George O. Ademowo

Bio: George O. Ademowo is an academic researcher from University of Ibadan. The author has contributed to research in topics: Drug resistance & Artemisinin. The author has an hindex of 4, co-authored 7 publications receiving 272 citations.

Polymorphisms in Plasmodium falciparum chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors That Affect Treatment Outcomes for P. falciparum Malaria After Artemether-Lumefantrine and Artesunate-Amodiaquine

Abstract: Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Age as a risk factor for thrombocytopenia and anaemia in children treated for acute uncomplicated falciparum malaria.

Abstract: Background & objectives: Anaemia is commonly observed in children with malaria, but reports on leucocyte and platelet count abnormalities associated with malaria are inconsistent. This study examined the effect of age, gender, parasite density and temperature on haematological parameters in children with acute uncomplicated malaria. Methods: Haematological parameters were determined in children with acute uncomplicated malaria, and these were correlated with age, sex, temperature and parasite density. Statistical analysis was done using SAS 9.1. Results: Six hundred and ninety five children with acute uncomplicated malaria participated in the study. The mean age was 51.7 months ± 33.8. At presentation, anaemia occurred in 43.8% of the patients and children <5 yr had a significantly lower haematocrit (28.4% ± 4.8) than that of older children (32.8% ± 4.8) (p <0.001), but the haematocrit was not significantly different by days 14 and 28. There was no difference between both sexes. Leucocytosis was more frequently seen than leucopenia (9.5% vs 3%). Thrombocytopenia was found in 59.3% of enrolled patients. More than half of the patients with thrombocytopenia had recovered by Day 28. Baseline platelet count was related to Day 14 (r = 0.6, p <0.0001) and Day 28 (r = 0.2, p = 0.0015) and the haematocrit on Day 28 (r = 0.12, p = 0.00197). Platelet count showed no correlation with temperature, parasite density and leucocyte count. Haematocrit correlated with age (r = 0.4, p<0.0001); but not with parasite density or temperature. Leucocyte count showed no correlation with age or parasite density. Conclusion: While thrombocytopenia was the most common haematological finding and may be of diagnostic importance, anaemia and leucocytosis were more common in the under fives.

Lymphatic Filariasis in Nigeria; Micro-stratification Overlap Mapping (MOM) as a Prerequisite for Cost-Effective Resource Utilization in Control and Surveillance

Abstract: Background Nigeria has a significant burden of lymphatic filariasis (LF) caused by the parasite Wuchereria bancrofti. A major concern to the expansion of the LF elimination programme is the risk of serious adverse events (SAEs) associated with the use of ivermectin in areas co-endemic with Loa filariasis. To better understand this, as well as other factors that may impact on LF elimination, we used Micro-stratification Overlap Mapping (MOM) to highlight the distribution and potential impact of multiple disease interventions that geographically coincide in LF endemic areas and which will impact on LF and vice versa. Methodology/Principal findings LF data from the literature and Federal Ministry of Health (FMoH) were collated into a database. LF prevalence distributions; predicted prevalence of loiasis; ongoing onchocerciasis community-directed treatment with ivermectin (CDTi); and long-lasting insecticidal mosquito net (LLIN) distributions for malaria were incorporated into overlay maps using geographical information system (GIS) software. LF was prevalent across most regions of the country. The mean prevalence determined by circulating filarial antigen (CFA) was 14.0% (n = 134 locations), and by microfilaria (Mf) was 8.2% (n = 162 locations). Overall, LF endemic areas geographically coincided with CDTi priority areas, however, LLIN coverage was generally low (<50%) in areas where LF prevalence was high or co-endemic with L. loa. Conclusions/Significance The extensive database and series of maps produced in this study provide an important overview for the LF Programme and will assist to maximize existing interventions, ensuring cost effective use of resources as the programme scales up. Such information is a prerequisite for the LF programme, and will allow for other factors to be included into planning, as well as monitoring and evaluation activities given the broad spectrum impact of the drugs used.

Species composition and temporal distribution of mosquito populations in Ibadan, Southwestern Nigeria.

