- NANOCARRIERS FOR EFFECTIVE DELIVERY OF BENZNIDAZOLE AND NIFURTIMOX IN THE TREATMENT OF CHAGAS DISEASE: A REVIEW. [Review]
- ATActa Trop 2019 Jul 09; :105080
- Neglected tropical diseases (NTDs) constitute a group of infectious diseases prevalent in countries with tropical and subtropical climate that affect the poorest individuals and produce high chronic …
Neglected tropical diseases (NTDs) constitute a group of infectious diseases prevalent in countries with tropical and subtropical climate that affect the poorest individuals and produce high chronic disability associated with serious problems for the health system and socioeconomic development. Chagas disease or American trypanosomiasis is included on the NTDs list. However, even though this disease affects more than 10 million people, mostly in Latin America, causing the death of over 10,000 people every year, only two drugs are approved for its treatment, benznidazole and nifurtimox. These antiparasitic agents were developed almost half a century ago and present several biopharmaceutical disadvantages such as low aqueous solubility and permeability limiting their bioavailability. In addition, both therapeutic agents are available only as tablets and a liquid pediatric formulation is still lacking. Therefore, novel pharmaceutical strategies to optimize the pharmacotherapy of Chagas disease are urgently required. In this regard, nanotechnological approaches may be a crucial alternative for the delivery of both drugs ensuring an effective pharmacotherapy although the successful bench-to-bedside translation remains a major challenge. The present work reviews in detail the formulation and in-vitro/in-vivo analysis of different nanoformulations of nifurtimox and benznidazole in order to enhance their solubility, dissolution, bioavailability and trypanocidal activity.
- Investigation of a combination of amiodarone and itraconazole for treatment of American trypanosomiasis (Chagas disease) in dogs. [Journal Article]
- JAJ Am Vet Med Assoc 2019 Aug 01; 255(3):317-329
- CONCLUSIONS: Results suggested efficacy of this trypanocidal drug combination for the treatment of T cruzi infection in dogs.
- Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii. [Journal Article]
- BMBioorg Med Chem 2019 Jul 04
- As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically ev…
As an extension of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting farnesyl diphosphate synthase, a series of linear 2-alkylaminomethyl-1,1-bisphosphonic acids (compounds 21-33), that is, the position of the amino group was one carbon closer to the gem-phosphonate moiety, were evaluated as growth inhibitors against the clinically more relevant dividing form (amastigotes) of T. cruzi. Although all of these compounds resulted to be devoid of antiparasitic activity, these results were valuable for a rigorous SAR study. In addition, unexpectedly, the synthetic designed 2-cycloalkylaminoethyl-1,1-bisphosphonic acids 47-49 were free of antiparasitic activity. Moreover, long chain sulfur-containing 1,1-bisphosphonic acids, such as compounds 54-56, 59, turned out to be nanomolar growth inhibitors of tachyzoites of T. gondii. As many bisphosphonate-containing molecules are FDA-approved drugs for the treatment of bone resorption disorders, their potential nontoxicity makes them good candidates to control American trypanosomiasis and toxoplasmosis.
- Recent Theoretical Studies Concerning Important Tropical Infections. [Journal Article]
- CMCurr Med Chem 2019 Jul 11
- Neglected tropical diseases (NTDs) form a group of diseases that are strongly associated with poverty, flourish in impoverished environments, and thrive best in tropical areas, where they tend to pre…
Neglected tropical diseases (NTDs) form a group of diseases that are strongly associated with poverty, flourish in impoverished environments, and thrive best in tropical areas, where they tend to present overlap. They comprise several diseases, and the symptoms vary dramatically from disease to disease, often causing from extreme pain, and untold misery that anchors populations to poverty, permanent disability, and death. They affect more than 1 billion people worldwide; mostly in poor populations living in tropical and subtropical climates. In this review, several complementary in silico approaches are presented; including identification of new therapeutic targets, novel mechanisms of activity, high-throughput screening of small-molecule libraries, as well as in silico quantitative structure-activity relationship and recent molecular docking studies. Current and active research against Sleeping Sickness, American trypanosomiasis, Leishmaniasis and Schistosomiasis infections will hopefully lead to safer, more effective, less costly and more widely available treatments against these parasitic forms of Neglected Tropical Diseases (NTDs) in the near future.
