Antiproliferative activity on Trypanosoma cruzi (Y strain) of the triterpene 3ß,6ß,16ß-trihidroxilup-20 (29)-ene isolated from Combretum leprosum.

Chagas disease infects approximately seven million people worldwide. Benznidazole is effective only in the acute phase of the disease, with an average cure rate of 80% between acute and recent cases. Therefore, there is an urgent need to find new bioactive substances that can be effective against parasites without causing so many complications to the host. In this study, the triterpene 3ß-6ß-16ß-trihydroxilup-20 (29)-ene (CLF-1) was isolated from Combretum leprosum, and its molecular structure was determined by NMR and infrared spectroscopy. The CLF-1 was also evaluated in vitro and in silico as potential trypanocidal agent against epimastigote and trypomastigote forms of Trypanosoma cruzi (Y strain). The CLF-1 demonstrated good results highlighted by lower IC50 (76.0 ± 8.72 µM, 75.1 ± 11.0 µM, and 70.3 ± 45.4 µM) for epimastigotes at 24, 48 and 72 h, and LC50 (71.6 ± 11.6 µM) for trypomastigotes forms. The molecular docking study shows that the CLF-1 was able to interact with important TcGAPDH residues, suggesting that this natural compound may preferentially exert its effect by compromising the glycolytic pathway in T. cruzi. The ADMET study together with the MTT results indicated that the CLF-1 is well-absorbed in the intestine and has low toxicity. Thus, this work adds new evidence that CLF-1 can potentially be used as a candidate for the development of new options for the treatment of Chagas disease.Communicated by Ramaswamy H. Sarma.

Co-morbid infections in Hansen's disease patients in the United States: considerations for treatment.

120 patients attending a Hansen's disease public health satellite clinic were evaluated for selected latent co-morbidities, consisting of strongyloidiasis, Chagas disease, hepatitis B, HIV, and tuberculosis, and potential exacerbation by immunosuppressive therapy. Implications for treatment of Hansen's disease are discussed.

Short-term follow-up of chagasic patients after benzonidazole treatment using multiple serological markers.

BACKGROUND: Conventional serological tests, using total soluble proteins or a cocktail of recombinant proteins from T. cruzi as antigens, are highly sensitive for Chagas disease diagnosis. This type of tests, however, does not seem to be reliable tools for short- and medium-term monitoring of the evolution of patients after antiparasitic treatment. The aim of the present study was to search for immunological markers that could be altered in the sera from Chagas disease patients after benznidazole treatment, and therefore have a potential predictive diagnostic value. METHODS: We analyzed the reactivity of sera from chagasic patients during different clinical phases of the disease against a series of immunodominant antigens, known as KMP11, PFR2, HSP70 and Tgp63. The reactivity of the sera from 46 adult Chronic Chagas disease patients living in a non-endemic country without vector transmission of T. cruzi (15 patients in the indeterminate stage, 16 in the cardiomiopathy stage and 16 in the digestive stage) and 22 control sera from non-infected subjects was analyzed. We also analyzed the response dynamics of sera from those patients who had been treated with benznidazole. RESULTS: Regardless of the stage of the sickness, the sera from chagasic patients reacted against KMP11, HSP70, PFR2 and Tgp63 recombinant proteins with statistical significance relative to the reactivity against the same antigens by the sera from healthy donors, patients with autoimmune diseases or patients suffering from tuberculosis, leprosy or malaria. Shortly after benznidazole treatment, a statistically significant decrease in reactivity against KMP11, HSP70 and PFR2 was observed (six or nine month). It was also observed that, following benznidazole treatment, the differential reactivity against these antigens co-relates with the clinical status of the patients. CONCLUSIONS: The recombinant antigens KMP11, PFR2, Tgp63 and HSP70 are recognized by Chagas disease patients' sera at any clinical stage of the disease. Shortly after benznidazole treatment, a drop in reactivity against three of these antigens is produced in an antigen-specific manner. Most likely, analysis of the reactivity against these recombinant antigens may be useful for monitoring the effectiveness of benznidazole treatment.

Present situation and new strategies for Chagas disease chemotherapy: a proposal.

Treatments for Chagas disease have been administered since the first attempts by Mayer & Rocha Lima (1912, 1914) and up to the drugs currently in use (nifurtimox and benznidazole), along with potential drugs such as allopurinol and first, second and third-generation antifungal agents (imidazoles and triazoles), in separate form. Several diseases such as tuberculosis, leprosy and AIDS only came under control after they were treated with associations of drugs with different mechanisms of action. This not only boosts the action of the different compounds, but also may avoid the development of parasite resistance .To this end, over the short term, we propose experimental studies on laboratory animals and clinical trials with the following associations: (i) nifurtimox (8 mg/kg/day) + benznidazole (5 mg/kg/day) x 60 consecutive days; (ii) nifurtimox (8 mg/kg/day) or benznidazole (5 mg/kg/day) + allopurinol (8-10 mg/kg/day) x 60 days and (iii) nifurtimox (8 mg/kg/day) or benznidazole (5 mg/kg/day) + ketoconazole, fluconazole or itraconazole (5-6 mg/kg/day) x 60 consecutive days. The doses of the drugs and the treatment schedules for the clinical trials must be adapted according to the side effects. From these, other double or triple associations could be made, using drugs with different mechanisms of action. This proposal does not exclude investigations on new drugs over the median and long terms, targeting other aspects of the metabolism of Trypanosoma cruzi. Until such time as the ideal drug for specific treatment of Chagas disease might be discovered, we need to develop new strategies for achieving greater efficacy with the old drugs in associations and to develop rational experimentation with new drugs.