Abstract: Nigeria has a high burden of vector borne diseases such as malaria and lymphatic filariasis (LF). This study aimed to determine the species composition of mosquitoes in Ibadan, Southwest Nigeria as well as determine their role in malaria and LF transmission. Adult mosquitoes were collected by Pyrethrum Spray Catch (PSC) and identified and graded according to their abdominal conditions. The mosquitoes were dissected to determine the parity status and to check for microfilariae of Wuchereria bancrofti. The presence of circumsporozoite protein of Plasmodium falciparum was examined using ELISA. A total of 1600 mosquitoes were collected of which 31 (1.9%) were Anopheles gambiae s.l. while 1756 (98%) were Culex sp. None of the mosquitoes examined was positive for Plasmodium falciparum and Wuchereria bancrofti. The lack of adequate sanitary conditions in the area could be responsible for the large number of mosquitoes collected. Health education could help in sensitizing the inhabitants.

Evaluation of in vivo anti-malarial potential of omidun obtained from fermented maize in Ibadan, Nigeria

Abstract: The menace of resistance to anti-malarial drugs is a great challenge to malaria control, necessitating the search for new anti-malarial agents. This search has led to the exploration of natural products for efficacy in malaria therapy. Omidun is the supernatant of fermenting maize (ogi) slurry that has been widely investigated and reported to possess several health benefits and it is used traditionally as solvent for preparing anti-malarial herbs. However, there is no information on the anti-malarial activity of omidun itself. This study was conducted to investigate the prophylactic, curative and suppressive anti-malarial potential of omidun. Experimental mice in the curative group were infected with 1 × 106 cells of Plasmodium berghei strain ANKA and treated with either 0.2 ml of omidun containing 3 × 109 cfu/ml of viable lactic acid bacteria or 0.2 ml of 5 mg/kg of chloroquine (positive control) or 0.2 ml of saline (negative control) for 4 days from day 3 post infection. The prophylactic group of mice were pre-treated with either omidun, chloroquine or saline for 4 days before infection with P. berghei, while the suppressive group was treated with omidun or chloroquine or saline and infected with P. berghei simultaneously. A group of mice were uninfected but treated (with omidun and control samples), while a final group was uninfected and untreated (controls). Parasitaemia and histopathology analysis were done in all groups. The curative and suppressive groups showed a significant difference between the omidun-treated mice (100% parasitaemia reduction) and the untreated mice (54.5% parasitaemia increase). There was no significance difference between the omidun treatment and chloroquine (positive control) treatment in suppressive group as both treatment had 100% parasitaemia reduction. The omidun prophylactic treatment however did not show any parasitaemia suppression, but a significant difference was observed between the omidun treatment (85% increase) and the chloroquine (positive control) treatment (100% reduction) in the group. Omidun treatment is non-toxic to the kidney. This study provides scientific evidence supporting omidun usage in the treatment of malaria. Consequently, further work may yield the specific component of omidun responsible for the anti-malarial activity.

Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data

Abstract: Background: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. Methods: The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Results: Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (98 % cure rates (if parasitemia <135,000/μL). Conclusions: Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic.

Abstract: In this Review, David Fidock discusses malarial resistance to artemisinin-based combination therapies, among others, and presents strategies for designing new therapeutics and to overcome resistance. The global adoption of artemisinin-based combination therapies (ACTs) in the early 2000s heralded a new era in effectively treating drug-resistant Plasmodium falciparum malaria. However, several Southeast Asian countries have now reported the emergence of parasites that have decreased susceptibility to artemisinin (ART) derivatives and ACT partner drugs, resulting in increasing rates of treatment failures. Here we review recent advances in understanding how antimalarials act and how resistance develops, and discuss new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria.

Platelets kill intraerythrocytic malarial parasites and mediate survival to infection

Abstract: Platelets play a critical role in the pathogenesis of malarial infections by encouraging the sequestration of infected red blood cells within the cerebral vasculature. But platelets also have well-established roles in innate protection against microbial infections. We found that purified human platelets killed Plasmodium falciparum parasites cultured in red blood cells. Inhibition of platelet function by aspirin and other platelet inhibitors abrogated the lethal effect human platelets exert on P. falciparum parasites. Likewise, platelet-deficient and aspirin-treated mice were more susceptible to death during erythrocytic infection with Plasmodium chabaudi. Both mouse and human platelets bind malarial-infected red cells and kill the parasite within. These results indicate a protective function for platelets in the early stages of erythrocytic infection distinct from their role in cerebral malaria.

Drug resistance in Plasmodium

Abstract: Haldar and colleagues discuss markers and mechanisms of resistance to artemisinins and artemisinin-based combination therapies. They describe the identification of Plasmodium falciparum Kelch 13 as the primary and, to date, sole causative maker of artemisinin resistance in P. falciparum and explore two proposed resistance mechanisms. They emphasize continuing challenges to improve detection strategies and new drug development strategies.