Population pharmacokinetics of antimalarial naphthoquine in combination with artemisinin in Tanzanian children and adults: dose optimization

The combination antimalarial therapy of artemisinin-naphthoquine (ART-NQ) was developed as a single-dose therapy, aiming to improve adherence relative to the multiday schedules of other artemisinin combination therapies. The pharmacokinetics of ART-NQ has not been well characterized, especially in children. A pharmacokinetic study was conducted in adults and children over 5 years of age (6 to 10, 11 to 17, and >/=18 years of age) with uncomplicated malaria in Tanzania. The median weights for the three age groups were 20, 37.5, and 55 kg, respectively. Twenty-nine patients received single doses of 20 mg/kg of body weight for artemisinin and 8 mg/kg for naphthoquine, and plasma drug concentrations were assessed at 13 time points over 42 days from treatment. We used nonlinear mixed-effects modeling to interpret the data, and allometric scaling was employed to adjust for the effect of body size. The pharmacokinetics of artemisinin was best described by one-compartment model and that of naphthoquine by a two-compartment disposition model. Clearance values for a typical patient (55-kg body weight and 44.3-kg fat-free mass) were estimated as 66.7 L/h (95% confidence interval [CI], 57.3 to 78.5 L/h) for artemisinin and 44.2 L/h (95% CI, 37.9 to 50.6 L/h) for naphthoquine. Nevertheless, we show via simulation that patients weighing >/=70 kg achieve on average a 30% lower day 7 concentration compared to a 48-kg reference patient at the doses tested, suggesting dose increases may be warranted to ensure adequate exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01930331.)

Extracts of common pesticidal plants increase plant growth and yield in common bean plants

Common bean (Phaseolus vulgaris) is an important food and cash crop in many countries. Bean crop yields in sub-Saharan Africa are on average 50% lower than the global average, which is largely due to severe problems with pests and diseases as well as poor soil fertility exacerbated by low-input smallholder production systems. Recent on-farm research in eastern Africa has shown that commonly available plants with pesticidal properties can successfully manage arthropod pests. However, reducing common bean yield gaps still requires further sustainable solutions to other crop provisioning services such as soil fertility and plant nutrition. Smallholder farmers using pesticidal plants have claimed that the application of pesticidal plant extracts boosts plant growth, potentially through working as a foliar fertiliser. Thus, the aims of the research presented here were to determine whether plant growth and yield could be enhanced and which metabolic processes were induced through the application of plant extracts commonly used for pest control in eastern Africa. Extracts from Tephrosia vogelii and Tithonia diversifolia were prepared at a concentration of 10% w/v and applied to potted bean plants in a pest-free screen house as foliar sprays as well as directly to the soil around bean plants to evaluate their contribution to growth, yield and potential changes in primary or secondary metabolites. Outcomes of this study showed that the plant extracts significantly increased chlorophyll content, the number of pods per plant and overall seed yield. Other increases in metabolites were observed, including of rutin, phenylalanine and tryptophan. The plant extracts had a similar effect to a commercially available foliar fertiliser whilst the application as a foliar spray was better than applying the extract to the soil. These results suggest that pesticidal plant extracts can help overcome multiple limitations in crop provisioning services, enhancing plant nutrition in addition to their established uses for crop pest management

Phytochemical analysis of Tephrosia vogelii across East Africa reveals three chemotypes that influence its use as a pesticidal plant

Tephrosia vogelii is a plant species chemically characterized by the presence of entomotoxic rotenoids and used widely across Africa as a botanical pesticide. Phytochemical analysis was conducted to establish the presence and abundance of the bioactive principles in this species across three countries in East Africa: Tanzania, Kenya, and Malawi. Analysis of methanolic extracts of foliar parts of T. vogelii revealed the occurrence of two distinct chemotypes that were separated by the presence of rotenoids in one, and flavanones and flavones that are not bioactive against insects on the other. Specifically, chemotype 1 contained deguelin as the major rotenoid along with tephrosin, and rotenone as a minor component, while these compounds were absent from chemotype 2, which contained previously reported flavanones and flavones including obovatin‐3‐O‐methylether. Chemotype 3 contained a combination of the chemical profiles of both chemotype 1 and 2 suggesting a chemical hybrid. Plant samples identified as chemotype 1 showed chemical consistency across seasons and altitudes, except in the wet season where a significant difference was observed for samples in Tanzania. Since farmers are unable to determine the chemical content of material available care must be taken in promoting this species for pest management without first establishing efficacy. While phytochemical analysis serves as an important tool for quality control of pesticidal plants, where analytical facilities are not available simple bioassays could be developed to enable extension staff and farmers to determine the efficacy of their plants and ensure only effective materials are adopted

Lymph node dendritic cells harbor inducible replication-competent HIV despite years of suppressive ART.