- Discovery and characterization of trypanocidal cysteine protease inhibitors from the 'malaria box'. [Journal Article]
- EJEur J Med Chem 2019 Jun 22; 179:765-778
- Chagas disease, Human African Trypanosomiasis, and schistosomiasis are neglected parasitic diseases for which new treatments are urgently needed. To identify new chemical leads, we screened the 400 c…
Chagas disease, Human African Trypanosomiasis, and schistosomiasis are neglected parasitic diseases for which new treatments are urgently needed. To identify new chemical leads, we screened the 400 compounds of the Open Access Malaria Box against the cysteine proteases, cruzain (Trypanosoma cruzi), rhodesain (Trypanosoma brucei) and SmCB1 (Schistosoma mansoni), which are therapeutic targets for these diseases. Whereas just three hits were observed for SmCB1, 70 compounds inhibited cruzain or rhodesain by at least 50% at 5 μM. Among those, 15 commercially available compounds were selected for confirmatory assays, given their potency, time-dependent inhibition profile and reported activity against parasites. Additional assays led to the confirmation of four novel classes of cruzain and rhodesain inhibitors, with potency in the low-to mid-micromolar range against enzymes and T. cruzi. Assays against mammalian cathepsins S and B revealed inhibitor selectivity for parasitic proteases. For the two competitive inhibitors identified (compounds 7 and 12), their binding mode was predicted by docking, providing a basis for structure-based optimization efforts. Compound 12 also acted directly against the trypomastigote and the intracellular amastigote forms of T. cruzi at 3 μM. Therefore, through a combination of experimental and computational approaches, we report promising hits for optimization in the development of new trypanocidal drugs.
- Cardiac involvement in trypanosomiasis in sheep experimentally infected by Trypanosoma vivax (Ziemman, 1905). [Journal Article]
- EPExp Parasitol 2019 Jul 04
- The objective of the present study was to evaluate the clinical signs, electrocardiographic signs and evolution of histopathological lesions in the heart of sheep experimentally infected by Trypanoso…
The objective of the present study was to evaluate the clinical signs, electrocardiographic signs and evolution of histopathological lesions in the heart of sheep experimentally infected by Trypanosoma vivax during the acute and chronic phases of infection as well as to investigate the presence of parasitic DNA in the heart using polymerase chain reaction (PCR). Twenty-two male sheep were divided into the following four groups: G1, which consisted of six sheep infected by T. vivax that were evaluated until 20 days post-infection (dpi; acute phase); G2, which consisted of six sheep infected by T. vivax that were evaluated until 90 dpi (chronic phase); and G3 and G4 groups, which each consisted of five uninfected sheep. At the end of the experimental period, electrocardiographic evaluations and necroscopic examinations were performed. Fragments of the heart were collected and stained by Hematoxylin-Eosin and Masson's trichrome, and the fragments were also evaluated by PCR for T. vivax. G2 animals presented clinical signs suggestive of heart failure and electrocardiogram alterations characterized by prolonged P, T and QRS complex durations as well as by a cardiac electrical axis shift to the left and increased heart rate. In these animals, mononuclear multifocal myocarditis and interstitial fibrosis were also observed. PCR revealed positivity for T. vivax in two G1 animals and in all G2 animals. Thus, these findings suggested that T. vivax is responsible for the occurrence of cardiac lesions, which are related to heart failure, electrocardiographic alterations and mortality of the infected animals.
- Prevalence of haemoprotozoan diseases in cattle of Cauvery delta region of Tamil Nadu. [Journal Article]
- JPJ Parasit Dis 2019; 43(2):308-312
- A study was carried out to determine the prevalence of haemoparasites in cattle in Cauvery delta region over a period of one year. A total of 228 giemsa stained blood smears were screened for the pre…
A study was carried out to determine the prevalence of haemoparasites in cattle in Cauvery delta region over a period of one year. A total of 228 giemsa stained blood smears were screened for the presence of haemoprotozoa, out of which 34 animals were found to be positive. An overall prevalence of haemoparasites in the sampled cattle were 14.9%, among this Anaplasma sp (8.3%), Babesia sp (3.95%), Theileria sp (2.19%) and Trypanosoma sp (0.44%) as single or mixed blood parasitic infections. In this study Anaplasmosis (14%) was highly prevalent during the winter season and Babesiosis (13.73%) was highly prevalent during summer months followed by Anaplasmosis (9.8%) and Theileriosis (7.8%), the lowest prevalence of Trypanosomiasis was observed during the rainy season. The seasonal variation in prevalence of haemoprotozoan disease might be due to influence of climatic factors on density of vector population in that geographical area. Haemogram revealed decreased level of haemoglobulin, packed cell volume and total erythrocyte count. The serum biochemistry revealed elevated level of liver enzyme Asparate transaminase enzyme. All haemoparasitaemic animals were treated with specific drugs and recovered successfully.
