Fatai A. Fehintola

Activities of Amodiaquine, Artesunate, and Artesunate-Amodiaquine against Asexual- and Sexual-Stage Parasites in Falciparum Malaria in Children

ABSTRACT The activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual- and sexual-stage parasites were evaluated in 360 Nigerian children with uncomplicated Plasmodium falciparum malaria randomized to the standard dose regimens of the three drugs/combination. Clinical recovery from illness occurred in all children. There were no significant differences in fever clearance times. Patients treated with artesunate or artesunate-amodiaquine had significantly shorter parasite clearance times (1.4 ± 0.5 days or 1.4 ± 0.6 days versus 3.2 ± 2.3 days, P = 0.0001) and lower gametocyte carriage rates (3.3 or 1.7% versus 11.7%, P = 0.001) than those treated with amodiaquine alone. Gametocytemia was detected in 62 patients (11.7% before treatment and 5.6% after treatment). The pretreatment gametocyte sex ratio, which was female biased, increased significantly during the course of treatment with amodiaquine but not with artesunate and artesunate-amodiaquine. These results suggest that artesunate and artesunate-amodiaquine reduce gametocyte carriage and may reduce transmissibility in P. falciparum malaria by accelerating asexual clearance and influencing gametocyte sex ratio.

Risk factors for gametocyte carriage in uncomplicated falciparum malaria in children.

The risk factors associated with gametocytaemia at presentation and after treatment with different antimalarial drug regimens were evaluated in 767 children enrolled prospectively in 5 antimalarial drug trials between July 1996 and December 2002 in a hyperendemic area of southwestern Nigeria. The children were assigned to one of 6 treatment groups: chloroquine (CQ) only; pyrimethamine-sulfadoxine (PS) only; amodiaquine (AQ) only; CQ combined with chlorpheniramine (CQCP); or PS combined with CQ (CQPS) or AQ (AQPS). At enrolment, 115 (15%) of 767 children were gametocyte carriers. During follow-up, 15.6% of all patients (i.e. 120 patients) developed patent gametocytaemia, which in 85% (102 patients) had developed by day 7 following treatment. In a multiple regression model, 4 factors were found to be independent risk factors for the presence of gametocytaemia at enrolment: male gender (adjusted odds ratio [AOR] = 0.55, 95% confidence interval [CI] 0.36-0.83, P=0.005), absence of fever (AOR = 1.61, 95% CI 1.05-2.5, P=0.03), duration of illness >3 days (AOR=1.57, 95% CI 1.0-2.4, P=0.047), and asexual parasite densities less than 5000/microl (AOR=0.42, 95% CI 0.24-0.73, P=0.002). The presence of patent gametocytaemia at enrolment (AOR=0.04, 95% CI 0.02-0.07, P<0.001) and recrudescence of asexual parasites within 14 days were associated with the presence of gametocytaemia 7 or 14 days after enrolment (AOR=0.5, 95% CI 0.3-0.8, P=0.007). Delay in the time taken to clear the initial parasitaemia (>2 days) was associated with increased risk of subsequent gametocyte carriage. These findings may have implications for malaria control efforts in sub-Saharan Africa where control of the disease depends almost entirely on chemotherapy.

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.

Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children

Background  Increasing drug resistance in Plasmodium falciparum has necessitated renewed search for cheap, effective alternatives to commonly available antimalarials, chloroquine and pyrimethamine–sulphadoxine, for the treatment of malaria in Africa. Probenecid, an inhibitor of organic anion transporters and multiresistance‐associated proteins, can chemosensitize P. falciparum to pyrimethamine and sulphadoxine in vitro, but the clinical significance is unclear. We assessed the safety, treatment efficacy, and effects on gametocyte carriage of adding probenecid to pyrimethamine–sulphadoxine.

Effects of antifolates - co-trimoxazole and pyrimethamine-sulfadoxine - on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria

Antimalarial drugs including the antifolate, pyrimethamine-sulfadoxine (PS), can modulate the prevalence and intensities of gametocytaemia following treatment of acute malaria infections. They may also directly influence the transmission and spread of drug insensitivity. Little is known of the effects of co-trimoxazole (Co-T), another antifolate antimalarial, on gametocytes in children with acute malaria infections. We compared the effects of Co-T and PS on the prevalence and intensities of gametocytaemia and gametocyte sex ratios in 102 children aged 0.5-12 years presenting with acute and uncomplicated falciparum malaria. Compared to pre-treatment, both drugs significantly increased gametocyte carriage post-initiation of treatment. However, gametocyte carriage was significantly lower on day 14 in those treated with Co-T than PS. Significant increase in gametocytaemia with time occurred in PS--but not Co-T-treated children. Kaplan-Meier survival curve of the cumulative probability of remaining gametocyte-free in children who were agametocytaemic at enrollment showed that by day 7 of follow up, children treated with PS had a significantly higher propensity to have developed gametocytes than in Co-T-treated children (Log-rank statistic 5.35, df = 1, P = 0.02). Gametocyte sex ratio changes were similar following treatment with both drugs. PS and Co-T treatment of acute malaria infections in children from this endemic area is associated with significant increases in prevalence and intensities of gametocytaemia but these effects are more marked in those treated with PS than Co-T.

