RESUMO
Gambiense human African trypanosomiasis is a deadly disease that has been declining in incidence since the start of the Century, primarily due to increased screening, diagnosis and treatment of infected people. The main treatment regimen currently in use requires a lumbar puncture as part of the diagnostic process to determine disease stage and hospital admission for drug administration. Fexinidazole is a new oral treatment for stage 1 and non-severe stage 2 human African trypanosomiasis. The World Health Organization has recently incorporated fexinidazole into its treatment guidelines for human African trypanosomiasis. The treatment does not require hospital admission or a lumbar puncture for all patients, which is likely to ease access for patients; however, it does require concomitant food intake, which is likely to reduce adherence. Here, we use a mathematical model calibrated to case and screening data from Mushie territory, in the Democratic Republic of the Congo, to explore the potential negative impact of poor compliance to an oral treatment, and potential gains to be made from increases in the rate at which patients seek treatment. We find that reductions in compliance in treatment of stage 1 cases are projected to result in the largest increase in further transmission of the disease, with failing to cure stage 2 cases also posing a smaller concern. Reductions in compliance may be offset by increases in the rate at which cases are passively detected. Efforts should therefore be made to ensure good adherence for stage 1 patients to treatment with fexinidazole and to improve access to care.
Assuntos
Tripanossomicidas/administração & dosagem , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/transmissão , República Democrática do Congo/epidemiologia , Humanos , Modelos Teóricos , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/fisiologia , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/parasitologiaRESUMO
BACKGROUND: Nifurtimox-eflornithine combination therapy (NECT) for the treatment of second stage gambiense human African trypanosomiasis (HAT) was added to the World Health Organization's Essential Medicines List in 2009 after demonstration of its non-inferior efficacy compared to eflornithine therapy. A study of NECT use in the field showed acceptable safety and high efficacy until hospital discharge in a wide population, including children, pregnant and breastfeeding women, and patients with a HAT treatment history. We present here the effectiveness results after the 24-month follow-up visit. METHODOLOGY/PRINCIPAL FINDINGS: In a multicenter, open label, single arm phase IIIb study, second stage gambiense HAT patients were treated with NECT in the Democratic Republic of Congo. Clinical cure was defined 24 months after treatment as survival without clinical and/or parasitological signs of HAT. Of the 629 included patients, 619 (98.4%) were discharged alive after treatment and were examined for the presence of trypanosomes, white blood cell count in cerebro-spinal fluid, and disease symptoms. The clinical cure rate of 94.1% was comparable for all subpopulations analyzed at the 24-month follow-up visit. Self-reported adverse events during follow-up were few and concerned mainly nervous system disorders, infections, and gastro-intestinal disorders. Overall, 28 patients (4.3%) died during the course of the trial. The death of 16 of the 18 patients who died during the follow-up period was assessed as unlikely or not related to NECT. Within 24 months, eight patients (1.3%) relapsed and received rescue treatment. Sixteen patients were completely lost to follow-up. CONCLUSIONS/SIGNIFICANCE: NECT treatment administered under field conditions was effective and sufficiently well tolerated, no major concern arose for children or pregnant or breastfeeding women. Patients with a previous HAT treatment history had the same response as those who were naïve. In conclusion, NECT was confirmed as effective and appropriate for use in a broad population, including vulnerable subpopulations. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov, number NCT00906880.
Assuntos
Antiprotozoários/administração & dosagem , Eflornitina/administração & dosagem , Nifurtimox/administração & dosagem , Tripanossomicidas/administração & dosagem , Tripanossomíase Africana/tratamento farmacológico , Adolescente , Adulto , Idoso , Antiprotozoários/efeitos adversos , Criança , Pré-Escolar , República Democrática do Congo , Quimioterapia Combinada , Eflornitina/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nifurtimox/efeitos adversos , Gravidez , Resultado do Tratamento , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/genética , Trypanosoma brucei gambiense/fisiologia , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/patologia , Adulto JovemRESUMO
The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled "Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology".