Although gut and lymph node (LN) memory CD4 T cells represent major HIV and simian immunodeficiency virus (SIV) tissue reservoirs, the study of the role of dendritic cells (DCs) in HIV persistence has long been limited to the blood due to difficulties to access lymphoid tissue samples. In this study, we show that LN migratory and resident DC subpopulations harbor distinct phenotypic and transcriptomic profiles. Interestingly, both LN DC subpopulations contain HIV intact provirus and inducible replication-competent HIV despite the expression of the antiviral restriction factor SAMHD1. Notably, LN DC subpopulations isolated from HIV-infected individuals treated for up to 14 years are transcriptionally silent but harbor replication-competent virus that can be induced upon TLR7/8 stimulation. Taken together, these results uncover a potential important contribution of LN DCs to HIV infection in the presence of ART

The Candidate Blood-stage Malaria Vaccine P27A Induces a Robust Humoral Response in a Fast Track to the Field Phase 1 Trial in Exposed and Nonexposed Volunteers.

P27A is an unstructured 104mer synthetic peptide from Plasmodium falciparum trophozoite exported protein 1 (TEX1), the target of human antibodies inhibiting parasite growth. The present project aimed at evaluating the safety and immunogenicity of P27A peptide vaccine in malaria-nonexposed European and malaria-exposed African adults. This study was designed as a staggered, fast-track, randomized, antigen and adjuvant dose-finding, multicenter phase 1a/1b trial, conducted in Switzerland and Tanzania. P27A antigen (10 or 50 μg), adjuvanted with Alhydrogel or glucopyranosil lipid adjuvant stable emulsion (GLA-SE; 2.5 or 5 μg), or control rabies vaccine (Verorab) were administered intramuscularly to 16 malaria-nonexposed and 40 malaria-exposed subjects on days 0, 28, and 56. Local and systemic adverse events (AEs) as well as humoral and cellular immune responses were assessed after each injection and during the 34-week follow-up. Most AEs were mild to moderate and resolved completely within 48 hours. Systemic AEs were more frequent in the formulation with alum as compared to GLA-SE, whereas local AEs were more frequent after GLA-SE. No serious AEs occurred. Supported by a mixed Th1/Th2 cell-mediated immunity, P27A induced a marked specific antibody response able to recognize TEX1 in infected erythrocytes and to inhibit parasite growth through an antibody-dependent cellular inhibition mechanism. Incidence of AEs and antibody responses were significantly lower in malaria-exposed Tanzanian subjects than in nonexposed European subjects. The candidate vaccine P27A was safe and induced a particularly robust immunogenic response in combination with GLA-SE. This formulation should be considered for future efficacy trials. NCT01949909, PACTR201310000683408

Scope for non-crop plants to promote conservation biological control of crop pests and serve as sources of botanical insecticides

Besides providing food and shelter to natural enemies of crop pests, plants used in conservation biological control interventions potentially provide additional ecosystem services including providing botanical insecticides. Here we concurrently tested the strength of these two services from six non-crop plants in managing cabbage pests in Ghana over three successive field seasons. Crop margin plantings of Ageratum conyzoides, Tridax procumbens, Crotalaria juncea, Cymbopogon citratus, Lantana camara and Talinum triangulare were compared with a bare earth control in a three-way split plot design such that the crop in each plot was sprayed with either a 10% (w/v) aqueous extract from the border plant species, a negative control (water) and a positive control (emamectin benzoate ‘Attack’ insecticide). Pests were significantly less numerous in all unsprayed treatments with non-crop plant margins and in corresponding sprayed treatments (with botanical or synthetic insecticide positive control) while treatments with bare earth margin or sprayed with water (negative controls) had the highest pest densities. Numbers of predators were significantly depressed by synthetic insecticide but higher in other treatments whether unsprayed or sprayed with botanical insecticide. We conclude that some plant species have utility in both conservation biological control and as source of botanical insecticides that are relatively benign to natural enemies. In this crop system, however, the additional cost associated with using botanical insecticides was not justified by greater levels of pest suppression than achieved from border plants alone