The effects of artemether-lumefantrine vs amodiaquine-sulfalene-pyrimethamine on the hepatomegaly associated with Plasmodium falciparum malaria in children.

An open randomized controlled study of artemether-lumefantrine (AL) and amodiaquine-sulfalene-pyrimethamine (ASP) for the treatment of uncomplicated Plasmodium falciparum malaria was carried out in 181 children. In 79 children, the hepatomegaly reduction ratios (HRR) and the speed of resolution of hepatomegaly, the hepatomegaly resolution rates (HRSR), were calculated and compared between the two treatment groups. HRR and HRSR were similar in the two treatment groups. HRSR was 71% and 62% in AL- and ASP-treated children, respectively, 14 days after commencing treatment. There was no significant correlation between HRR and parasite reduction ratio in the same patient. In children in whom parasitaemia cleared and hepatomegaly resolved within 14 days, recurrence of parasitaemia was associated with reoccurrence of hepatomegaly, suggesting that the propensity for recurrence of infection drives the malaria-attributable hepatomegaly in children from this endemic area. Combination therapy may provide additional beneficial effects on pathophysiological processes and changes associated with falciparum malaria by rapid clearing of asexual parasitaemia and reducing the propensity for recurrence of infection.

Effects of pyrimethamine-sulphadoxine, chloroquine plus chlorpheniramine, and amodiaquine plus pyrimethamine-sulphadoxine on gametocytes during and after treatment of acute, uncomplicated malaria in children

The effects of pyrimethamine-sulphadoxine (PS), chloroquine plus chlorpheniramine, a H1 receptor antagonist that reverses chloroquine resistance in Plasmodium falciparum in vitro and in vivo (CQCP), and amodiaquine plus pyrimethamine-sulphadoxine (AQPS) on gametocyte production were evaluated in 157 children with acute, symptomatic, uncomplicated falciparum malaria who were treated with these drugs. PS was significantly less effective than CQCP or AQPS at clearing asexual parasitaemia or other symptoms of malaria. Gametocyte carriage on days 3, 7, and 14 were significantly higher in those treated with PS. The ratio of the density (per æl blood) of peripheral young gametocyte (PYG), that is, < stage III to peripheral mature gametocyte (PMG), that is, stage IV and V, an index of continuing generation of gametocytes, rose to 1 by day 7 of treatment in those treated with PS, but remained consistently below 1 in the other treatment groups. PYG-PMG density ratio increased significantly from day 0-14 in those treated with PS and CQCP (chi2 = 76, P = 0.000001 and chi2 = 42.2, P = 0.00001, respectively) but decreased significantly in those treated with AQPS (chi2 = 53.2, P = 0.000001). Both PS-sensitive and -resistant infections generated PYG (18 of 29 vs 13 of 20, chi2 = 0.04, P = 0.93) but PYG was present only in those with resistant response to CQCP. Combination of PS with amodiaquine (AQ), that is, (AQPS) resulted in less production of PYG, but in this setting, PYG was not indicative of response to AQPS. These data indicate that PS enhanced production or release of young gametocytes when used alone, but generated less young gametocytes when used in combination with AQ. PYG may be used as an indicator of response to CQCP but not PS or PS-based combination drugs.

Linkage disequilibrium between two distinct loci in chromosomes 5 and 7 of Plasmodium falciparum and in vivo chloroquine resistance in Southwest Nigeria.

