Alternative Treatment for Schistosomiasis Shows Promise

Parasitologists have tested drugs derived from the oxadiazole class of chemical compounds and found them to be effective potential replacements for praziquantel, the present drug of choice for treatment of schistosomiasis.

The World Health Organization estimates that 600 million people worldwide are at risk of infection with schistosomiasis, with 200 million already infected, and over 120 million having a symptomatic infection. The disease is endemic in over seventy-five countries.
Schistosomes are blood flukes that have two distinct life-cycle stages: a sexual stage in mammals and an asexual stage in freshwater snails. Humans acquire infection when they come into contact with freshwater lakes and rivers containing infective schistosome larvae. In the body of the host, male and female worms mature into adults and form a permanent mating pair that lives up to five years. Approximately six weeks after the initial infection, the females begin to produce between 200 and 3,000 eggs a day, depending on the species.

The host's granulomatous inflammatory response to these eggs is responsible for most of the damage associated with chronic schistosomiasis. Shistosoma haematobium eggs, which are mainly found around the bladder, can result in hematuria, ureteric obstruction, and bladder cancer. Eggs of the other species usually lodge in mesenteric vessels draining to the liver and cause periportal fibrosis, with the subsequent development of portal hypertension, splenomegaly, esophageal varices, and progressive liver dysfunction. Eggs in the bowel mucosa cause ulcerations and polyp formation leading to diarrhea and abdominal pain. When portal hypertension occurs, eggs are shunted to the lungs, where pulmonary hypertension may occur.

Treatment for schistosomiasis, which is responsible for more than 280,000 deaths annually, depends almost exclusively on praziquantel. Millions of people are treated annually with praziquantel, and drug-resistant parasites thus are likely to evolve. Finding a replacement for praziquantel has been given a high priority.

Investigators at Illinois State University (Normal, USA) and the [U.S.] National Institutes of Health's Chemical Genomics Center (NCGC, Bethesda, MD, USA) using a quantitative high-throughput screening assay found that oxadiazole 2-oxides were able to inhibit a parasite enzyme, thioredoxin glutathione reductase (TGR), with activities in the low micromolar to low nanomolar range. Further details published in the March 16, 2008, online edition of the journal Nature Medicine revealed that treatment with 4-phenyl-1,2,5-oxadiazole-3-carbonitrile-2-oxide led to marked reductions in worm burdens in infected mice, and that this compound killed the parasite in all of its stages, from larva to adult.

"This builds upon my lab's previous findings that Schistosoma worms survive in the host due to a protective enzyme TGR. By teaming with NCGC, we were able to move our research one step closer to the clinic by identifying a class of compounds that specifically target that enzyme,” said senior author Dr. David L. Williams, professor of biology at Illinois State University, "Still, much remains to be done. Our ultimate goal is to see our basic biological findings translated into help for people with schistosomiasis.”

Dr. Christopher P. Austin, director of NCGC, said, "Our center has brought pharmaceutical-scale chemical screening, informatics, and medicinal chemistry to bear on neglected diseases that affect millions globally, but are not worked on by the pharmaceutical industry, since they cannot generate the needed financial returns. This study demonstrates the wonderful things that can happen when the NCGC's scientific capabilities and infrastructure are combined with the biological expertise of individual academic investigators.”


Related Links:
Illinois State University
NIH Chemical Genomics Center