Use-case scenarios for an anti-Cryptosporidium therapeutic.

Cryptosporidium is a widely distributed enteric parasite that has an increasingly appreciated pathogenic role, particularly in pediatric diarrhea. While cryptosporidiosis has likely affected humanity for millennia, its recent "emergence" is largely the result of discoveries made through major epidemiologic studies in the past decade. There is no vaccine, and the only approved medicine, nitazoxanide, has been shown to have efficacy limitations in several patient groups known to be at elevated risk of disease. In order to help frontline health workers, policymakers, and other stakeholders translate our current understanding of cryptosporidiosis into actionable guidance to address the disease, we sought to assess salient issues relating to clinical management of cryptosporidiosis drawing from a review of the literature and our own field-based practice. This exercise is meant to help inform health system strategies for improving access to current treatments, to highlight recent achievements and outstanding knowledge and clinical practice gaps, and to help guide research activities for new anti-Cryptosporidium therapies

Drosophila Carrying Pex3 or Pex16 Mutations Are Models of Zellweger Syndrome That Reflect Its Symptoms Associated with the Absence of Peroxisomes

The peroxisome biogenesis disorders (PBDs) are currently difficult-to-treat multiple-organ dysfunction disorders that result from the defective biogenesis of peroxisomes. Genes encoding Peroxins, which are required for peroxisome biogenesis or functions, are known causative genes of PBDs. The human peroxin genes PEX3 or PEX16 are required for peroxisomal membrane protein targeting, and their mutations cause Zellweger syndrome, a class of PBDs. Lack of understanding about the pathogenesis of Zellweger syndrome has hindered the development of effective treatments. Here, we developed potential Drosophila models for Zellweger syndrome, in which the Drosophila pex3 or pex16 gene was disrupted. As found in Zellweger syndrome patients, peroxisomes were not observed in the homozygous Drosophila pex3 mutant, which was larval lethal. However, the pex16 homozygote lacking its maternal contribution was viable and still maintained a small number of peroxisome-like granules, even though PEX16 is essential for the biosynthesis of peroxisomes in humans. These results suggest that the requirements for pex3 and pex16 in peroxisome biosynthesis in Drosophila are different, and the role of PEX16 orthologs may have diverged between mammals and Drosophila. The phenotypes of our Zellweger syndrome model flies, such as larval lethality in pex3, and reduced size, shortened longevity, locomotion defects, and abnormal lipid metabolisms in pex16, were reminiscent of symptoms of this disorder, although the Drosophila pex16 mutant does not recapitulate the infant death of Zellweger syndrome. Furthermore, pex16 mutants showed male-specific sterility that resulted from the arrest of spermatocyte maturation. pex16 expressed in somatic cyst cells but not germline cells had an essential role in the maturation of male germline cells, suggesting that peroxisome-dependent signals in somatic cyst cells could contribute to the progression of male germ-cell maturation. These potential Drosophila models for Zellweger syndrome should contribute to our understanding of its pathology

Antimalarial activity of KAF156 in falciparum and vivax malaria

Background: KAF156 belongs to a new class of antimalarials (imidazolopiperazines), with activity against asexual and sexual blood stages and the pre-erythrocytic liver stages of malaria parasites. Methods: We conducted a phase 2, open-label, two-part study in five centers in Thailand and Vietnam, to assess the antimalarial efficacy, safety, tolerability and pharmacokinetic profile of KAF156 in adult patients with acute P.vivax or P.falciparum malaria. Multiple dose (400 mg once daily for 3 days) cohorts assessing parasite clearance rates were followed by a single dose cohort in falciparum malaria (800 mg) assessing 28 day cure rates. Results: Median (interquartile range) parasite clearance times were 45 (42 to 48) hours in falciparum malaria (N=10), and 24 (20 to 30) hours in vivax malaria (N=10) after the multiple dose regimen, and 49 (42 to 54) hours in falciparum malaria (N=21) after the single dose. There were 7 malaria recrudescences and 1 reinfection, and 13 of 21 (62%, 95% CI: 41-80%) patients remained free of parasitemia for 28 days. The mean (SD) KAF156 terminal elimination half-life was 44 (8.9) hours. There were no serious adverse events in this small study. Commonest adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia and hyperbilirubinemia. Vomiting, grade 2 or higher, occurred in 2 and 1 patient discontinued treatment (repeated vomiting after 800 mg single dose). There were more adverse events reported in the longer follow-up single-dose cohort. Conclusions: KAF156 showed antimalarial activity in treating a small number of adult patients with uncomplicated P.vivax or P.falciparum malaria without evident safety concerns

Antimalarial activity of KAF156 in falciparum and vivax malaria

Background: KAF156 belongs to a new class of antimalarials (imidazolopiperazines), with activity against asexual and sexual blood stages and the pre-erythrocytic liver stages of malaria parasites. Methods: We conducted a phase 2, open-label, two-part study in five centers in Thailand and Vietnam, to assess the antimalarial efficacy, safety, tolerability and pharmacokinetic profile of KAF156 in adult patients with acute P.vivax or P.falciparum malaria. Multiple dose (400 mg once daily for 3 days) cohorts assessing parasite clearance rates were followed by a single dose cohort in falciparum malaria (800 mg) assessing 28 day cure rates. Results: Median (interquartile range) parasite clearance times were 45 (42 to 48) hours in falciparum malaria (N=10), and 24 (20 to 30) hours in vivax malaria (N=10) after the multiple dose regimen, and 49 (42 to 54) hours in falciparum malaria (N=21) after the single dose. There were 7 malaria recrudescences and 1 reinfection, and 13 of 21 (62%, 95% CI: 41-80%) patients remained free of parasitemia for 28 days. The mean (SD) KAF156 terminal elimination half-life was 44 (8.9) hours. There were no serious adverse events in this small study. Commonest adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia and hyperbilirubinemia. Vomiting, grade 2 or higher, occurred in 2 and 1 patient discontinued treatment (repeated vomiting after 800 mg single dose). There were more adverse events reported in the longer follow-up single-dose cohort. Conclusions: KAF156 showed antimalarial activity in treating a small number of adult patients with uncomplicated P.vivax or P.falciparum malaria without evident safety concerns

Payments for Ecosystem Services, Poverty and Sustainability: The Case of Agricultural Soil Carbon Sequestration

This chapter explores the potential impacts of payments for ecosystem services on poverty and sustainability of farm households, using the example of agricultural soil carbon sequestration. Economic analysis shows that there is a variety of technical and economic factors affecting adoption of practices that increase soil carbon and their impacts on poverty, hence, the net effect of these factors is an empirical question. The evidence suggests that carbon payments could have a positive impact on the sustainability of production systems while also raising incomes and reducing poverty. However, carbon contracts are found to have only modest impacts on poverty, even at relatively high carbon prices. Moreover, the participation of poor farmers in carbon contracts is likely to be constrained by the same economic and institutional factors that have inhibited their use of more productive, more sustainable practices in the first place. Thus, payments for ecosystem services are most likely to have a positive impact on poverty and sustainability when they are implemented in an enabling economic and institutional environmen

Spiroindolones, a potent compound class for the treatment of malaria

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria mode