Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine-pyrimethamine-resistant falciparum malaria during pregnancy.

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.     

Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children

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.     

Carotid atherosclerosis and right ventricular diastolic dysfunction in a sample of hypertensive Nigerian patients

Aim

To determine the association of carotid atherosclerosis and right ventricular diastolic dysfunction (DD) among treated hypertensive Nigerian patients.

Methods

This was a single center cross-sectional study performed at the Cardiology Clinic of LAUTECH Teaching Hospital, Ogbomoso, Nigeria between January and December 2012. The study included 122 hypertensive Nigerians (mean age, 57.3 ± 14.7 years, 36.9% women). Patients’ clinical, demographic, and echocardiographic parameters were obtained. Diastolic dysfunction was assessed with the trans-tricuspid Doppler flow.

Results

Patients with DD were significantly older than those with normal diastolic function. Mean and maximum carotid intima media thickness measurements were significantly higher among patients with right ventricular DD than in those with normal diastolic function. Mean systolic blood pressure (148.3 ± 31.9 vs 128.0 ± 2.8 mm Hg, P = 0.049) and interventricular septal thickness in diastole (12.8 ± 2.3 vs 11.6 ± 2.8mm, P = 0.048) were significantly higher and tricuspid annular pulmonary systolic excursion (33.6 ± 4.9 vs 23.0 ± 4.2 mm, P = 0.035) was significantly lower in patients with right ventricular DD than in those with normal diastolic function. Carotid intima media thickness measurements were correlated with early trans-tricuspid Doppler flow and early transtricuspid diastolic flow/late right atrial transtricupsid diastolic flow ratio.

Conclusion

Right ventricular DD in hypertensive patients was significantly correlated with increased carotid atherosclerosis. Carotid intima media thickness measurements may therefore be a surrogate marker for DD in hypertensive subjects.Systemic hypertension has been shown to be associated with right ventricular abnormalities in both morphology and function. Right ventricular diastolic dysfunction (DD) may be an early indicator of hypertensive heart disease accompanying left ventricular DD (1-3). It can be diagnosed by various means including the ratio of early and late trans-tricuspid Doppler inflow velocities and tissue Doppler velocities.Atherosclerosis is the underlying factor for many cases of cardiovascular morbidity and mortality (4). A useful surrogate marker for carotid atherosclerosis is carotid intima media thickness (5). This parameter reflects the severity of thickening/atherosclerosis of the major arteries and is directly linked with the severity of hypertension and target organ damage associated with hypertension (2,4). DD is a typical part of the cardiovascular risk spectrum with increased risk for accelerating progressive cardiac dysfunction (6). However, it is still not known whether carotid intima media thickness, which has been shown to correlate with many conventional cardiovascular risk factors, is associated with right ventricular DD, especially among Africans (7). This study aims to determine the association between right ventricular DD and carotid intima media thickness in a sample of Nigerian hypertensive patients.     

Polymorphisms in Plasmodium falciparum dhfr and dhps genes and age related in vivo sulfadoxine-pyrimethamine resistance in malaria-infected patients from Nigeria

Mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes have been used as means to predict treatment failure to sulfadoxine-pyrimethamine (SP) and for monitoring/surveillance of resistance to the drug in many areas where malaria is endemic. However, patients responses to treatment are significantly dependent on factors like host immunity profile of treated patients. In order to investigate the relationship between molecular markers of SP resistance, host immunity and clinical outcome, the association between pre-treatment dhfr and dhps genotypes, age and treatment outcomes was evaluated in 109 children treated with SP for acute uncomplicated malaria in Ibadan, Nigeria. Seventy-three percent of the children were cured with the drug, while 27% failed treatment after 28 days of follow-up. All children infected with parasites harboring less than two dhfr/dhps mutations were cured with SP. The dhfr triple (Asn-108/Ile-51/Arg-59) mutants or the dhps double mutants (Gly-437/Glu-540) were independently associated with SP treatment failure in children aged less than 5 years, but not in older children. The dhfr and dhps quintuple mutant (dhfr triple mutant+dhps double mutant) was the genotype most strongly associated with SP treatment failure (OR=24.72, 95%CI=8.24-74.15) in both younger and older children.     

Comparative clinical characteristics and response to oral antimalarial therapy of children with and without Plasmodium falciparum hyperparasitaemia in an endemic area

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 aged < 3 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.     