- Trypanosoma cruzi circulating among dogs and triatomines in the endemic countryside of the State of Rio Grande do Norte, Brazil. [Journal Article]
- ATActa Trop 2019 Jun 27; :105067
- Vector transmission of Trypanosoma cruzi occurs in several areas of Brazil, including the northeastern region, and domestic animals can serve as reservoirs of the parasite. The aim of this study was …
Vector transmission of Trypanosoma cruzi occurs in several areas of Brazil, including the northeastern region, and domestic animals can serve as reservoirs of the parasite. The aim of this study was to monitor dogs as domestic reservoirs for infection by T. cruzi, and the main triatomine species involved in parasite transmission in rural areas of municipalities in the State of Rio Grande do Norte, in northeastern, Brazil. Blood samples from dogs (n = 40) and manual triatomine capture were performed in domiciliary and peridomiciliary environments in rural areas of the towns of Acari, Caraúbas and Marcelino Vieira, between 2013 and 2016. Subsequently, infection of dogs was determined by Polymerase Chain Reaction (PCR), Enzyme-Linked Immunosorbent Assay (ELISA) for the detection of IgM and IgG isotypes and Indirect Immunofluorescence (IIF) reactions for detection of IgG. Triatomine infection was determined by PCR. Forty (16/40) percent of the dogs were seropositive for T. cruzi; 20.0% (8/40) of such reactivity indicated the acute phase, and 20.0% (8/40), the chronic phase. PCR was positive in 42.5% (17/40) of the dogs' blood samples. Specimens of Triatoma brasiliensis, Triatoma pseudomaculata, Rhodnius nasutus and Panstrongylus lutzi were found to be infected; however only T. brasiliensis nymphs and adults were infected in both environments. Triatomines evaluation showed 82.5% (94/114) of PCR positivity. Taken together, our results confirm that dogs are domestic reservoirs of T. cruzi in northeastern Brazil and T. brasiliensis is the main triatomine species correlated with parasite transmission in domiciliary environments. There is a continuing need to control peridomiciliary populations of triatomines and to implement continuous surveillance strategies for reservoirs with the help from the community.
- Geoclimatology and sleep in Africa: A mini-review. [Review]
- RNRev Neurol (Paris) 2019 Jun 25
- Sleeping habits and morningness-eveningness questionnaires (chronotype), and polysomnography (internal sleep organization) were proposed to healthy volunteers living under natural climates from diffe…
Sleeping habits and morningness-eveningness questionnaires (chronotype), and polysomnography (internal sleep organization) were proposed to healthy volunteers living under natural climates from different locations in West Africa (Niger, Côte d'Ivoire) and Central Africa (Angola, Congo). Under the Sahelian dry climate, 138 Niger medical students (130 had afternoon naps) completed 1792 sleep questionnaires during 7-day sessions in the cool-dry and hot-dry seasons. As everywhere else on Earth, daily sleep lasted 7 to 8hours. In Abidjan (hot-humid climate), 78 medical students reported shorter sleep time, because of course schedules. Also in Abidjan, 23 African sportsmen and Expatriate soldiers slept at night and in afternoon naps. They reported similar sleep amounts than Niger students. In Congo villages, during a 5-year human African trypanosomiasis (HAT) research campaign, 45 healthy volunteers expressed morning chronotypes. The 71 HAT patients shifted from the indifferent chronotype towards morningness type. Chronotyping such patients may help evaluating treatment efficacy on brain function alterations. French soldiers executing missions in Africa were typed for morningness-eveningness. Regarding malaria prophylaxis and mosquito control, morning chronotype was more compliant than evening type. Polysomnography demonstrated internal sleep organization differences in different geoclimatic zones. The Sahelian climate promoted N3 slow-wave sleep in Africans and Expatriates during both the cool-dry and hot-dry seasons, with higher amounts in the hot-dry season. Increasing heat load by physical exercise further augmented N3. Rapid-eye-movement R sleep was high compared with values from temperate and hot-humid climates. Supramaximal exercise triggered a surprising R stage increase in the hot-dry season. In Côte d'Ivoire, Caucasian and African volunteers fragmented their sleep, although internal sleep organization approached that of temperate climates. Sleep patterns were also similar in Angola high hills and on Congo River shores. Therefore, Africans and Caucasians living in Niger hot-dry Sahelian climate exhibited major differences with those exposed to hot-humid or temperate climates.
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- What is your diagnosis? Abnormal platelets dot plot from a dog. [Journal Article]
- VCVet Clin Pathol 2019 Jun 27