Assuntos
Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Desenho de Fármacos , Leishmaniose/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Tripanossomíase Africana/tratamento farmacológico , Animais , Antiprotozoários/síntese química , Antiprotozoários/classificação , Doença de Chagas/parasitologia , Doença de Chagas/transmissão , Descoberta de Drogas , Humanos , Insetos Vetores/efeitos dos fármacos , Insetos Vetores/parasitologia , Leishmania/efeitos dos fármacos , Leishmania/genética , Leishmania/crescimento & desenvolvimento , Leishmania/metabolismo , Leishmaniose/parasitologia , Leishmaniose/transmissão , Estágios do Ciclo de Vida/efeitos dos fármacos , Estágios do Ciclo de Vida/genética , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Estrutura Molecular , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/genética , Trypanosoma brucei gambiense/crescimento & desenvolvimento , Trypanosoma brucei gambiense/metabolismo , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/genética , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/metabolismo , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/transmissãoRESUMO
African trypanosomes cause diseases in humans and livestock. Human African trypanosomiasis is caused by Trypanosoma brucei rhodesiense and T. b. gambiense. Animal trypanosomoses have major effects on livestock production and the economy in developing countries, with disease management depending mainly on chemotherapy. Moreover, only few drugs are available and these have adverse effects on patients, are costly, show poor accessibility, and parasites develop drug resistance to them. Therefore, novel trypanocidal drugs are urgently needed. Here, the effects of synthesized nitrofurantoin analogs were evaluated against six species/strains of animal and human trypanosomes, and the treatment efficacy of the selected compounds was assessed in vivo. Analogs 11 and 12, containing 11- and 12-carbon aliphatic chains, respectively, showed the highest trypanocidal activity (IC50 < 0.34 µM) and the lowest cytotoxicity (IC50 > 246.02 µM) in vitro. Structure-activity relationship analysis suggested that the trypanocidal activity and cytotoxicity were related to the number of carbons in the aliphatic chain and electronegativity. In vivo experiments, involving oral treatment with nitrofurantoin, showed partial efficacy, whereas the selected analogs showed no treatment efficacy. These results indicate that nitrofurantoin analogs with high hydrophilicity are required for in vivo assessment to determine if they are promising leads for developing trypanocidal drugs.
Assuntos
Nitrofuranos/administração & dosagem , Nitrofuranos/síntese química , Nitrofurantoína/análogos & derivados , Tripanossomicidas/administração & dosagem , Tripanossomicidas/síntese química , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Linhagem Celular , Modelos Animais de Doenças , Feminino , Camundongos , Estrutura Molecular , Nitrofuranos/química , Nitrofuranos/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacosRESUMO
The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 µM (95% confidence interval [8.1; 10]), 5.5 µM [4.5; 6.6], and 50 µM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.
Assuntos
Eflornitina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Eflornitina/administração & dosagem , Humanos , Tripanossomicidas/químicaRESUMO
Trypanosoma brucei parasites cause Human African Trypanosomiasis and the current drugs for its treatment are often inefficient and toxic. This urges the need to development of new antitrypanosomal agents. We report the synthesis and biological profiling of 3'-deoxy-3'-fluororibonucleosides derived from 7-deazaadenine nucleosides bearing diverse substituents at position 7. They were synthesized through glycosylation of 6-chloro-7-bromo- or -7-iodo-7-deazapurine with protected 3'-fluororibose followed by cross-coupling reactions at position 7 and/or deprotection. Most of the title nucleosides displayed micromolar or submicromolar activity against Trypanosoma brucei brucei. The most active were the 7-bromo- and 7-iododerivatives which exerted double-digit nanomolar activity against T. b. brucei and T. b. gambiense and no cytotoxicity and thus represent promising candidates for further development.
Assuntos
Ribonucleosídeos/farmacologia , Tripanossomicidas/farmacologia , Linhagem Celular Tumoral , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ribonucleosídeos/síntese química , Ribonucleosídeos/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/toxicidade , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei gambiense/efeitos dos fármacosRESUMO
Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein current treatments suffer from several drawbacks such as toxicity, low activity, and poor pharmacokinetic properties, and hence the need for alternative treatment is apparent. To this effect, we screened in vitro a library of 2-quinazolinone derivatives for antitrypanosomal activity against T.b. brucei and cytotoxicity against HeLa cells. Seven compounds having no overt cytotoxicity against HeLa cells exhibited antitrypanosomal activity in the range of 0.093-45 µM were identified. The activity data suggests that the antitrypanosomal activity of this compound class is amenable to substituents at N1 and C6 positions. Compound 14: having a molecular weight of 238Da, ClogP value of 1 and a total polar surface area of 49 was identified as the most active, exhibiting an IC50 value of 0.093 µM Graphical Abstract.
