of declining linkage disequilibrium with increasing molecular distance, but it is notable that the Cseg allele was in absolute linkage disequilibrium with the two flanking SNPs, whereas the Fseg allele was associated with a broader range of SNP haplotypes. Finally, there was no association between the Cseg/Fseg alleles of eba-175 in parasites and the M/N alleles of the glycophorin A erythrocyte receptor in the human subjects.

Objectives: To examine the kinetics of the disposition of Plasmodium falciparum during treatment with amodiaquine, a Mannich base derivative of chloroquine and chloroquine. Additional aims were to compare P. falciparum kinetics in children in whom initial treatment with chloroquine failed and following re-treatment with amodiaquine, and in siblings in whom there was household clustering of falciparum infections. An important aim was to validate the kinetic method of evaluating therapeutic efficacy in a randomised trial involving the antimalarial drugs amodiaquine and chloroquine. Design: Nonblind, randomised, controlled trial. Patients and Participants: 210 children aged 0.5 to 12 years who presented with acute, symptomatic, uncomplicated P. falciparum malaria between September and December 2000. Methods: Children were randomised to receive amodiaquine 30 mg/kg given over 3 days (n = 104) or chloroquine base 30 mg/kg given over 3 days (n = 106). Clinical and parasitological assessments were done pretreatment and 24-hourly for 168 hours and at 336, 504 and 672h. Parasite disposition kinetics were estimated from parasite concentrations by using a noncompartmental method. Results: Following treatment, the areas under the parasite density versus time curve (AUCpd) and the half-life of parasitaemia (t1/2pd) were significantly lower with amodiaquine than with chloroquine [518.7 ± 47.5 (standard error) vs 810.7 ± 101.3 asexual forms/μl · h, p = 0.01, and 3.5 ± 0.1 (class IIb) vs 4.5 ± 0.3h (class IV), p = 0.001, respectively]. The volume of blood completely cleared of parasites per unit time (CLBpd) was higher (not significant) with amodiaquine than with chloroquine. Fractional reduction of AUCpd at 24 and 48h was significantly higher (0.87 ± 0.01 vs 0.8 ± 0.02, p = 0.001; 0.98 ± 0.001 vs 0.93 ± 0.02, p = 0.02, respectively) and the t1/2,pd index was significantly lower (1.9 ± 0.05 vs 2.5 ± 0.2, p = 0.0035) with amodiaquine than with chloroquine. In children where initial treatment with chloroquine failed (n = 20), t1/2,pd and t1/2,pd index following re-treatment with amodiaquine were significantly lower [3.9 ± 0.4 (class IIIa) vs 6.0 ± 1.03h (class V), p = 0.047; 2.1 ± 0.19 vs 4.3 ± 0.9, p = 0.03, respectively] and the CLBpd was higher (not significant) than during initial treatment with chloroquine. In siblings in whom there was clustering of infections (amodiaquine n = 12; chloroquine n = 11), there was no difference in parasite kinetic profiles. Both drugs were relatively well tolerated. Conclusions: These findings indicate that amodiaquine produces more favourable P. falciparum disposition kinetic profiles than chloroquine, indicating a better efficacy, and may be used as an alternative to chloroquine in chloroquine-resistant infections in endemic areas. The kinetic method of evaluating therapeutic efficacy can be employed in formal therapeutic trials of antimalarial drugs.

The clinical characteristics and the kinetics of the disposition of the hepatomegaly associated with acute, uncomplicated Plasmodium falciparum malaria were investigated in 162 children in an endemic area of Nigeria. Hepatomegaly was significantly more common in the younger than in the older children. Complete resolution occurred in 48% following antimalarial chemotherapy. In the children in whom hepatomegaly did not resolve, a reduction in liver size of17% by the time parasitaemia was cleared (usually on day 3) was associated with non-resolution of hepatomegaly by days 7 or 14 of follow-up. An increase in liver size to at least 125% of the baseline value by day 4 or 5 was associated with a lack of therapeutic response, providing the child involved was aged5 years. In the children who had complete clearance of parasitaemia and resolution of hepatomegaly, there was no significant relationship between the parasitaemia-derived conventional indices of therapeutic response [i.e. time to clearance of 50% (PC50) or 90% (PC90) of the parasitaemia, and the parasite-clearance time (PCT)] and the corresponding parameters derived from measurement of liver size [i.e. time for resolution of 50% (HR50) or 90% (HR90) of the hepatomegaly and the hepatomegaly-resolution time (HRT)] in the same patients. However, as the HR50:PC50, HR90:PC90 and HRT:PCT ratios were similar (range = 1.6-2.1), the liver parameters may have therapeutic application. In the children with drug-sensitive P. falciparum infections and in whom hepatomegaly completely resolved, the area produced by plotting liver size against time (i.e. the area under the curve of hepatomegaly v. time, or AUChp) increased in proportion to the liver size below the costal margin (P = 0.02, from analysis of variance), but there was no significant difference in the half-lives of hepatomegaly (t1/2hp) or in the ratios of liver size to AUChp, indicating that the kinetics of the resolution of hepatomegaly were linear in the range examined. Comparison of the kinetic indices of hepatomegaly and parasitaemia showed that, although the half-lives of parasitaemia and hepatomegaly and the corresponding clearance values were similar, there was no correlation between these parameters among those in whom hepatomegaly completely resolved and parasitaemia completely cleared. These results indicate that routine clinical measurement of the liver size in children with hepatomegaly during acute, uncomplicated, P. falciparum malaria may have some use in evaluating and monitoring the therapeutic responses of infections. The resolution of hepatomegaly, a reflection of pathological changes, lags behind clearance of parasitaemia in children with P. falciparum malaria, and supports the use of the liver 'rate' as a malariometric index for assessing the intensity of transmission in endemic areas.

