Alicia Evans

Sulfadoxine-pyrimethamine pharmacokinetics in malaria: pediatric dosing implications.

Our objective was to characterize the pharmacokinetic properties of sulfadoxine‐pyrimethamine in African adults and children with acute falciparum malaria. Despite decades of widespread use, there are few data to inform dose recommendations.

Cigarette smoke impairs cytokine responses and BCG containment in alveolar macrophages

Background There is a strong epidemiological link between smoking and tuberculosis (TB), but the association is confounded by socioeconomic and other factors. A direct relationship between cigarette smoke and poor treatment-related outcomes in patients with TB is therefore questionable. We investigated whether constituents of tobacco smoke impair mycobacterial host immune responses in vitro. Methodology Preparation of a cigarette smoke extract (CSE) from Marlboro Red cigarettes was standardised and reproducibility verified by mass spectroscopy. Macrophages were derived from peripheral blood monocytes (MDM) and alveolar macrophages from bronchoalveolar lavage fluid from healthy non-smoking volunteers. Mycobacterial uptake (flow cytometric detection of fluorescence using green fluorescent protein-labelled BCG), cytokine responses (ELISA) and mycobacterial containment (colony forming units) was evaluated in both macrophage populations with and without co-culture with CSE, nicotine and a nicotine receptor blocker. Results Cigarette smoke failed to impair the uptake of mycobacteria by monocyte-derived or alveolar macrophages. CSE (vs no CSE) reduced the mean (SD) BCG-driven macrophage (MDM) interferon γ (IFN-γ), tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) responses by 56.4 (18.6)%, 67.0 (33.4)% and 77.7 (27.7)%, respectively (p<0.001). Nicotine alone impaired IL-10 and TNF-α production by 48.8 (37)% and 49 (50)%, respectively (p<0.05) through an α-7 nicotine receptor-independent mechanism. In 5-day cultures, CSE impaired mycobacterial (BCG) containment in both monocyte-derived and alveolar macrophages. Conclusions Cigarette smoke attenuates effector cytokine responses and impairs mycobacterial containment within infected human macrophages derived from the peripheral blood and alveolar compartments, thus supporting the hypothesis that cigarette smoke subverts mycobacteria-related immunity.

Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali.

BackgroundSulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs.MethodsIn a randomized controlled trial, children aged 6-59 months with uncomplicated falciparum malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 μl of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters.ResultsFourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] μg/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; p = 0.001) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; p < 0.001). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients.ConclusionDespite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated falciparum malaria treatment in young Malian children.

A Pharmacokinetic Study of Antimalarial 3,5-Diaryl-2-aminopyridine Derivatives

Malaria caused by Plasmodium falciparum is responsible for approximately 80% of the incidence and 90% of deaths which occur in the World Health Organization (WHO) African region, with children and pregnant women having the highest incidence. P. falciparum has developed resistance, and therefore new effective candidate antimalarial drugs need to be developed. Previous studies identified 3,5-diaryl-2-aminopyridines as potential antimalarial drug candidates; therefore, derivatives of these compounds were synthesized in order to improve their desired properties and pharmacokinetic (PK) properties of the derivatives were investigated in a mouse model which was dosed orally and intravenously. Collected blood samples were analyzed using liquid chromatography coupled to mass spectrometer (LC-MS/MS). The mean peak plasma level of 1.9 μM was obtained at 1 hour for compound 1 and 3.3 μM at 0.5 hours for compound 2. A decline in concentration was observed with a half-life of 2.53 and 0.87 hours for compound 1 in mice dosed orally and intravenously, respectively. For compound 2 a half-life of 2.96 and 0.68 hours was recorded. The bioavailability was 69% and 59.7% for compound 1 and compound 2, respectively.