Assuntos
Quinazolinonas/farmacologia , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Testes de Sensibilidade Parasitária , Quinazolinonas/química , Quinazolinonas/uso terapêutico , Testes de Toxicidade Aguda , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/parasitologiaAssuntos
Cooperação Internacional , Programas de Rastreamento/métodos , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana , Animais , Anticorpos Antiprotozoários/sangue , Chade , Côte d'Ivoire , Vetores de Doenças , Guiné , Humanos , Controle de Insetos/métodos , Inseticidas/administração & dosagem , Trypanosoma brucei gambiense/isolamento & purificação , Trypanosoma brucei rhodesiense/isolamento & purificação , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/prevenção & controle , Moscas Tsé-Tsé/parasitologia , UgandaRESUMO
The compounds from eight different thiazolidine and thiazole series were assessed as potential antileishmanial scaffolds. They were tested for antileishmanial activity against promastigotes of Leishmania major using in vitro primary screen and dose response assays. The compounds from six thiazolidine and thiazole series were identified as the hits with antileishmanial activity against L. major. However, the analyses of structure-activity relations (SARs) showed that the interpretable SARs were obtained only for phenyl-indole hybrids (compounds C1, C2, C3 and C5) as the most effective compounds against L. major promastigotes (IC50 < 10 µM) with low toxicity to human fibroblasts. For the scaffold of these compounds, the most significant SAR patterns were: free N3 position of thiazolidinone core, absence of big fragments at the C5 position of thiazolidinone core and presence of halogen atoms or nitro group in the phenyl ring of phenyl-indole fragment. As previous studies showed that these compounds also have activity against the two Trypanosoma species, Trypanosoma brucei and Trypanosoma gambiense, their scaffold could be associated with a broader antiparasitic activity.
Assuntos
Tiazolidinas/farmacologia , Tripanossomicidas/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Leishmania major/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/toxicidade , Relação Estrutura-Atividade , Tiazolidinas/química , Tiazolidinas/toxicidade , Tripanossomicidas/química , Tripanossomicidas/toxicidade , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei gambiense/efeitos dos fármacosRESUMO
Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.
Assuntos
Proteínas de Membrana/antagonistas & inibidores , Proteínas de Protozoários/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Tripanossomicidas/síntese química , Tripanossomicidas/farmacologia , Animais , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Proteínas de Membrana/biossíntese , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mioblastos/efeitos dos fármacos , Mioblastos/parasitologia , Proteínas de Protozoários/biossíntese , Ratos , Relação Estrutura-Atividade , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/metabolismo , Trypanosoma brucei rhodesiense/efeitos dos fármacosRESUMO
Different compounds have been investigated as potent drugs for trypanosomiasis treatment, but no new drug has been marketed in the past 3 decades. 4-Thiazolidinone/thiazole as privileged structures and thiosemicarbazides cyclic analogs are well known scaffolds in novel antitrypanosomal agent design. We present here the design and synthesis of new hybrid molecules bearing thiazolidinone/thiazole cores linked by the hydrazone group with various molecular fragments. Structure optimization led to compounds with phenyl-indole or phenyl-imidazo[2,1-b][1,3,4]thiadiazole moieties showing excellent antitrypanosomal activity towards Trypanosoma brucei brucei and Trypanosoma brucei gambiense. Biological study allowed identifying compounds with the submicromolar levels of IC50, good selectivity indexes and relatively low cytotoxicity upon human primary fibroblasts as well as low acute toxicity.