Objectives To evaluate the effects of standard parenteral doses of artemether given over 5 days and to compare these effects with those of a single loading dose of artemether followed by a single oral dose of mefloquine on Plasmodium falciparum in vivo and on ex vivo parasite viability, and to assess the relationships between P. falciparum viability ex vivo and the responses in vivo to these regimens in children with severe non-cerebral falciparum malaria.

Objectives: To compare the therapeutic efficacy and tolerability of two regimens of chlorpheniramine in combination with chloroquine in children with acute, symptomatic, uncomplicated falciparum malaria. A further aim was to examine the kinetics of the disposition of Plasmodium falciparum during treatment with these regimens. Chlorpheniramine reverses chloroquine resistance in Plasmodium falciparum in vitro and in vivo. Methods: 96 children with acute, symptomatic, uncomplicated falciparum malaria who were resident in an endemic area where the rate of chloroquine resistance is 35 to 45% were treated in this randomised study. They received high-dose chlorpheniramine (6mg + 12 mg/day in children aged ≤5 years; 8mg + 18 mg/day in those aged >5 years) plus chloroquine 10 mg/kg daily for 3 days (n = 47), or very high-dose (150% of high dose) chlorpheniramine plus chloroquine (n = 49) orally. Clinical and parasitological assessment was done daily on days 0–7 and day 14. Parasite disposition kinetics were evaluated from parasite concentrations using a noncompartmental method. Results: Both high-and very high-dose chlorpheniramine plus chloroquine regimens produced similar parasite (67.2 ± 14.4 vs 67.2 ± 14.4 h) and fever (36.0 ± 19.2 vs 36.0 ± 19.2 h) clearance times and cure rates (95.7 vs 95.9%), respectively. The areas under the parasite density versus time curve, the half-lives of parasitaemia and the volume of blood completely cleared of parasites per unit time were also similar for the two treatment regimens. Both treatment regimens were relatively well tolerated, but sleepiness was significantly more frequent in the very high-dose group. Biochemical and haematological parameters were not adversely affected by either regimen. Conclusions: Very high-dose chlorpheniramine in combination with chloroquine has no therapeutic advantage over high-dose chlorpheniramine in combination with chloroquine in this endemic area at the present time. The indices of therapeutic responses derived from the evaluation of parasite kinetic parameters produced conclusions similar to those of the conventional indices for the measurement of therapeutic responses to antimalarial drugs.

Objective: To examine the cardiac effects of halofantrine by evaluating the apatterns of change in the ECG, including the PR and QTC intervals and the presence or absence of rhythm disturbances, following treatment with halofantrine of children with acute, symptomatic, uncomplicated falciparum malaria. Design and Setting: This was an observational study performed in Nigeria in 1994 to 1995 and in 1997. Patients and Participants: 63 children who were enrolled in studies on the antimalarial efficacy of halofantrine. Methods: A 12-lead ECG was recorded before and at specific intervals after administration of halofantrine (24 mg/kg of bodyweight) for a total monitoring period of 1 to 2 weeks. Changes in the ECG intervals and the patterns of change were analysed using defined criteria. Results: There was no clinical cardiac intolerance to halofantrine. 76% of the children (48 of 63) showed changes in their ECG. There was a significant increase in PR interval only at 8 hours after treatment. The rate-corrected QT (QTC) interval increased following treatment, with significant differences from time zero from 6 or 8 to 96 hours. A grouping of the patterns of the ECG change based on the type of interval prolongation, the relationship to the time-course of therapy or drug administration, the duration of prolongation and the absence or presence of rhythm disturbance showed the following patterns: no change (24%), early or late monophasic prolongation of PR interval (3%), early monophasic (60%) or late monophasic (1.5%) prolongation of QTC interval, biphasic prolongation of QTC interval (4.7%), early monophasic prolongation of both PR and QTC intervals (1.5%), biphasic prolongation of both PR and QTC intervals (1.5%), other patterns (3%). Conclusion: Halofantrine has significant effects on ECG intervals with varying patterns of change; the biphasic and late monophasic changes suggest that adverse cardiac effects may be early, early and late, or late in appearing. In children, the currently recommended dose of halofantrine for the treatment of malaria may produce serious cardiac effects.