Chloroquine (CQ) resistance in Plasmodium falciparum is associated with polymorphisms in loci on pfcrt and pfmdr1 genes. In this study, we determined the association and linkage disequilibrium between in vivo CQ resistance and P. falciparum polymorphisms in pfcrt gene at codon 76 and pfmdr1 gene at codon 86 in isolates obtained from 111 children with acute uncomplicated falciparum malaria in Nigeria. Patients were treated with standard dosage of CQ and followed up for 28 days. Filter paper samples were collected at enrollment and during follow-up for parasites genotypes and identification of pfcrt and pfmdr1 mutations. Association and linkage disequilibrium between mutant pfcrtT76 and pfmdr1Y86 alleles in pretreatment isolates of P. falciparum was determined. Fifty-five out of the 111 patients (49.5%) failed treatment. Single mutant pfcrtT76 or pfmdr1Y86 alleles were found in 55 out of 111 P. falciparum isolates screened at enrollment. Of these 55 isolates, the mutant pfcrtT76 and pfmdr1Y86 alleles were found in 84%. Both mutant pfcrtT76 (p=0.0196) and pfmdr1Y86 (p=0.000042) alleles were associated with in vivo CQ resistance. In addition, the mutant pfcrtT76 (p=0.047) and pfmdr1Y86 (p=0.006) alleles were significantly selected by CQ in patients who failed treatment. Association analysis between paired single alleles at pfcrt and pfmdr1 loci showed a significant association (p=0.0349 and chi(2)=4.45) between the pfcrt T76 allele on chromosome 7 and the pfmdr1Y86 allele on chromosome 5 and that these two mutant alleles were in linkage disequilibrium (p=0.000, D'=0.64, and r(2)=0.28). Considering the high level of CQ resistance and drug use in the study area, the observed linkage disequilibrium between the mutant pfcrtT76 and pfmdr1Y86 alleles is maintained epistatically through directional CQ selective pressure.

Predictors of the failure of treatment with trimethoprim-sulfamethoxazole in children with uncomplicated, Plasmodium falciparum malaria.

In many African countries, trimethoprim-sulfamethoxazole (TS) is recommended for the treatment of children with malaria and pneumonia - in accordance with the guidelines for the integrated management of childhood illness (IMCI) - and, in some settings, for the home management of febrile illnesses. There have been few studies, however, of the risk of failure of treatment with this drug combination in children with acute, Plasmodium falciparum malaria. The factors that identify children at risk of treatment failure after being given TS were therefore evaluated in 101 children with acute, symptomatic, uncomplicated, P. falciparum malaria, in a hyper-endemic area of south-western Nigeria. Overall, 11% of the children failed treatment by day 14. In a multivariate analysis, two factors were found to be independent predictors of the failure of treatment with TS: an age of <3 years (adjusted odds ratio=0.1; 95% confidence interval=0.02-0.53; P=0.007); and a body temperature of >or=38 degrees C 2 days after the commencement of treatment (adjusted odds ratio=4.9; 95% confidence interval=1.2-21.3; P=0.03). These findings may have implications for control efforts in some sub-Saharan African countries, where TS is recommended for the management of malaria in children, with or without pneumonia.

Predictors of the failure of treatment with pyrimethamine-sulfadoxine in children with uncomplicated falciparum malaria.

The prevalence of pyrimethamine-sulfadoxine (PS)-resistant Plasmodium falciparum malaria has been increasing in sub-Saharan Africa or other parts of the world in the last one or two decades. The factors that identify children at risk of treatment failure after being given PS were evaluated in 291 children with acute, symptomatic, uncomplicated, P. falciparum malaria. The children took part in four antimalarial drug trials between July 1996 and July 2004 in a hyperendemic area of southwestern Nigeria. Following treatment, 64 (22%) of 291 children failed treatment by day 7 or 14. In a multivariate analysis, an age < or = 1.5 years (AOR=2.9, 95% CI 1.3-6.4, P = 0.009) and presence of fever (AOR = 3.3, 95% CI 1.28-7.14, P = 0.01) were independent predictors of the failure of treatment with PS at presentation. Following treatment, delay in parasite clearance >3 days (AOR = 2.56, CI 1.19-5.56, P = 0.016) was an independent predictor of the failure of treatment with PS. In addition, compared with the children who had no fever then, children with fever three or more days after starting treatment were more likely to be treatment failures. These findings may have implications for malaria control efforts in some sub-Saharan African countries where treatment of malaria disease depends almost entirely on PS monotherapy, and for programmes employing PS or PS-based combination therapy.