Assuntos
Tiazolidinas/farmacologia , Tripanossomicidas/farmacologia , Animais , Linhagem Celular , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química , Tiazolidinas/toxicidade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/toxicidade , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei gambiense/efeitos dos fármacosRESUMO
Background and objectives: Sleeping sickness and malaria alike are insect-borne protozoan diseases that share overlapping endemic areas in sub-Saharan Africa. The causative agent for malaria has developed resistance against all currently deployed anti-malarial agents. In the case of sleeping sickness, the currently deployed therapeutic options are limited in efficacy and activity spectra, and there are very few drug candidates in the development pipeline. Thus, there is a need to search for new drug molecules with a novel mode of actions. Materials and Methods: In the current study, an in vitro screening of a library of tetralone derivatives and related benzocycloalkanones was effected against T. b. brucei and P. falciparum. Results: Several hits with low micromolar activity (0.4-8 µM) against T. b. brucei were identified. Conclusions: The identified hits have a low molecular weight (<280 Da), a low total polar surface area (<50 Ų), and a defined structure activity relationship, which all make them potential starting points for further hit optimization studies.
Assuntos
Malária/tratamento farmacológico , Tetralonas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Humanos , Malária/fisiopatologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Tetralonas/uso terapêutico , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/patogenicidade , Tripanossomíase Africana/fisiopatologiaRESUMO
Human and animal African trypanosomiasis (HAT & AAT, respectively) remain a significant health and economic issue across much of sub-Saharan Africa. Effective control of AAT and potential eradication of HAT requires affordable, sensitive and specific diagnostic tests that can be used in the field. Small RNAs in the blood or serum are attractive disease biomarkers due to their stability, accessibility and available technologies for detection. Using RNAseq, we have identified a trypanosome specific small RNA to be present at high levels in the serum of infected cattle. The small RNA is derived from the non-coding 7SL RNA of the peptide signal recognition particle and is detected in the serum of infected cattle at significantly higher levels than in the parasite, suggesting active processing and secretion. We show effective detection of the small RNA in the serum of infected cattle using a custom RT-qPCR assay. Strikingly, the RNA can be detected before microscopy detection of parasitaemia in the blood, and it can also be detected during remission periods of infection when no parasitaemia is detectable by microscopy. However, RNA levels drop following treatment with trypanocides, demonstrating accurate prediction of active infection. While the small RNA sequence is conserved between different species of trypanosome, nucleotide differences within the sequence allow generation of highly specific assays that can distinguish between infections with Trypanosoma brucei, Trypanosoma congolense and Trypanosoma vivax. Finally, we demonstrate effective detection of the small RNA directly from serum, without the need for pre-processing, with a single step RT-qPCR assay. Our findings identify a species-specific trypanosome small RNA that can be detected at high levels in the serum of cattle with active parasite infections. This provides the basis for the development of a cheap, non-invasive and highly effective diagnostic test for trypanosomiasis.
Assuntos
Doenças dos Bovinos/diagnóstico , RNA Citoplasmático Pequeno/sangue , Partícula de Reconhecimento de Sinal/sangue , Trypanosoma brucei gambiense/genética , Trypanosoma congolense/genética , Tripanossomíase Africana/veterinária , Tripanossomíase Bovina/diagnóstico , Animais , Biomarcadores/sangue , Bovinos , Doenças dos Bovinos/parasitologia , Feminino , Genoma de Protozoário , Masculino , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Bovina/tratamento farmacológicoRESUMO
Fexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease. During the course of a dose ranging assessment in patients with chronic indeterminate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases were observed and clinical investigations were suspended. We retrospectively analyzed all available pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in patients with Chagas disease and g-HAT to assess the determinants of toxicity. A population pharmacokinetic model was fitted to plasma concentrations (n = 4,549) of the bioactive fexinidazole sulfone metabolite, accounting for the majority of the bioactive exposure, from three phase 1 studies, two g-HAT phase 2/3 field trials, and one Chagas disease phase 2 field trial (n = 462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver-related pharmacodynamic outcomes in Chagas disease patients. Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure dependent and, thus, dose dependent in patients with Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in patients with g-HAT. In contrast, no evidence of hepatotoxicity was observed in patients with g-HAT. Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease patients. Regimens of shorter duration should be evaluated in clinical trials with patients with Chagas disease. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.