Objective: To examine the kinetics of the disposition of Plasmodium falciparum during treatment with antimalarial drugs in 565 children presenting with acute, symptomatic, uncomplicated malaria. Methods: We conducted a prospective study using conventional principles for the disposition of drugs to characterise the kinetics of the disposition of parasitaemia in children treated with antimalarial drugs. We also evaluated the relationship between the indices of parasite kinetics and the conventional indices of therapeutic response to antimalarial drugs. Parasite kinetic parameters were estimated from parasite densities (parasite concentrations) by the noncompartmental method. Results: In drug-sensitive P. falciparum infections, the areas under the parasite density versus time curve (AUCpd) increased in proportion to parasite load from 2500 to 320 000 asexual forms/μl blood [p = 0.0004, analysis of variance (ANOVA)], but there was no significant difference in the half-lives of reduction of parasitaemia (t1/2pd), the volume of blood completely cleared of parasites per unit time (CLBpd) or the parasite density: AUCpd ratio, indicating that the kinetics of the disposition of parasitaemia were linear in the concentration range examined. In drug-sensitive infections, AUCpd, t1/2pd and CLBpd were similar for chloroquine, pyrimethamine-sulfadoxine, halofantrine, chloroquine plus chlorphenamine (chlorpheniramine), and cotrimoxazole (trimethoprim-sulfamethoxazole). However, t1/2pd was significantly lower (p = 0.00001, ANOVA) and CLBpd significantly higher (p = 0.00001, ANOVA) for artemether when compared with other antimalarials used in sensitive infections, suggesting a relatively superior rapidity of action. In age, gender and parasite-density matched children, CLBpd was significantly higher (p = 0.00003) in sensitive than in moderately or severely resistant infections. In treatment-sensitive infections, there was a correlation between t1/2pd and parasite clearance time (PCT) [r2 = 0.988, p = 0.00001]. The PCT: t1/2pd ratio was similar for all drugs (range 18–21; p = 0.072, ANOVA) and remained constant (p = 0.925, ANOVA) irrespective of PCT. A new index to classify the rapidity of action of antimalarial drugs in vivo based on the relationship between t1/2pd and PCT is presented. Conclusions: The kinetics of the disposition of P. falciparum parasitaemia in children with drug-sensitive infections are linear. The kinetic and other derived indices presented here may be used to evaluate and monitor the therapeutic responses of infections and the rapidity of antimalarial action in children.

The gastrointestinal manifestations of acute symptomatic uncomplicated falciparum malaria were studied in 184 consecutive children aged from 6 months to 15 years. Vomiting was the most common and epigastralgia the least common presenting symptom. Peripheral parasite density was higher in children who were vomiting than in those who were not. There was no relationship between the density of peripheral parasitaemia and the duration of gastrointestinal symptoms at presentation. All gastrointestinal symptoms cleared within 3 days after instituting antimalarial therapy.

Malaria parasites are sexually reproducing protozoa, although the extent of effective meiotic recombination in natural populations has been debated. If meiotic recombination occurs frequently, compared with point mutation and mitotic rearrangement, linkage disequilibrium between polymorphic sites is expected to decline with increasing distance along a chromosome. The rate of this decline should be proportional to the effective meiotic recombination rate in the population. Multiple polymorphic sites covering a 5-kb region of chromosome 9 (the msp1 gene) have been typed in 547 isolates from six populations in Africa to test for such a decline and estimate its rate in populations of Plasmodium falciparum . The magnitude of two-site linkage disequilibrium declines markedly with increasing molecular map distance between the sites, reaching nonsignificant levels within a map range of 0.3–1.0 kb in five of the populations and over a larger map distance in the population with lowest malaria endemicity. The rate of decline in linkage disequilibrium over molecular map distance is at least as rapid as that observed in most chromosomal regions of other sexually reproducing eukaryotes, such as humans and Drosophila . These results are consistent with the effective recombination rate expected in natural populations of P. falciparum , predicted on the basis of the underlying molecular rate of meiotic crossover and the coefficient of inbreeding caused by self-fertilization events. This is conclusive evidence to reject any hypothesis of clonality or low rate of meiotic recombination in P. falciparum populations. Moreover, the data have major implications for the design and interpretation of population genetic studies of selection on P. falciparum genes.

In the face of growing chloroquine resistance of Plasmodium falciparum, efforts to prolong the clinical usefulness of the drug have partly concentrated on its combination with potential resistance-reversing compounds. However, clinical studies on such combinations have been limited. We have compared the efficacy of halofantrine, an arylaminoalcohol effective in chloroquine resistant malaria, and a combination of chloroquine plus chlorpheniramine, a histamine H1 receptor antagonist which reverses chloroquine resistance of P. falciparum in vitro and in vivo, in 100 children with acute symptomatic uncomplicated falciparum malaria in an area in Nigeria where the rate of chloroquine resistance is 35-45%. Both chloroquine plus chlorpheniramine and halofantrine produced similar parasite and fever clearance times and cure rates (96%). Both treatment regimens were relatively well tolerated. Pruritus was commoner in patients treated with chloroquine plus chlorpheniramine than in those treated with halofantrine. Intravascular haemolysis occurred in one patient, and abdominal pain with or without diarrhoea occurred in 4 patients, treated with halofantrine. In vitro, the chloroquine resistance of P. falciparum isolates obtained from the patients was reversed by verapamil. All patients with isolates which were chloroquine-resistant in vitro were cured by either therapy. These results indicate that chloroquine plus chlorpheniramine is as effective as halofantrine and is without overt deleterious effect in treating acute uncomplicated chloroquine-resistant falciparum malaria in children, and may be a clinically useful alternative for this purpose in Nigeria.

