Fall in hematocrit per 1000 parasites cleared from peripheral blood: a simple method for estimating drug-related fall in hematocrit after treatment of malaria infections.

A simple method to estimate antimalarial drug-related fall in hematocrit (FIH) after treatment of Plasmodium falciparum infections in the field is described. The method involves numeric estimation of the relative difference in hematocrit at baseline (pretreatment) and the first 1 or 2 days after treatment begun as numerator and the corresponding relative difference in parasitemia as the denominator, and expressing it per 1000 parasites cleared from peripheral blood. Using the method showed that FIH/1000 parasites cleared from peripheral blood (cpb) at 24 or 48 hours were similar in artemether-lumefantrine and artesunate-amodiaquine-treated children (0.09; 95% confidence interval, 0.052-0.138 vs 0.10; 95% confidence interval, 0.069-0.139%; P = 0.75) FIH/1000 parasites cpb in patients with higher parasitemias were significantly (P < 0.0001) and five- to 10-fold lower than in patients with lower parasitemias suggesting conservation of hematocrit or red cells in patients with higher parasitemias treated with artesunate-amodiaquine or artemether-lumefantrine. FIH/1000 parasites cpb were similar in anemic and nonanemic children. Estimation of FIH/1000 parasites cpb is simple, allows estimation of relatively conserved hematocrit during treatment, and can be used in both observational studies and clinical trials involving antimalarial drugs.

Pharmacokinetic disposition of sulfadoxine in children with acute uncomplicated falciparum malaria treated with sulfadoxine-pyrimethamine in South West Nigeria.

Sulfadoxine (SDX)-pyrimethamine is currently recommended as a partner drug with artesunate in the chemotherapy of malaria. However, information on pharmacokinetic disposition of SDX-pyrimethamine in children is limited. Efforts in this study were thus devoted to evaluation of pharmacokinetic disposition of SDX using high-pressure liquid chromatographic techniques and effects of pharmacokinetic variability on treatment outcome in Nigerian children with falciparum malaria. The blood concentration profile of SDX was similar in patients whose infection responded to treatment and those who failed treatment; mean SDX concentration values were similar for day 3 (179 vs 157 µg/mL, P = 0.734), day 7 (84 vs 51 µg/mL, P = 0.365), and day 14 (50 vs 14 µg/mL, P = 0.151). Extent of exposure (area under the curve) to SDX was also similar in the patients (1196 vs 1013 µg d/mL, P = 0.561). Pearson's correlation, showed significant correlation between area under the curve and D3 or D7 concentration of SDX (P = 0.001, r = 0.702 or P = 0.001, r = 0.835, respectively). Age-stratified analysis showed that SDX concentrations were significantly higher in older children (older than 5 years); the mean maximum concentration (125 vs 295 µg/mL, P = 0.001), extent of exposure (812 vs 1562 µg d/mL, P = 0.001), day 3 concentration (98 vs 250 µg/mL, P = 0.001), and day 7 concentration (54 vs 128 µg/mL, P = 0.007) were higher. The study revealed no differences in posttreatment blood SDX concentrations in patients who responded to treatment and those who failed to respond to treatment. Furthermore, there was an age-related pharmacokinetic variability of SDX in the group of children studied with potential impact on treatment outcome.

Interaction between ciprofloxacin and chloroquine in mice infected with chloroquine resistant Plasmodium berghei: interaction between ciprofloxacin and chloroqune.

The increasing spread of chloroquine resistant malaria has intensified the search for new antimalarial treatment, especially drugs that can be used in combination. Ciprofloxacin (CFX) a fluoroquinolone commonly used to treat bacterial infections has been shown to possess significant antimalarial activity both in vitro and in vivo. Thus efforts in this study were devoted to evaluating the antimalarial activity of combination of chloroquine (CQ) with varying doses (10, 20, 40 80, 160 mg/kg body weight) of CFX in groups of 35 mice inoculated intraperitoneally with 10(7) chloroquine resistant strain Plasmodium berghei ANKA. Parasitological activity and survival of the animals were assessed over 21 days. Parasitemia in non-treated control mice peaked at 78% on day 9 and none survived by day 10. However, the combination of CQ with 160 mg/kg body weight of CFX resulted in a reduction in parasitemia between days 9 and 14 and this was significantly lower than that obtained with CQ alone or CQ combined with the lower doses of CFX (p < 0.05). In addition, the combination of CQ with 160 mg/kg CFX significantly reduced mortality in the infected animals (p = 0.0002) compared with the other treatment groups. The results from this study support the potential usefulness of CFX in combination with antimalarial drugs for the treatment of chloroquine resistant human malaria.