Assuntos
Medula Óssea/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nitroimidazóis/efeitos adversos , Nitroimidazóis/farmacocinética , Tripanossomicidas/efeitos adversos , Tripanossomicidas/farmacocinética , Administração Oral , Animais , Teorema de Bayes , Medula Óssea/metabolismo , Doença de Chagas/tratamento farmacológico , Doença de Chagas/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Método Duplo-Cego , Humanos , Fígado/metabolismo , Masculino , Nitroimidazóis/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Sulfonas/farmacologia , Resultado do Tratamento , Tripanossomicidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/metabolismoRESUMO
We conducted a retrospective study on mortality trends and risk factors in 781 naïve cases of advanced stage-2 sleeping sickness admitted between 1989 and 2012 at the National Reference Center for Human African Trypanosomiasis (HAT), Department of Neurology, Kinshasa University, Democratic Republic of Congo (DRC). Death was the outcome variable whereas age, gender, duration of disease, location of trypanosomes in body fluids, cytorachy, protidorachy, clinical status (assessed on a syndromic and functional basis) on admission, and treatment regimen were predictors in logistic regression models run at the 0.05 significance level. Death proportions were 17.2% in the standard melarsoprol schedule (3-series of intravenous melarsoprol on 3 successive days at 3.6 mg/kg/d, with a one-week interval between the series, ARS 9); 12.1% in the short schedule melarsoprol (10 consecutive days of intravenous melarsoprol at 2.2 mg/kg/d, ARS 10), 5.4% in the first-line eflornithine (14 days of eflornithine at 400 mg/kg/d in 4 infusions a day DFMO B), 9.1% in the NECT treatment regimen (eflornithine for 7 days at 400, mg/kg/d in 2 infusions a day combined with oral nifurtimox for 10 days at 15 mg/kg/d in 3 doses a day); and high (36%) in the group with select severely affected patients given eflornithine because of their clinical status on admission, at the time when this expensive drug was kept for treatment of relapses (14 days at 400 mg/kg/d in 4 infusions a day, DFMO A). After adjusting for treatment, death odds ratios were as follows: 10.40 [(95% CI: 6.55-16.51); p = .000] for clinical dysfunction (severely impaired clinical status) on admission, 2.14 [(95% CI: 1.35-3.39); p = .001] for high protidorachy, 1.99 [(95% CI: 1.18-3.37); p = .010] for the presence of parasites in the CSF and 1.70 [(95% CI: 1.03-2.81); p = .038] for high cytorachy. A multivariable analysis within treatment groups retained clinical status on admission (in ARS 9, ARS 10 and DFMO B groups) and high protidorachy (in ARS 10 and DFMO B groups) as significant predictors of death. The algorithm for initial clinical status assessment used in the present study may serve as the basis for further development of standardized assessment tools relevant to the clinical management of HAT and information exchange in epidemiological reports.
Assuntos
Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/mortalidade , Adolescente , Adulto , República Democrática do Congo/epidemiologia , Gerenciamento Clínico , Quimioterapia Combinada , Eflornitina/administração & dosagem , Eflornitina/uso terapêutico , Feminino , Registros Hospitalares , Humanos , Masculino , Melarsoprol/administração & dosagem , Melarsoprol/uso terapêutico , Pessoa de Meia-Idade , Análise Multivariada , Nifurtimox/administração & dosagem , Nifurtimox/uso terapêutico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Tripanossomicidas/administração & dosagem , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Adulto JovemRESUMO
Thousands of death in Africa and other developing nations are still attributed to trypanosomiasis. Excessive sleep has been associated with increased inflammation. We report herein, the synthesis, antitrypanosomal and anti-inflammatory activities of eight new carboxamide derivatives bearing substituted benzenesulfonamides. The base promoted reactions of l-proline and L-4-hydroxyproline with substituted benzenesulfonyl chlorides gave the benzenesulfonamides (11a-h) in excellent yields. Boric acid mediated amidation of the benzenesulfonamides (11a-h) and p-aminobenzoic acid (12) gave the new carboxamides (13a-h) in excellent yields. The new carboxamides were tested for their antitrypanosomal and anti-inflammatory activities against Trypanosome brucei gambiense and inhibition of carrageenan-induced rat paw edema. Compound 13f was the most potent antitrypanosomal agent with an IC50 value of 2â¯nM as against 5â¯nM for melarsoprol; whereas compound 13a was the most potent anti-inflammatory agent with