The effect of combining promethazine with chloroquine was examined against Plasmodium falciparum in vitro in the Aotus-P. falciparum model and in bioassays from volunteers given promethazine. The combination of chloroquine plus promethazine (1 x 10(-6) M) reversed chloroquine resistance in standard P. falciparum clones and patient parasite isolates from Nigeria. The combination reduced the 50% inhibitory concentrations (IC50s) for chloroquine against resistant parasites by 32-92%. Coadministration of promethazine with chloroquine also demonstrated a dose-dependent effect in Aotus monkeys infected with chloroquine-resistant P. falciparum. Monkeys were given a chloroquine dose (20 mg/kg of body weight for seven days), which normally has no effect on parasitemia, plus 10, 20, 40, or 80 mg of promethazine/kg of body weight. In one monkey, parasitemia was suppressed at the lowest promethazine dose, but re-treatment with 20 mg/kg resulted in clearance of parasitemia. Initial treatment with chloroquine and 20 or 40 mg/kg of promethazine cleared parasitemia in some animals followed by recrudescence. Re-treatment at higher doses cured one monkey and resulted in initial clearance and delayed recrudescence 28 or 63 days after treatment in two monkeys. Recrudescent parasitemia in the two monkeys was low (10 parasites/microl of blood) and subsequently cleared without re-treatment. An in vitro bioassay model was developed to examine the effects of clinically achievable doses of promethazine on parasites susceptibilities in vitro. Plasma samples taken at hourly intervals from patients given a single oral dose of 25 mg of promethazine decreased the IC50 values for chloroquine by 20-58% with the most significant reductions occurring in plasma obtained from volunteers 3-4 hr after ingestion. Plasma obtained from two volunteers 6 hr after ingestion of the drug demonstrated no effect on chloroquine susceptibility, suggesting that study of the pharmacokinetic disposition and potential interaction is warranted to optimize the dose regimen in patients for antimalarial efficacy. Historic use of this drug combination for treatment or prevention of chloroquine-associated pruritus or as an antiemetic suggest that the combination is safe and effective when used at standard dosages. The results from this study demonstrate that promethazine is a potent modulator of chloroquine resistance. Clinical evaluation of therapeutic regimens is required to validate clinical efficacy of this promising combination for treatment of uncomplicated chloroquine-resistant malaria.

The efficacy of chloroquine plus chlorpheniramine, a histamine H receptor antagonist, which reverses chloroquine 1 insensitivity in Plasmodium falciparum in vitro and in vivo , was evaluated in 30 pregnant women with recrudescent chloroquine-resistant Plasmodium falciparum malaria. All patients had at least one or more treatment failures with one or more courses of chloroquine or pyrimethamine-sulphadoxine. There was a prompt response to treatment with parasitaemia and fever clearing in all patients within 48 and 96 hours respectively of commencement of therapy with the combination. The cure rate on day 14 was 77%. Parasitaemia recurred in seven patients after day 14 and was successfully treated with oral mefloquine. The combination was well tolerated; pruritus and drowsiness were the only noticeable adverse effects. The progress of pregnancy and its outcome were not adversely affected by treatment with the combination. When fully developed, the combination of chloroquine plus chlorpheniramine may be an alternative in the treatment of chloroquine-resistant malaria during pregnancy in Nigerian women.

The correlation of P. falciparum lactate dehydrogenase (pLDH) activities and patent infections was evaluated for monitoring therapeutic responses and drug resistance in 70 patients with microscopically confirmed P. falciparum malaria in Nigeria. Each patient was treated with standard dosages of artemether (53 patients), chloroquine (7 patients), sulfadoxine-pyrimethamine (6 patients), or halofantrine (4 patients). Response of infection to treatment was monitored by microscopic examination of thick and thin blood smears, clinical symptoms, and levels of pLDH activities in blood products. pLDH activity was determined using an antibody capture technique and 3-acetyl pyridine adenine dinucleotide developed to enhance sensitivity of the enzyme detection. All patients treated with artemether were cured while 5 patients treated with chloroquine, 1 treated with sulfadoxine-pyrimethamine, and 2 treated with halofantrine suffered recrudescent infections after treatment. pLDH activity was detected in blood products obtained from patients with patent or recrudescent infections determined by microscopy and clinical symptoms. Levels of pLDH activities in whole blood and packed cells from the patients correlated with qualitative detection of parasites in blood smears and in patients with high gametocyte counts. Gametocyte counts in the patients after treatment ranged from 40 gametocytes/microliter of blood to 4923 gametocytes/microliter of blood. There is a consistent relationship between patent infection and pLDH activities that could easily be determined in whole blood and packed cells from the patients. Further development of the procedure will enhance its valuable application in clinical management of drug-resistant malaria in the endemic areas.

In a previous report we described the synergistic antimalarial interaction between two structurally similar compounds, rufigallol and exifone. To explain this phenomenon, we proposed that exifone is transformed inside the parasitized erythrocyte into a xanthone with potent antimalarial properties. We speculated that the transformation process was induced by the prooxidant activity of rufigallol. On the basis of this model we hypothesized that exifone would act synergistically with other oxidant drugs. In the present study we have found a similar synergistic interaction between exifone and ascorbic acid (vitamin C) against both chloroquine-susceptible and multidrug-resistant strains of Plasmodium falciparum. The prooxidant activity of ascorbic acid against Plasmodium-infected erythrocytes is believed to result from an intraerythrocytic Fenton reaction occurring in the acidic food vacuole of the parasite. The hydroxyl radicals produced during this process are believed to attack exifone, which undergoes cyclodehydration to become 2,3,4,5,6-pentahydroxyxanthone (X5). Evidence presented to support this "xanthone hypothesis" includes the demonstration that the exifone ==> X5 transformation occurs readily in vitro under mildly acidic conditions in the presence of iron, ascorbic acid, and oxygen.