Comparative efficacy of chloroquine and cotrimoxazole in the treatment of acute uncomplicated falciparum malaria in Nigerian children

OBJECTIVES: To evaluate the efficacy of two dosing regimens of cotrimoxazole in the treatment of falciparum malaria and compare the efficacy with that of chloroquine, the first-line antimalaria drug in the area of study. DESIGN: A prospective cross sectional study. SETTINGS: Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria. SUBJECTS: Ninety eight children with acute symptomatic uncomplicated falciparum malaria. MAIN OUTCOME MEASURES: Fever and other symptoms clearance times, parasite clearance times and the cure rates for chloroquine, three day and five day cotrimoxazole. RESULTS: Ninety eight children with acute symptomatic uncomplicated falciparum malaria were randomised to receive three doses of oral chloroquine and two regimens of cotrimoxazole. Pre-treatment clinical and parasitological parameters were similar in the three treatment groups. The fever and other symptoms clearance times were comparable in all the treatment groups: 1.83 +/- 1.3, 1.9 +/- 1.0 and 2.4 +/- 1.3 days for chloroquine, three day cotrimoxazole and five day cotrimoxazole, respectively p = 0.24. Parasite clearance times for the three treatment groups were also similar; 3.0 +/- 1.0, 3.1 +/- 0.7, and 3.0 +/- 1.0 days respectively for chloroquine, three day- and five day- cotrimoxazole; p = 0.96. The cure rates for chloroquine, three day and five day cotrimoxazole were 74.2%, 88.2% and 84.8%, respectively (x2 = 2.40, p = 0.30). The three treatment regimens were well tolerated. CONCLUSION: These results indicate that cotrimoxazole is as effective as chloroquine in treatment of acute symptomatic uncomplicated falciparum malaria in children resident in an endemic area of southwest Nigeria. It is an added advantage when malaria coexists with respiratory tract infections for which cotrimoxazole is the recommended drug.     

Plasmodium falciparum gametocytaemia in Nigerian children: before,during and after treatment with antimalarial drugs

We evaluated gametocyte carriage and intensities of gametocytaemia in 710 children presenting with acute, symptomatic, uncomplicated Plasmodium falciparum malaria who were treated with various antimalarial drug regimens: chloroquine (CQ); chloroquine plus chlorpheniramine, a histamine H1 receptor antagonist that reverses CQ resistance in P. falciparum in vitro and in vivo (CQCP); chloroquine plus ketotifen, a histamine H1 receptor antagonist that reverses CQ resistance in P. falciparum in vitro but not in vivo in the present study (CQK); chloroquine plus pyrimethamine-sulphadoxine (CQPS); amodiaquine (AQ); amodiaquine plus pyrimethamine-sulphadoxine (AQPS); and pyrimethamine-sulphadoxine (PS). On presentation, gametocyte carriage was significantly higher in CQ-resistant (CQ-R) than in CQ-sensitive (CQ-S) infections. Following CQ treatment, gametocyte carriage was significantly higher at all times after treatment and gametocyte density significantly higher on day 7 of follow-up in children with CQ-R than CQ-S infections. CQ treatment of CQ-R infections resulted in significantly higher density of gametocytaemia on day 7 compared with pre-treatment (day 0), but similar treatment of CQ-S infections resulted in significantly lower density of gametocytaemia on day 14 compared with day 0. Among children with CQ-R infections, those with mild (RI) resistance carried gametocytes significantly more often than those with moderate (RII) resistance on days 5 and 7 of follow-up (P = 0.04 and 0.01, respectively). Disposition kinetics of gametocytaemia using a non-compartmental method showed that the half life of gametocytaemia was longer and the clearance slower in children with CQ-R than in those with CQ-S infections. PS treatment was associated with significantly higher gametocyte carriage at all times between days 1 and 14, and significantly higher gametocytaemias on days 7 and 14 than in the other treatment regimens. Combination of AQ with PS significantly decreased gametocyte carriage at all times between days 1 and 14 of follow-up. Continuing use of CQ in CQ-R infections may encourage transmission of CQ-R infections; SP monotherapy is associated with significant gametocyte carriage and gametocytaemia and may encourage transmission of SP resistant infections as resistance to the drug increases.     

Predictors of the failure of treatment with chloroquine in children with acute, uncomplicated, Plasmodium falciparum malaria, in an area with high and increasing incidences of chloroquine resistance

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 of < or =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 of > or =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 enrolment >4 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.