Effects of pyrimethamine-sulphadoxine, chloroquine plus chlorpheniramine, and amodiaquine plus pyrimethamine-sulphadoxine on gametocytes during and after treatment of acute, uncomplicated malaria in children.

The effects of pyrimethamine-sulphadoxine (PS), chloroquine plus chlorpheniramine, a H1 receptor antagonist that reverses chloroquine resistance in Plasmodium falciparum in vitro and in vivo (CQCP), and amodiaquine plus pyrimethamine-sulphadoxine (AQPS) on gametocyte production were evaluated in 157 children with acute, symptomatic, uncomplicated falciparum malaria who were treated with these drugs. PS was significantly less effective than CQCP or AQPS at clearing asexual parasitaemia or other symptoms of malaria. Gametocyte carriage on days 3, 7, and 14 were significantly higher in those treated with PS. The ratio of the density (per microl blood) of peripheral young gametocyte (PYG), that is, < or = stage III to peripheral mature gametocyte (PMG), that is, stage IV and V, an index of continuing generation of gametocytes, rose to 1 by day 7 of treatment in those treated with PS, but remained consistently below 1 in the other treatment groups. PYG-PMG density ratio increased significantly from day 0-14 in those treated with PS and CQCP (chi2 = 76, P = 0.000001 and chi2 = 42.2, P = 0.00001, respectively) but decreased significantly in those treated with AQPS (chi2 = 53.2, P = 0.000001). Both PS-sensitive and -resistant infections generated PYG (18 of 29 vs 13 of 20, chi2 = 0.04, P = 0.93) but PYG was present only in those with resistant response to CQCP. Combination of PS with amodiaquine (AQ), that is, (AQPS) resulted in less production of PYG, but in this setting, PYG was not indicative of response to AQPS. These data indicate that PS enhanced production or release of young gametocytes when used alone, but generated less young gametocytes when used in combination with AQ. PYG may be used as an indicator of response to CQCP but not PS or PS-based combination drugs.

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.

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.

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.

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 enrolment 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.

Predictors of the failure of treatment with chloroquine plus chlorpheniramine, in children with acute, uncomplicated, Plasmodium falciparum malaria.

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 of < or =3 years (adjusted odds ratio = 11.1; 95% confidence interval = 2.2-55.3; P = 0.003) and a parasitaemia that took >3 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 of > or =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.

Plasmodium falciparum malaria in Nigerian children during high and low transmission seasons: gametocyte carriage and response to oral chloroquine.

Plasmodium falciparum malaria during high and low transmission seasons was evaluated in 1031 children treated with different antimalarial drug in a hyperendemic area of southwestern Nigeria. Seventy-three (10.5%) of 693 and forty (11.8%) of 338 children were gametocyte carriers in the high transmission seasons (HTS) and low transmission seasons (LTS), respectively. In a multiple regression model, two factors were found to be independent risk factors for the presence of gametocytemia at enrolment in the HTS: duration of illness >3 d, and asexual parasite densities less than 10,000/microl. Similarly male gender, duration of illness >4 d and parasite density less than 5000/mul were found independent risk factors for presence of gametocytemia during LTS. The presenting parasitemia, parasite clearance times, intensity of gametocytemia and proportion carrying gametocytes post treatment differ significantly in the 333 (32.3%) of these children that were treated with chloroquine in the two seasons. These findings may be important in our understanding of P. falciparum transmission sustenance, response to chloroquine therapy and contribution of chloroquine to gametocyte carriage as seasonal changes occur.

Plasmodium falciparum hyperparasitaemia in children. Risk factors, treatment outcomes, and gametocytaemia following treatment.