Chlorpheniramine, a histamine H1 receptor antagonist, reverse chloroquine resistance in Plasmodium falciparum in vitro. However, the clinical significance of this remains unclear. We have evaluated the efficacy of chloroquine and a chloroquine-chlorpheniramine combination in 112 consecutive children with acute symptomatic uncomplicated falciparum malaria. There was no significant difference in the parasite and fever clearance times in the 2 treatment groups. However, the proportion of patients in whom parasitaemia increased 24 h after commencement of treatment was significantly higher in the chloroquine group than in the chloroquine-chlorpheniramine group (28.5% vs. 8.3%, chi 2 = 6.61, P < 0.01). There was also a higher proportion of children with RII and RIII responses to treatment in the chloroquine than in the chloroquine-chlorpheniramine group but the difference was not statistically significant. The cure rate on day 14 was higher in the chloroquine-chlorpheniramine group than in the chloroquine group. Chloroquine and its combination with chlorpheniramine were well tolerated, the only prominent adverse effect being pruritus, with equal incidence in both groups. Chlorpheniramine reversed chloroquine resistance in vitro in a similar manner to verapamil in isolates of P. falciparum obtained from the patients. Failure of a response in vivo to chloroquine correlated with resistance in vitro in patients treated with this drug. In contrast, all but one patient with isolates which were chloroquine resistant in vitro were successfully treated with chloroquine-chlorpheniramine combination. These data suggest the enhanced efficacy of chloroquine-chlorpheniramine combination in treating acute uncomplicated P. falciparum infection in children from an endemic area of Nigeria.

SummaryA safe and efficient method for obtaining blood smears for the diagnosis of placental malaria infection is required in order to reduce the risks associated with direct blood contact. We describe a simple and safe method of needle aspiration of the placenta for the diagnosis of placental malaria infection. The method was compared with the conventional incision method in 60 consecutive placentae obtained at term. The quality of the blood smear prepared with the methods were similar. There was a significant correlation between parasite counts from samples prepared with both the incision and aspiration methods. Altman-Bland analysis of the counts revealed narrow limits of agreement with an insignificant bias. The method is useful for obtaining blood smears from the placenta for the diagnosis of placental malaria infection and reducing contact with potential pathogens in blood.

SummarySeventy-three placentae and 73 newborn babies were examined from 72 consecutive parturient Nigerian women at term. Ten of the placentae had ring forms of Plasmodium falciparum only, 17 placentae had ring forms and schizonts, and two placentae had only schizonts. Pigment granules alone was present in two placentae, and pigment granules in combination with ring forms and/or schizonts were seen in 10 placentae. There was seasonal variation in both maternal and placental parasite infection. There was also a positive correlation between peripheral and placental parasite density. First-born babies of primigravidae with infected placentae weighed less and had body lengths lower than those of first-born babies with non-infected placentae but the difference was not statistically significant. Their weights and lengths were also significantly less than those of babies of multigravidae with infected placentae. Peripheral parasitaemia was present in 16 of 73 (21 per cent) newborn babies. Parasite density in the...

Isolates (UCH-23 and OM) and cloned strains of Plasmodium falciparum (Clones W-2 and D-6) were maintained in continuous culture for 28 to 150 days using culture media supplemented with 10% (v/v) heat inactivated semi-immune human plasma. Microscopic appearance and growth rates (R) of the parasites in media supplemented with semi-immune human plasma [R = 1.13 (W-2), 0.92 (D-6), 0.75 (OM) and 0.84 (UCH-23)] were comparable to those of parallel cultures maintained in media supplemented with 10% (v/v) heat inactivated non-immune human plasma [R = 1.42 (W-2), 0.83 (D-6), 0.66 (OM) and 0.89 (UCH-23)]. In addition, IC50 for chloroquine and mefloquine against the two cloned strains of P. falciparum maintained in culture media supplemented with either non-immune human plasma or semi-immune human plasma were identical. Although growth rates of new isolates (UCH-23 and OM) fluctuated over time, they stabilized between the 12th and 19th day of adaptation to culture. This fluctuation in growth rates of the new isolates underscores the influence of population dynamics during adaptation of P. falciparum to continuous culture. Sixty-eight percent of the primary isolates (170 of 250) obtained from patients in Ibadan were successfully adapted and maintained in continuous culture using semi-immune human plasma. The results of these studies indicate that semi-immune human plasma is a suitable supplement for continuous cultivation and drug susceptibility testing of P. falciparum. This finding will have practical implications in malaria endemic areas where difficulties in obtaining non-immune human plasma or serum limits establishment of continuous culture of P. falciparum and its application in studies on malaria.

Antigens associated with the surface of merozoites of the malaria parasite Plasmodium falciparum are directly accessible to immune attack and therefore are prime vaccine candidates. We have previously shown that one of the two known merozoite surface antigens (merozoite surface antigen 2; MSA-2) exhibits considerable sequence and antigenic diversity in different isolates. The sequences of MSA-2 from three isolates revealed a central domain composed of repeats that vary in number, length, and sequence, flanked in turn by nonrepetitive variable sequences and by conserved N- and C-terminal domains. We report here the sequences of a further four MSA-2 alleles, containing repetitive sequences that are related but not identical to each other. The seven alleles of MSA-2 can be divided into two distinct allele families on the basis of nonrepetitive sequences. Hybridization studies with repeat probes indicated that all of the 44 P. falciparum isolates examined contained repeat regions similar to those defined in known MSA-2 sequences.

Intrinsic interactions of calcium antagonists (broadly defined) and quinoline-containing antimalarial drugs were evaluated against chloroquine-sensitive and chloroquine-resistant clones of Plasmodium falciparum in vitro . Verapamil, D-600 (methoxyverapamil), Ro 11-2933/001 (tiapamil analogue), chlorpromazine, SKF 21133-A (chlorpromazine analogue), and diltiazem each potentiated the efficacy of the quinoline-containing antimalarials chloroquine, desethylchloroquine, and quinine with a chloroquineresistant clone of P. falciparum , but did not affect the response of the quinoline-susceptible clone. Similar concentrations of either chlorpromazine or Ro 11-2933/001 lowered the IC 50 of the resistant clone to approximately the same level as that observed for the sensitive clone for each of the quinolines tested. This reversal of resistance by many of the same calcium antagonists underscores the similarities in one mechanism of multi-drug resistance in neoplastic cells and quinoline-resistance in P. falciparum .

