Late pregnancy and OCP use impair biotransformation of the active antimalarial metabolite CG from the parent PG. This may be mediated by oestrogen inhibition of CYP2C19 activity. The dose of PG should be increased by 50% in these groups.
BackgroundAchieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations.MethodsThe WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data.ResultsOf 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI −1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL).ConclusionsCurrent artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0456-7) contains supplementary material, which is available to authorized users.
The extent and duration of changes on lymphocyte function and serum immunoglobulin (Ig) levels were examined in 12 women who walked 45 min at 60% VO2 max in a laboratory setting. A 2-factor, 2 x 6 design with repeated measures on both factors was utilized. The first factor was condition (exercise and rest), and the second factor was time (six times of measurement over a 24-h period), with treatment order counterbalanced. The 45-min walk, in comparison to rest in a seated position, was not associated with significant changes in circulating numbers of interleukin-2-activated T cells (CD5 and CD25) or on spontaneous or concanavalin-A-stimulated lymphocyte proliferation. A trend for decreased phytohemagglutinin-stimulated lymphocyte proliferation in comparison to the rest condition, however, was seen 1.5 h following the exercise bout (p = 0.047). The patterns of change for serum IgG, IgA, and IgM were significantly different (p = 0.001, p less than 0.001, p = 0.010, respectively) between conditions. IgG rose 7.2% immediately following exercise, and then returned to baseline 1.5 h later, which contrasted significantly with changes in the rest condition. These same patterns of change occurred also with IgA and IgM, but increases immediately following exercise were not significant, although a trend was seen for IgA (p = 0.03). The 45-min walk had no effect on plasma cortisol and epinephrine levels relative to the rest condition, but was associated with a significant 89% increase in norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Objective To assess the safety of benzyl benzoate lotion (BBL) and permethrin, topical treatments for scabies, during pregnancy.Design A retrospective controlled cohort study.Population Refugee and migrant women attending antenatal clinics (ANC) on the Thai-Burmese border between August 1993 and April 2006.Methods Women treated with either BBL (25%) or permethrin (4%) were identified from a manual search of antenatal records. Each case of scabies was matched with four scabies-free controls for gravidity, age, smoking status, malaria, period of treatment and gestational age at treatment. Conditional Poisson regression was used to estimate risk ratios for outcomes of pregnancy (proportion of abortions, congenital abnormalities, neonatal deaths, stillbirths and premature babies), mean birthweight and estimated median gestational age, for scabies and scabies-free women, independently for BBL and permethrin.Results There were no statistically significant differences in pregnancy outcomes between women who were treated with either BBL (n = 444) compared with their matched controls (n = 1,776) or permethrin (n = 196) treated women and their matched controls (n = 784). Overall, only 10.9% (n = 66) of treatments were in the first trimester. Retreatment rates were higher with BBL 16.4%, than permethrin 9.7%, P = 0.038. Scabies was more common during cooler periods. ConclusionWe found no evidence of adverse effects on pregnancy outcome due to topical 25% BBL or 4% permethrin.
Pulmonary disease remains a major problem for the 33 million individuals who are thought to be infected with human immunodeficiency virus (HIV) worldwide. Respiratory infections are responsible for a large number of the 2 million deaths that occur each year in association with HIV disease. In countries where the majority of the population can access highly active antiretroviral therapy, morbidity and mortality rates have been cut by up to 80%. This has allowed the withdrawal of specific opportunistic infection prophylaxis when immune restoration is deemed to be adequate. Recommendations have been published concerning Pneumocystis carinii prophylaxis. This year has also seen further reports of drug-resistant isolates of Pneumocystis carinii. The clinical relevance of this is still debated. Tuberculosis remains a global problem. The complexity of the interactions between specific anti-HIV and anti-tuberculous treatment have been highlighted. In the developing world, the importance of immunization and prophylaxis (against bacteria and mycobacteria) have recently been further defined in a number of studies.
History has shown us that wherever antimalarial drugs are deployed antimalarial drug resistance will follow. A pattern has emerged with the drugs falling to resistance first in South East Asia and subsequently in India, Latin America and Africa. The decline in chloroquine efficacy led to millions of avoidable deaths from malaria in sub-Saharan Africa throughout the 1980s and '90s.Artemisinin based combination treatments (ACTs) are the recommended first line treatments for falciparum malaria worldwide. The unique properties of the artemisinin derivatives, in particular their ability to reduce peripheral blood parasitaemia rapidly, make them the most potent antimalarial drug class ever used. They are partnered with slower acting antimalarial drugs and given over 3 days. Resistance to both the artemisinin derivatives and their partner drugs (mefloquine and piperaquine) has emerged in South East Asia over the last decade. Now failure rates of the combinations exceed 30% at some locations. Alarmingly, malaria is on the rise again in western Cambodia where incidence rates had reduced dramatically over the last decade.Genetic studies have identified several mutations in a gene encoding for a plasmodial kelch protein associated with artemisinin resistance. Sampling from several sites throughout Asia has suggested resistance may have emerged multiple times at different locations. This is unlike chloroquine resistance which is thought to have emerged only twice and then spread globally. This finding has implications for global surveillance and containment strategies. Newer antimalarial drug compounds are in development but are still several years away from registration. The most practical solution to contain the threat of antimalarial drug resistance before the death toll from malaria rises is to intensify our efforts to eliminate falciparum malaria.
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