A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.

Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.

A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax.

The Plasmodium liver stage is an attractive target for the development of antimalarial drugs and vaccines, as it provides an opportunity to interrupt the life cycle of the parasite at a critical early stage. However, targeting the liver stage has been difficult. Undoubtedly, a major barrier has been the lack of robust, reliable, and reproducible in vitro liver-stage cultures. Here, we establish the liver stages for both Plasmodium falciparum and Plasmodium vivax in a microscale human liver platform composed of cryopreserved, micropatterned human primary hepatocytes surrounded by supportive stromal cells. Using this system, we have successfully recapitulated the full liver stage of P. falciparum, including the release of infected merozoites and infection of overlaid erythrocytes, as well as the establishment of small forms in late liver stages of P. vivax. Finally, we validate the potential of this platform as a tool for medium-throughput antimalarial drug screening and vaccine development.

Improvements in the status of folate and cobalamin in pregnant Newfoundland women are consistent with observed reductions in the incidence of neural tube defects.

BACKGROUND: Historically, the province of Newfoundland and Labrador had one of the highest rates of neural tube defects (NTDs) in North America (1976-1991: 3.2/1000 births), which could be partially explained by the sub-optimal status of folate and cobalamin in this population. In order to gain evidence of the impact of folate fortification programs, as well as prenatal education programs, a cross-sectional study was conducted to obtain data on the folate and cobalamin status of pregnant Newfoundland women in the post-folate fortification era. Additionally, the rates of NTDs were determined. METHODS: Blood samples were collected during the first prenatal clinic (at approximately 16 weeks gestation) from 365 pregnant women in Newfoundland in 2002. Samples were analyzed for serum folate, cobalamin and homocysteine. In addition, rates of neural tube defects were calculated from data collected from the Provincial Medical Genetics Program, Newfoundland. Data were compared to historical data from a similar population of pregnant women in Newfoundland. RESULTS: The status of both folate and cobalamin has significantly improved (p<0.0001) in the post-fortification era, concurrent with a significant reduction in the number of neural tube defects (NTDs), from 4.67 (years 1992-1996) to 1.01 (years 1998-2002) per 1000 total births. INTERPRETATION: These data provide evidence that both folate and cobalamin status of pregnant Newfoundland women have improved since 1997. The data for cobalamin provide evidence that strategies in addition to folate fortification programs are contributing to the improvements of poor water-soluble vitamin status in this population, thus providing a partial explanation for the dramatic reductions in NTD rates observed since 1995.