This study was carried out in two rural communities: Kaani and Boue, in Khana Local Government Area (LGA) and, in one urban community, Eleme, in Eleme LGA, all in Rivers State, South-South Nigeria. The investigations involved in-depth interviews conducted with 104 health care givers comprising indigenous healers: herbalists, sellers of herbal remedies and community elders. Information was obtained on types of fevers (febrile illnesses) treated, symptoms and methods of establishing illnesses, and traditional herbs used in the prevention and treatment of febrile illnesses. On types of febrile illnesses treated, respondents presented the following: malaria (78.8%), typhoid (23.1%), yellow fever (21.2%), high fever (19.2 %), convulsion (15.4%), and pregnancy fever (2.9%). Other illnesses treated were yellow eyes (4.8%) headache (11.5%), waist pain (14.4%), and joint pains, (8.7%). Respondents determined whether a person had fever by the following: physical examination (85.4 %), listening to patients' complaints (9.4 %), through divination and inspiration (9.4 %), while others (0.2 %) were not quite explicit on their methods of diagnoses. On the treatment of febrile illnesses, respondents used herb teas (88.5%), herb powders (42.3%), incantation (3.3 %), and performance of sacrifice (4.8%) or use of special fluids (27.9%). Majority of the respondents, in describing the best herbal medicines for the treatment of febrile illnesses, 62.5 % said that dogonyaro ( Azadiracta indica ) was the best medicine. Other responses were: lemon grass ( Cymbopogon citratys , 51.9 %), mango ( Mangifera indica ) bark (29.8 %); lime ( Citrus limetta ) juice (30.0 %), paw paw ( Carica papaya ) leaf/fruit (20.2 %); guava ( Psidium guajava ) leaf (18.3 %), akpagbogoro ( Salacia nitida ), 7.7 %, plantain ( Musa sapientum ) sucker (6.7 %), Lipton tea (3.8 %) and scent leaf ( Ocimum gratissimum ), 1.9%. Keywords : Malaria, fever, febrile illness, herbal remedies, Nigeria West African Journal of Pharmacology and Drug Research Vol. 21 (1&2) 2005: pp. 48-54

The cardiac effects of halofantrine were assessed in 42 children with acute symptomatic uncomplicated Plasmodium falciparum malaria by electrocardiographic (ECG) and clinical monitoring over a period of 14 d. The children were treated with oral halofantrine 8 mg/kg body weight every 6 h for 3 doses. There was significant prolongation of the P-R interval (compared with the pre-treatment value) only at 8 h after drug administration. However, first degree auriculoventricular (AV) block occurred in 2 children at 8 h or 8 and 48 h, and second degree AV block in another child at 48 h. There was significant prolongation of the Q-Tc interval at 8, 16, 24, 48 and 72 h after treatment; the proportions of children with Q-Tc interval > 0.44 s were also significantly higher at all these times except 72 h. Rhythm disturbance was rare. There was no significant ECG change at 168 or 336 h. Despite the ECG abnormalities, there was no clinical symptom. These findings indicate that, in children, the currently recommended dose of halofantrine for the treatment of falciparum malaria may produce serious cardiac side effects.

An in-vitro model based on the semi-automated microdilution technique has been developed for selecting compounds that might be used clinically for the reversal of chloroquine resistance. This was used initially to test the susceptibility of Plasmodium falciparum clone W2 to chloroquine (CQ). The model was then employed to investigate the effects of each of four resistance-reversing agents (verapamil, desipramine, chlorpheniramine and promethazine, at 1 microM) on this parasite's susceptibility to CQ, with and without alpha(1)-acid glycoprotein (AGP), at a patho-physiological concentration (1.25 g/litre), in the culture medium. In the absence of AGP, each of the resistance-reversing agents reduced the median inhibitory concentrations of CQ by 82%-97%, from a baseline value of about 94 ng/ml. In the presence of AGP, however, most of the resistance-reversing agents had much less effect. There appears to be competitive interaction between CQ, the resistance-reversing agents and AGP. The binding kinetics between CQ, resistance-reversing agents, AGP and other plasma proteins will clearly need to elucidated if clinically effective resistance-reversing agents are to be selected in vitro.