Plasmodium falciparum gametocyte carriage, sex ratios and asexual parasite rates in Nigerian children before and after a treatment protocol policy change instituting the use of artemisinin-based combination therapies.

The effects of artemisinin-based combination therapies (ACTs) on transmission of Plasmodium falciparum were evaluated after a policy change instituting the use of ACTs in an endemic area. P. falciparum gametocyte carriage, sex ratios and inbreeding rates were examined in 2,585 children at presentation with acute falciparum malaria during a 10-year period from 2001-2010. Asexual parasite rates were also evaluated from 2003-2010 in 10,615 children before and after the policy change. Gametocyte carriage declined significantly from 12.4% in 2001 to 3.6% in 2010 (χ2 for trend = 44.3, p < 0.0001), but sex ratios and inbreeding rates remained unchanged. Additionally, overall parasite rates remained unchanged before and after the policy change (47.2% vs. 45.4%), but these rates declined significantly from 2003-2010 (χ2 for trend 35.4, p < 0.0001). Chloroquine (CQ) and artemether-lumefantrine (AL) were used as prototype drugs before and after the policy change, respectively. AL significantly shortened the duration of male gametocyte carriage in individual patients after treatment began compared with CQ (log rank statistic = 7.92, p = 0.005). ACTs reduced the rate of gametocyte carriage in children with acute falciparum infections at presentation and shortened the duration of male gametocyte carriage after treatment. However, parasite population sex ratios, inbreeding rates and overall parasite rate were unaffected.

Plasmodium falciparum gametocyte carriage, emergence, clearance and population sex ratios in anaemic and non-anaemic malarious children.

Anaemia in falciparum malaria is associated with an increased risk of gametocyte carriage, but its effects on transmission have not been extensively evaluated in malarious children. Plasmodium falciparum gametocyte carriage, emergence, clearance, population sex ratios (SR) (defined as the proportion of gametocytes that are male), inbreeding rates and temporal changes in SR were evaluated in 840 malarious children. Gametocyte carriage pre-treatment was at a level of 8.1%. Anaemia at enrolment was an independent risk factor for gametocyte carriage post-treatment. The emergence of gametocytes seven days post-treatment was significantly more frequent in anaemic children (7/106 vs. 10/696, p = 0.002). In the initially detected gametocytes, the proportion of children with a male-biased SR (MBSR) (> 0.5) was significantly higher in anaemic children (6/7 vs. 3/10, p = 0.027). Pre-treatment SR and estimated inbreeding rates (proportion of a mother's daughters fertilised by her sons) were similar in anaemic and non-anaemic children. Pre-treatment SR became more female-biased in non-anaemic children following treatment. However, in anaemic children, SR became male-biased. Anaemia was shown to significantly increase gametocyte emergence and may significantly alter the SR of emerging gametocytes. If MBSR is more infective to mosquitoes at low gametocytaemia, then these findings may have significant implications for malaria control efforts in endemic settings where malaria-associated anaemia is common.