Comparative efficacy of chloroquine plus chlorpheniramine and halofantrine in acute uncomplicated falciparum malaria in Nigerian children

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.

Cardiac effects of halofantrine in children suffering from acute uncomplicated falciparum malaria

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.

Comparative efficacy of chloroquine plus chlorpheniramine alone and in a sequential combination with sulfadoxine-pyrimethamine, for the treatment of acute, uncomplicated, falciparum malaria in children.

One hundred and eight children with acute, symptomatic, uncomplicated, falciparum malaria were randomized to receive chloroquine (for 3 days) plus chlorpheniramine alone (for seven days) (CQ-CP group; N = 55) or, in a sequential treatment, chloroquine plus chlorpheniramine for 3 days followed, on the fourth day, by a single oral dose of sulfadoxine-pyrimethamine (25 mg sulfadoxine/kg) (CQ-CP-SP group; N = 53). The mean (S.D.) parasite-clearance time in the CQ-CP group [2.1 (0.7) days; range = 1-5 days] was similar to that in the CQ-CP-SP [2.1 (0.8) days; range = 1-5 days]. The fever-clearance times were also similar: 1.2 (0.1) days (range = 1-3 days) v. 1.1 (0.4) days (range = 1-3 days). The cure rates on days 14, 21 and 28 were 98.2%, 96.3% and 92.7%, respectively in the CQ-CP group, and 100%, 100% and 96.2%, respectively, in the CQ-CP-SP group. The rates of gametocyte carriage were low and similar (5.4% in the CQ-CP group and 3.8% in the CQ-CP-SP group) throughout the duration of the study. Both treatment regimens were relatively well tolerated, the main adverse reactions being similar: sleepiness (on day 1) and pruritus (on days 1-3). No adverse effect was attributable to SP. The results indicate that sequential treatment, for 3 days with CQ and CP, followed by a single dose of SP, is effective and well tolerated in children with acute, uncomplicated, falciparum malaria and may be an alternative treatment for CQ- and/or SP-resistant falciparum malaria. Treatment with a CQ-CP combination (CQ and CP for 3 days and then CP alone for another 4 days) is also effective but requires continuing administration after the signs and symptoms of acute malaria have disappeared.

Age-related hearing loss, vitamin B12, and folate in the elderly.

OBJECTIVE: Determine the correlation between the hearing threshold and the serum levels of vitamin B12 (cobalamin) and folic acid among elderly subjects (> 60 years) with age-related hearing loss (ARHL). STUDY DESIGN: Cross-sectional. SETTING: Community. SUBJECTS AND METHODS: Subjects included elderly who were found apparently healthy following repeated examination by physicians. The pure tone average (PTA) for the speech and high frequencies, and the serum folate and cobalamin were determined and the correlation found. RESULTS: The mean ± SD values of serum folate among the subjects with normal PTA in the speech frequencies (0-30 dB) was 412.3 nmol/L ± 17.6 nmol/L, while among those with hearing loss (HL), it was 279.1 nmol/L ± 17.2 nmol/L (P = 0.01). In the high frequencies, the mean ± SD values among the subjects with normal PTA was 426.3 nmol/L ± 17.6 nmol/L, while among those with HL, it was 279.14 nmol/L ± 171.2 nmol/L. The serum cobalamin among the subjects with normal PTA within the speech frequencies was 49.7 pmol/L ± 9.4 pmol/L, while among those with speech-frequency HL, it was 42.6 pmol/L ± 10.2 pmol/L. However, for high frequencies, the mean ± SD values among the subjects with normal PTA was 47.4 pmol/L ± 7.3 pmol/L, while among those with HL, it was 41.3 pmol/L ± 9.2 pmol/L. Spearmans correlation revealed that low folate (correlation coefficient = −0.27, P = 0.01) and cyanocobalamin (correlation coefficient = −0.35, P = 0.02) were significantly associated with increasing hearing threshold in the high frequencies. After adjusting for age, serum folate (correlation coefficient = −0.01, P = 0.01) was significant, while vitamin B12 (correlation coefficient = −0.01, P = 0.74) was not. CONCLUSION: Serum folate was significantly lower among elderly with ARHL. Trials on nutritional supplementation may substantiate the role of serum folate in ARHL.

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

Abstract 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 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 100,000/μl (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.