Summary Background Artemisinin-based combination antimalarials are currently considered effective alternatives for the treatment of malaria in Africa, but there are few studies of such combinations in Nigerian children. We assessed the safety, treatment efficacy and effects on gametocyte carriage of the combination of artesunate plus amodiaquine and chloroquine plus pyrimethamine-sulfadoxine in children. Methods We evaluated 153 children who were aged 12 years or younger who had uncomplicated Plasmodium falciparum malaria. Patients were randomly assigned a combination of artesunate (4 mg/kg of body weight daily for 3 days) plus amodiaquine (30 mg/kg over 3 days), or chloroquine (25 mg/kg over 3 days) plus pyrimethamine-sulfadoxine (25 mg/kg of the sulfadoxine component at presentation). The primary endpoints were the proportions of children with adequate clinical and parasitological response, late parasitological failure, late clinical failure and early treatment failure. The parasitological cure rates on days 14–28 were also used as the primary endpoints. Results Both regimens were well tolerated; no child was withdrawn because of drug intolerance. All children treated with artesunate plus amodiaquine had adequate clinical and parasitological response (ACPR), while all but five children treated with chloroquine plus pyrimethamine-sulfadoxine had similar response. Fever clearance times were similar in the two treatment groups. However, the proportion of patients whose parasitaemia cleared by day 2 was significantly higher (100 vs. 50%, P = 0.00001) and parasite clearance was significantly faster (1.7 ± 0.4 vs. 2.5 ± 0.8 days, P = 0.0001) in children treated with artesunate plus amodiaquine. The cure rates on days 21 (100%vs. 94%, P = 0.03) and 28 (100%vs. 90%, P = 0.003) were also significantly higher in children treated with artesunate plus amodiaquine than in those treated with chloroquine plus pyrimethamine-sulfadoxine. Overall, a significantly higher proportion of children treated with chloroquine plus pyrimethamine-sulfadoxine carried gametocytes at least once during follow-up compared with those treated with artesunate plus amodiaquine [5 of 50 (10%) vs. 1 of 103 (0.97%), P = 0.01]. Conclusion The combination of artesunate plus amodiaquine is therapeutically superior to a combination of chloroquine plus pyrimethamine-sulfadoxine, and significantly reduced gametocyte carriage following treatment.

The efficacy of artemether and artemether followed by mefloquine was evaluated in 45 pregnant women with drug resistant Plasmodium falciparum malaria during the second and third trimesters. There was prompt clinical response to both treatment regimens. The parasite and fever clearance times and the cure rate were similar in both groups. Except for the correlation between initial parasite density and fever clearance time in the artemether-mefloquine group there was no correlation between initial parasite density and parasite or fever clearance times in the two groups. Similarly there was no correlation between parasite and fever clearance. Both treatment regimens were well tolerated. All newborn babies of the participating women were normal at birth. Physical and neurodevelopmental assessment of the newborn babies followed up for a period varying between 6 and 36 months were within normal limits. Artemether alone or with mefloquine are effective and do not produce undue deleterious effects in pregnant patients with drug resistant falciparum malaria during the second and third trimesters. (authors)

Summary Background Increasing resistance to sulfadoxine-pyrimethamine is leading to a decline in its effectiveness. We aimed to assess the safety profile of chlorproguanil-dapsone (CD), and to compare the safety and efficacy of this drug with that of sulfadoxine-pyrimethamine (SP) as treatment for uncomplicated falciparum malaria. Methods We undertook a double-blind, randomised trial in 1850 consecutively recruited children with uncomplicated falciparum malaria, pooling data from five African countries. Analyses were based on all randomised patients with available data. Findings CD was significantly more efficacious than SP (odds ratio 3·1 [95% CI 2·0–4·8]); 1313 patients (96%) given CD and 306 (89%) given SP achieved acceptable clinical and parasitological response by day 14. Adverse events were reported in 46% and 50% of patients randomised to CD and SP, respectively (treatment difference −4·4%, [95% CI −10·1 to 1·3]). Haemoglobin in the CD group was significantly lower than in the SP group at day 7, a difference of −4 g/L (95% CI −6 to −2). Mean day 14 haemoglobin (measured only for the small number of patients whose day 7 data caused concern) was 94 g/L (92–96) and 97 g/L (92–102) after CD and SP, respectively. Glucose-6-phosphate dehydrogenase deficient patients on CD had greater odds than those on SP of having a fall of 20 g/dL or more in haemoglobin when baseline temperature was high. Methaemoglobinaemia was seen in the CD group (n=320, mean 0·4% [95% CI 0·4–0·4]) before treatment, 4·2% (95% CI 3·8–4·6) (n=301) at day 3, and 0·6% (0·6–0·7) (n=300) at day 7). Interpretation CD had greater efficacy than SP in Africa and was well tolerated. Haematological adverse effects were more common with CD than with SP and were reversible. CD is a useful alternative where SP is failing due to resistance.

The susceptibility in vivo of Plasmodium falciparum to mefloquine, mefloquine/sulfadoxine/pyrimethamine and chloroquine was investigated in 115 children with acute uncomplicated falciparum malaria. Susceptibility of P. falciparum isolates to mefloquine and chloroquine in vitro was also investigated. Mefloquine alone and mefloquine/sulfadoxine/pyrimethamine showed similar response rates and both reduced parasitaemia and fever more rapidly than chloroquine. Mefloquine also promptly reduced parasitaemia and fever within 48 h in all chloroquine treatment failures. In vitro, 10% of isolates showed reduced susceptibility to mefloquine and 18% were resistant to chloroquine. These results suggest that the addition of sulfadoxine/pyrimethamine does not have a significant therapeutic advantage over mefloquine alone in the treatment of acute uncomplicated falciparum malaria in children from this endemic area.