Plasmodium falciparum gametocyte carriage, sex ratios and asexual parasite rates in Nigerian children before and after a treatment protocol policy change instituting the use of artemisinin-based combination therapies

The effects of artemisinin-based combination therapies (ACTs) on transmission of Plasmodium falciparum were evaluated after a policy change instituting the use of ACTs in an endemic area. P. falciparum gametocyte carriage, sex ratios and inbreeding rates were examined in 2,585 children at presentation with acute falciparum malaria during a 10-year period from 2001-2010. Asexual parasite rates were also evaluated from 2003-2010 in 10,615 children before and after the policy change. Gametocyte carriage declined significantly from 12.4 percent in 2001 to 3.6 percent in 2010 (@@χ2 for trend = 44.3, p < 0.0001), but sex ratios and inbreeding rates remained unchanged. Additionally, overall parasite rates remained unchanged before and after the policy change (47.2 percent vs. 45.4 percent), but these rates declined significantly from 2003-2010 (@@χ2 for trend 35.4, p < 0.0001). Chloroquine (CQ) and artemether-lumefantrine (AL) were used as prototype drugs before and after the policy change, respectively. AL significantly shortened the duration of male gametocyte carriage in individual patients after treatment began compared with CQ (log rank statistic = 7.92, p = 0.005). ACTs reduced the rate of gametocyte carriage in children with acute falciparum infections at presentation and shortened the duration of male gametocyte carriage after treatment. However, parasite population sex ratios, inbreeding rates and overall parasite rate were unaffected.

Plasmodium falciparum gametocyte carriage, emergence, clearance and population sex ratios in anaemic and non-anaemic malarious children

Anaemia in falciparum malaria is associated with an increased risk of gametocyte carriage, but its effects on transmission have not been extensively evaluated in malarious children. Plasmodium falciparum gametocyte carriage, emergence, clearance, population sex ratios (SR) (defined as the proportion of gametocytes that are male), inbreeding rates and temporal changes in SR were evaluated in 840 malarious children. Gametocyte carriage pre-treatment was at a level of 8.1 percent. Anaemia at enrolment was an independent risk factor for gametocyte carriage post-treatment. The emergence of gametocytes seven days post-treatment was significantly more frequent in anaemic children (7/106 vs. 10/696, p = 0.002). In the initially detected gametocytes, the proportion of children with a male-biased SR (MBSR) (> 0.5) was significantly higher in anaemic children (6/7 vs. 3/10, p = 0.027). Pre-treatment SR and estimated inbreeding rates (proportion of a mother's daughters fertilised by her sons) were similar in anaemic and non-anaemic children. Pre-treatment SR became more female-biased in non-anaemic children following treatment. However, in anaemic children, SR became male-biased. Anaemia was shown to significantly increase gametocyte emergence and may significantly alter the SR of emerging gametocytes. If MBSR is more infective to mosquitoes at low gametocytaemia, then these findings may have significant implications for malaria control efforts in endemic settings where malaria-associated anaemia is common.

Use of area under the curve to evaluate the effects of antimalarial drugs on malaria-associated anemia after treatment.

To evaluate the effects of antimalarial drugs on Plasmodium falciparum malaria-associated anemia, we use the area under the curve (AUC) of anemia levels after treatment as an approach to combine their duration and magnitude. The method involves numeric estimation, by trapezoidal rule, of AUC from a plot of deficit in hematocrit levels from 30% (the lower threshold of normal) versus time in anemic children. Using the method, we evaluated, in randomized trials, the effects of artesunate-mefloquine versus mefloquine alone and artemether-lumefantrine versus amodiaquine-artesunate on the time course of recovery from malaria-associated anemia in 109 children. Anemia resolution times were similar (10.9 ± 6.2 [standard deviation] versus 13.3 ± 8.9 days, P = 0.2), but mean AUC was significantly lower in artesunate-mefloquine- compared with mefloquine-treated children (35.5 ± 7.1 [standard error of mean] versus 49.8 ± 11.3 %·h, P = 0.02) indicating larger exposure to anemia in mefloquine-treated children. In artemether-lumefantrine- and amodiaquine-artesunate-treated children, both anemia resolution times (8.6 ± 5.3 [standard deviation] versus 8.6 ± 4.8 days, P = 0.98) and mean AUC (57.1 ± 12.9 [standard error of mean] versus 46.3 ± 8.7 %·h, P = 0.74) were similar. Estimation of AUC appears more robust than estimation of anemia resolution time in evaluating antimalarial drug effects and can be used in both observational studies and clinical trials assessing the effects of therapies on malaria-associated anemia.