The risk factors associated with hyperparasitemia at presentation and after treatment with different antimalarial drug regimens were evaluated in 1,048 children enrolled prospectively in seven antimalarial drug trials between July 1996 and September 2003 in a hyperendemic area of southwestern Nigeria. The outcomes of treatment of hyperparasitaemia, and gametocyte carriage following treatment were also evaluated. The children were assigned to one of seven treatment groups: chloroquine (CQ) only; pyrimethamine-sulfadoxine (PS) only; amodiaquine (AQ) only; CQ plus chlorpheniramine (CQCP); PS combined with CQ or AQ (COM); PS combined with probenecid (PPS); and halofantrine (HF). Hyperparasitaemia was found in 100 (9.5%) of the 1,048 children at enrolment (day 0). Following oral therapy, 1.2% of all patients (i.e. 13 patients) became hyperparasitaemic, which developed in all patients by day 1 of follow-up. In a multiple regression model, age < or = 5 years, and a core temperature (oral or rectal) > or = 39.5 degrees C were found to be independent risk factors for hyperparasitaemia at enrolment. Following therapy, the cure rate on day 14 was significantly lower in those treated with CQ compared to other treatment groups. Severe resistance (RIII) response to treatment occurred significantly more frequently in those with hyperparasitaemia at enrolment than in those without, and was seen in five and one child with hyperparasitaemia who were treated with CQ and CQCP, respectively. Gametocyte carriage was insignificantly lower at enrolment and at all times following treatment in children with hyperparasitaemia than in age- and gender-matched children without hyperparasitaemia who received the same treatment. The results are discussed in the light of management of uncomplicated hyperparasitaemia in children in endemic settings.

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 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. METHODS: We evaluated 151 children aged 12 years or younger who had uncomplicated P. falciparum malaria. Patients were randomly assigned pyrimethamine-sulphadoxine (25 mg/kg of the sulphadoxine component) or pyrimethamine-sulphadoxine as above plus probenecid 20-25 mg/kg of bodyweight in two divided doses daily for 3 days. The primary endpoints were parasitological cure rates on days 14 and 28. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. Fever (1.9 +/- 1.1 vs. 2.4 +/- 1.2 days, P = 0.02) and parasite clearance (2.3 +/- 0.9 vs. 2.7 +/- 1.1 days, P = 0.04) were significantly shorter, and the parasitological cure rate on day 14 (96.2%vs. 83.5%, P = 0.02) but not day 28 (79.4%vs. 72.6%, P = 0.4), was significantly higher in children treated with pyrimethamine-sulphadoxine-probenecid than in those treated with pyrimethamine-sulphadoxine. Gametocyte carriage was similar with both treatment regimens. CONCLUSIONS: The combination of pyrimethamine-sulphadoxine, and probenecid, at a relatively moderate dose, improved treatment efficacy but had no effect on gametocyte carriage. The pyrimethamine-sulphadoxine-probenecid combination merits further evaluation as a potential treatment for use in Nigeria.

Gametocyte sex ratios in children with asymptomatic, recrudescent, pyrimethamine-sulfadoxine-resistant, Plasmodium falciparum malaria.

The clinical features of the primary Plasmodium falciparum infections in 25 children, and of the recrudescent infections that emerged after pyrimethamine-sulfadoxine (PS) treatment of the children had failed, were evaluated. In addition, the gametocyte sex ratios in these children and in age- and gender-matched controls who had PS-sensitive (PS-S) infections were also examined. Compared with the primary infections, the recrudescent infections were accompanied by significantly fewer symptoms and lower levels of parasitaemia but significantly higher gametocytaemia:parasitaemia ratios. Although the mean gametocyte sex ratio was female-biased pre-treatment, in both the PS-resistant (PS-R) and PS-S infections it became male-biased on days 7 and 14 post-treatment. The times taken to attain a sex ratio of 1 were similar in both groups. The predominance of macrogametocytes seen 'early' post-treatment (on day 3) was later replaced by a predominance of microgametocytes (on days 7 and 14). Analysis of the disposition of gametocytaemia, from the time to attain a sex ratio of 1, showed that the area under the curve of the plot of the level of microgametocytaemia upsilon. time and the mean half-life of the microgametocytaemia were significantly greater and microgametocytaemia clearance was significantly slower than the corresponding values for macrogametocytaemia. Although sex ratios in Plasmodium may naturally become more male-biased as the infection progresses, it is possible that PS treatment may have contributed to the male-biased sex ratios observed post-treatment.

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.