A group of 161 children who presented with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria in an endemic area of Nigeria was investigated. The aims of the study were to determine the clinical characteristics and responses to oral chloroquine (CQ) therapy of children who were gametocytaemic on presentation and those who were not [including those who were found to have developed peripheral immature gametocytaemias (PIG) when checked 72 h after commencing treatment], and to follow the development of PIG 72-336 h after the start of treatment. The 40 consecutive children who did have peripheral gametocytaemia on presentation and the 40 who did not were similar in their clinical characteristics and responses to oral CQ therapy. Nine of the 40 children who did not initially have gametocytaemias but who subsequently developed PIG (stages I-III) 72-336 h after commencing CQ treatment failed the treatment. In order to evaluate the presence of PIG as an indicator of response to CQ, the smears of blood from 81 children--66 classified as resistant to CQ (60, five and one considered RI, RII, RIII, respectively) and 15 who, though considered to have sensitive responses to CQ, cleared their peripheral parasitaemias > or =72 h after commencing CQ therapy--were examined for PIG. Most (42) of the 66 children with CQ-resistant (CQ-R) infections but none of the 15 with sensitive responses had PIG. Among the 66 children with CQ-R infections, the clinical features of those with PIG were generally similar to those without PIG, although those with PIG were more likely to have hepato-splenomegaly and less likely to have hepatomegaly alone. In the children with CQ-R infections, plasma concentrations of CQ on days 7 and 14 were generally above the level necessary to clear sensitive infections in the study area. The results of molecular analyses of isolates from children with both CQ-R infections and PIG revealed that all 14 checked for mutations in pfcrt had the T76 mutation associated with CQ resistance, and that four of the five also checked for mutations in pfmdr1 had the Y86 mutation associated with CQ resistance. The detection of PIG 72 h after the commencement of CQ treatment may be used as a microscopical indicator of a poor response to CQ in children from this endemic area.

The susceptibilities of isolates of Plasmodium falciparum from Nigeria and two reference cloned strains (D6 and W2) to mefloquine or chloroquine alone and in combination with either penfluridol, a piperidine analogue, or verapamil were determined using a modification of the semiautomated microdilution technique. Six of the isolates showed reduced susceptibility to mefloquine in vitro . The response of the 6 isolates was similar to that of the mefloquine resistant reference clone D6, with 50% inhibitory concentration (IC 50 ) values = 3·29−9·72 ng/ml. Only 2 of the Nigerian isolates were sensitive to mefloquine (IC 50 = 1·16 ng/ml and 2·62 ng/ml) and were similar to the reference mefloquine sensitive clone W2 (IC 50 = 1·78 ng/ml). All the isolates tested were sensitive to chloroquine, with IC 50 values = 1·5−3·04 ng/ml. Simultaneous incubation of the parasites with a constant sub-inhibitory concentration of penfluridol (5·0 × 10 −7 m ) and mefloquine increased the susceptibility of the resistant parasites to mefloquine. Addition of the neuroleptic drug penfluridol did not alter the response of sensitive parasites to mefloquine or chloroquine. Similarly, addition of 1·0 × 10 −6 m verapamil did not affect the activity of mefloquine against the sensitive or resistant parasites.

Wellcome Trust (Grant Ref. 055487/Z/98/Z) and the Medical Research Council (Grant Ref. G9803180). London School of Hygiene and Tropical Medicine. Department of Infectious and Tropical Diseases. Keppel Street, London, UK. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Universiti Malaysia Sarawakc. Faculty of Medicine and Health Sciences. Kota Samarahan, Sarawak, Malaysia. London School of Hygiene and Tropical Medicine. Department of Infectious and Tropical Diseases. Keppel Street, London, UK. London School of Hygiene and Tropical Medicine. Department of Infectious and Tropical Diseases. Keppel Street, London, UK. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. University of Ibadan. College of Medicine. Postgraduate Institute of Medical Research and Training. Ibadan, Nigeria. London School of Hygiene and Tropical Medicine. Department of Infectious and Tropical Diseases. Keppel Street, London, UK. Comparing patterns of genetic variation at multiple loci in the genome of a species can potentially identify loci which are under selection. The large number of polymorphic microsatellites in the malaria parasite Plasmodium falciparum are available markers to screen for selectively important loci. The Pfs48/45 gene on Chromosome 13 encodes an antigenic protein located on the surface of parasite gametes, which is a candidate for a transmission blocking vaccine. Here, genotypic data from 255 P. falciparum isolates are presented, which show that alleles and haplotypes of five single nucleotide polymorphisms (SNPs) in the Pfs48/45 gene are exceptionally skewed in frequency among different P. falciparum populations, compared with alleles at 11 microsatellite loci sampled widely from the parasite genome. Fixation indices measuring inter-population variance in allele frequencies (FST) were in the order of four to seven times higher for Pfs48/45 than for the microsatellites, whether considered (i) among populations within Africa, or (ii) among different continents. Differing mutational processes at microsatellite and SNP loci could generally affect the population structure at these different types of loci, to an unknown extent which deserves further investigation. The highly contrasting population structure may also suggest divergent selection on the amino acid sequence of Pfs48/45 in different populations, which plausibly indicates a role for the protein in determining gamete recognition and compatibility. ? 2001 Elsevier Science B.V.

The clinical characteristics and the responses to oral antimalarial therapy of 104 children presenting consecutively with or without Plasmodium falciparum hyperparasitaemia (HP) were investigated in an endemic area. At presentation, although the 52 children with HP were significantly younger and had significantly higher heart rates than the 52 without, there were no significant differences between the two groups in their symptoms or in any other clinical feature of their malaria. Responses to oral antimalarial drugs were similar in both groups. Analysis of the disposition kinetics of parasitaemia, using a non-compartmental model similar to that used in characterizing drug disposition, showed that the two groups had similar half-lives of parasitaemia (t1/2pd), volumes of blood completely cleared of parasites per unit time (CLBpd), and parasite-clearance-time:t1/2pd ratios. Three children in the HP group, all aged3 years, progressed to cerebral malaria within 8 h of presentation, and another HP child presented with isolated trunkal ataxia, indicative of cerebellar involvement. No child in the non-HP group had any of the features of severe malaria. Although the clinical characteristics and responses to oral therapy of children with and without HP are therefore very similar, young children with HP appear to have an increased risk of developing other features of severe malaria.