Present situation and new strategies for Chagas disease chemotherapy: a proposal

Treatments for Chagas disease have been administered since the first attempts by Mayer & Rocha Lima (1912, 1914) and up to the drugs currently in use (nifurtimox and benznidazole), along with potential drugs such as allopurinol and first, second and third-generation antifungal agents (imidazoles and triazoles), in separate form. Several diseases such as tuberculosis, leprosy and AIDS only came under control after they were treated with associations of drugs with different mechanisms of action. This not only boosts the action of the different compounds, but also may avoid the development of parasite resistance .To this end, over the short term, we propose experimental studies on laboratory animals and clinical trials with the following associations: (i) nifurtimox (8 mg/kg/day) + benznidazole (5 mg/kg/day) x 60 consecutive days; (ii) nifurtimox (8 mg/kg/day) or benznidazole (5 mg/kg/day) + allopurinol (8-10 mg/kg/day) x 60 days and (iii) nifurtimox (8 mg/kg/day) or benznidazole (5 mg/kg/day) + ketoconazole, fluconazole or itraconazole (5-6 mg/kg/day) x 60 consecutive days. The doses of the drugs and the treatment schedules for the clinical trials must be adapted according to the side effects. From these, other double or triple associations could be made, using drugs with different mechanisms of action. This proposal does not exclude investigations on new drugs over the median and long terms, targeting other aspects of the metabolism of Trypanosoma cruzi. Until such time as the ideal drug for specific treatment of Chagas disease might be discovered, we need to develop new strategies for achieving greater efficacy with the old drugs in associations and to develop rational experimentation with new drugs.

Oral drug therapy for multiple neglected tropical diseases: a systematic review.

CONTEXT: The neglected tropical diseases include 13 conditions that occur in areas of extreme poverty and are poverty promoting. The neglected tropical diseases produce a disease burden almost as great as that associated with human immunodeficiency virus/AIDS, tuberculosis, or malaria, yet are virtually unknown by health care workers in North America, because they occur almost exclusively in the poorest regions of the world. Seven of the most prevalent diseases have existing oral drug treatments. Identifying treatments that are effective against more than 1 disease could facilitate efficient and inexpensive treatment. OBJECTIVES: To systematically review the evidence for drug treatments and to increase awareness that neglected tropical diseases exist and that treatments are available. DATA SOURCES AND STUDY SELECTION: Using a MEDLINE search (1966 through June 2007), randomized controlled trials (RCTs) were reviewed that examined simultaneous treatment of 2 or more of the 7 most prevalent neglected tropical diseases using oral drug therapy. DATA SYNTHESIS: Twenty-nine RCTs were identified, of which 3 targeted 4 diseases simultaneously, 20 targeted 3 diseases, and 6 targeted 2 diseases. Trials were published between 1972 and 2005 and baseline prevalence of individual diseases varied among RCTs. Albendazole plus diethylcarbamazine significantly reduced prevalence of elephantiasis (16.7% to 5.3%), hookworm (10.3% to 1.9%), roundworm (34.5% to 2.3%), and whipworm (55.5% to 40.3%). Albendazole plus ivermectin significantly reduced prevalence of elephantiasis (12.6% to 4.6%), hookworm (7.8% to 0%), roundworm (33.5% to 6.1%), and whipworm (42.7% to 8.9%). Levamisole plus mebendazole significantly reduced prevalence of hookworm (94.0% to 71.8%), roundworm (62.0% to 1.4%), and whipworm (93.1% to 74.5%). Pyrantel-oxantel significantly reduced hookworm (93.4% to 85.2%), roundworm (22.8% to 1.4%), and whipworm (86.8% to 59.5%), while albendazole alone significantly reduced prevalence of hookworm (8.1% to 1.3%), roundworm (28.4% to 0.9%), and whipworm (51.9% to 31.9%). No RCT examined treatment of river blindness or trachoma as part of an intervention to target 2 or more neglected tropical diseases. Adverse events were generally inadequately reported. CONCLUSIONS: At least 2 of the most prevalent neglected tropical diseases can be treated simultaneously with existing oral drug treatments, facilitating effective and efficient treatment. Increasing awareness about neglected tropical diseases, their global impact, and the availability of oral drug treatments is an essential step in controlling these diseases.

Patología regional argentina: enfermedades prevalentes y exóticas conminantes / Argentina regional pathology

Patologías por protozoarios: enfermedad de chagas; paludismo; leishmaniasis. Patologías por helmintos: hidatidosis; uncinariasis. Patologías por bacterias: brucelosis; lepra. Patologías por hongos: paracoccidioidomicosis; histoplasmosis. Patologías por virus: fiebre hemorrágica argentina. Patologías por intoxicaciones: hidroarsenicismo crónico regional endémico. Patologías exóticas conminantes: cólera; dengue; esquistosomiasis

Patología regional argentina: enfermedades prevalentes y exóticas conminantes / Argentina regional pathology

Patologías por protozoarios: enfermedad de chagas; paludismo; leishmaniasis. Patologías por helmintos: hidatidosis; uncinariasis. Patologías por bacterias: brucelosis; lepra. Patologías por hongos: paracoccidioidomicosis; histoplasmosis. Patologías por virus: fiebre hemorrágica argentina. Patologías por intoxicaciones: hidroarsenicismo crónico regional endémico. Patologías exóticas conminantes: cólera; dengue; esquistosomiasis