New drug candidates show promise for cure for Chagas disease
A team of researchers from Canada has developed a class of compounds which may help eradicate a neglected tropical disease that is currently hard to kill in its chronic form. The research was published ahead of print in Antimicrobial Agents and Chemotherapy.
Chagas disease or American trypanosomiasis, caused by Trypanosoma cruzi, affects about 18 million people living mostly in Latin America. The parasite is transmitted to humans by blood-sucking reduviid bugs, also known as kissing bugs due to their predilection for feeding on the faces of their victims. In the United States, Chagas disease is considered one of the neglected parasitic infections, a group of five parasitic diseases that have been targeted by CDC for public health action.
“While historically infection was largely confined to poor and rural populations in Central and South America, it has been emerging in the U.S., Canada, Europe, Japan, and Australia, due to immigration, and nonvectorial transmission is becoming a public health threat,” says Deborah Nicoll-Griffith of the Merck Frosst Centre for Therapeutic Research in Kirkland, Quebec, a researcher on the study. One 2005 estimate put the number of people infected within the U.S. at 300,000 (1/1000).
There are two phases of Chagas disease: the acute phase and the chronic phase. Both phases can be symptom free or life threatening. Left untreated the disease can lead to cardiac and digestive disorders, as the parasite burrows into the heart, esophagus and colon tissue where it causes damage over time.
The current standard of care, the drug benznidazole, has significant activity against the parasite during the acute phase, but is less effective once the disease becomes chronic.
Efforts to find new drugs focus on disrupting an enzyme, cruzipain, which the parasite uses for digestion, to produce other cellular machinery, to evade the host’s immune system, and to invade heart and gastrointestinal tissues.
Chagas disease
Chagas disease is an illness spread by insects. It is common in South and Central America.
Chagas disease is caused by a parasite. It is common in Latin America but not in the United States. Infected blood-sucking bugs, sometimes called kissing bugs, spread it. When the bug bites you, usually on your face, it leaves behind infected waste. You can get the infection if you rub it in your eyes or nose, the bite wound or a cut. The disease can also spread through contaminated food, a blood transfusion, a donated organ or from mother to baby during pregnancy.
If you notice symptoms, they might include
Fever
Flu-like symptoms
A rash
A swollen eyelid
These early symptoms usually go away. However, if you don’t treat the infection, it stays in your body. Later, it can cause serious intestinal and heart problems.
A physical exam and blood tests can diagnose it. You may also need tests to see whether the disease has affected your intestines and heart.
Medicines can kill the parasite, especially early on. You can also treat related problems. For example, a pacemaker helps with certain heart complications.
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Centers for Disease Control and Prevention
Nicoll-Griffith and her colleagues identified two compounds known as reversible cysteine protease inhibitors that fit cruzipain like jigsaw puzzle pieces, jamming the enzyme. In the study, they tested the efficacy of the compounds in mice against that of benznidazole. While all treatment groups showed a marked reduction in parasite burden, in all tissues, the two experimental compounds had greater cure rates of acute infections (90% and 78%) compared to benznidazole (71%.)
Chagas disease is an infection caused by a protozoan parasite (Trypanosoma cruzi) that can result in acute inflammatory skin changes (chagomas) and may eventually cause infection and inflammation of many other body tissues, especially those of the heart and intestinal tract.
Chagas disease was first described in 1909 in Brazil.
Chagas disease is caused by a protozoan parasite named Trypanosoma cruzi that is transmitted to humans from the feces of triatomine bugs (kissing bugs).
The parasites usually enter the mammalian (human) host through the bug bite, or breaks in the skin or conjunctiva, replicate in mammalian cells, and may eventually reach other organs through the blood.
Chagas disease may proceed through three phases in an individual: acute, intermediate or indeterminate, and chronic.
Chagas disease symptoms vary widely from no symptoms to severe in the chronic phase.
Acute-phase symptoms of Chagas disease may be swelling and/or redness at the skin infection site (termed chagoma), rash, swollen lymph nodes, fever, head and body aches, fatigue, nausea, vomiting and/or diarrhea, liver
and/or spleen enlargement, and the Romaña sign.
Chronic-phase symptoms and signs of Chagas disease may be irregular heartbeats, palpitations, fainting (syncope), cardiomyopathy, congestive heart failure, short of breath (dyspnea), emphysema, stroke, sudden death, chronic abdominal pain, chronic constipation, dilated colon, and difficulty swallowing.
Patient history, physical exam, direct microscopic visualization of the parasites, and detection of antibodies against the parasites are methods used to diagnose Chagas disease.
Treatment with antiparasitic drugs benznidazole (Rochagan, Ragonil) and nifurtimox (Lampit) kill or inhibit T. cruzi parasites.
Chronic-phase patients are usually treated using treatments directed at the specific symptoms or organ damage.
There is no vaccine against Chagas disease parasites for humans, but many experts suggest that elimination of primitive housing and education may prevent most cases of Chagas disease.
“The efficacy shown in these T. cruzi murine studies suggests that nitrile-containing cruzipain inhibitors show promise as a viable approach for a safe and effective treatment of Chagas disease,” write the researchers.
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A copy of the manuscript can be found online at bit.ly/asmtip1213e. The final version of the article is scheduled for the February 2014 issue of Antimicrobial Agents and Chemotherapy.
Antimicrobial Agents and Chemotherapy is a publication of the American Society for Microbiology (ASM). The ASM is the largest single life science society, composed of over 39,000 scientists and health professionals. Its mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.
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Jim Sliwa
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202-942-9297
American Society for Microbiology