percentage inhibition of carrageenan-induced rat paw edema of 58, 60, 67 and 84% after 0.5â¯h, 1â¯h, 2â¯h and 3â¯h administration respectively. The structure-activity relationship study revealed that substitution at the para position in the benzenesulfonamide ring increased both the antitrypanosomal and anti-inflammatory activities. The 4-hydroxyprolines (13a-d) showed higher anti-inflammatory activity than the prolines (13e-h). In contrast, the prolines (13e-h) had higher antitrypanosomal activities than the 4-hydroxyprolines. The link between excessive sleep and inflammation makes the report of this class of compounds possessing both antitrypanosomal and anti-inflammatory activity worthwhile. The pharmacokinetic studies showed that the compounds would not pose oral bioavailability, transport and permeability problems.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiprotozoários/farmacologia , Edema/tratamento farmacológico , Prolina/farmacologia , Sulfonamidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiprotozoários/síntese química , Antiprotozoários/química , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Masculino , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Prolina/síntese química , Prolina/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , BenzenossulfonamidasRESUMO
Arsenicals were introduced as monotherapies for the treatment of human African trypanosomiasis, or sleeping sickness, over 100 years ago. Toxicity has always been an issue but these drugs have proven to be both effective and quite durable. Unfortunately, melarsoprol-resistant parasites emerged as early as the 1970s and were widespread by the late 1990s. Resistance was due to mutations affecting an aquaglyceroporin (AQP2), a parasite solute and drug transporter. This is the only example of widespread drug resistance in trypanosomiasis patients for which the genetic basis is known. This link between melarsoprol and AQP2 illustrates how a drug transporter can improve drug selectivity but, at the same time, highlights the risk of resistance when the drug uptake mechanism is dispensable for parasite viability and virulence.
Assuntos
Melarsoprol/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Aquagliceroporinas/genética , Resistência a Medicamentos/genética , Humanos , Melarsoprol/farmacologia , Mutação , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/genéticaRESUMO
The parasitic protozoan Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) and nagana. Current drug therapies have limited efficacy, high toxicity and/or are continually hampered by the appearance of resistance. Antimicrobial peptides have recently attracted attention as potential parasiticidal compounds. Here, we explore circular bacteriocin AS-48's ability to kill clinically relevant bloodstream forms of T. brucei gambiense, T. brucei rhodesiense and T. brucei brucei. AS-48 exhibited excellent anti-trypanosomal activity in vitro (EC50â¯=â¯1-3â¯nM) against the three T. brucei subspecies, but it was innocuous to human cells at 104-fold higher concentrations. In contrast to its antibacterial action, AS-48 does not kill the parasite through plasma membrane permeabilization but by targeting intracellular compartments. This was evidenced by the fact that vital dye internalization-prohibiting concentrations of AS-48 could kill the parasite at 37⯰C but not at 4⯰C. Furthermore, AS-48 interacted with the surface of the parasite, at least in part via VSG, its uptake was temperature-dependent and clathrin-depleted cells were less permissive to the action of AS-48. The bacteriocin also caused the appearance of myelin-like structures and double-membrane autophagic vacuoles. These changes in the parasite's ultrastructure were confirmed by fluorescence microscopy as AS-48 induced the production of EGFP-ATG8.2-labeled autophagosomes. Collectively, these results indicate AS-48 kills the parasite through a mechanism involving clathrin-mediated endocytosis of VSG-bound AS-48 and the induction of autophagic-like cell death. As AS-48 has greater in vitro activity than the drugs currently used to treat T. brucei infection and does not present any signs of toxicity in mammalian cells, it could be an attractive lead compound for the treatment of sleeping sickness and nagana.
Assuntos
Autofagia/efeitos dos fármacos , Bacteriocinas/farmacologia , Morte Celular/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Endocitose/efeitos dos fármacos , Humanos , Microscopia de Fluorescência , Temperatura , Trypanosoma brucei brucei/ultraestrutura , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/sangue , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologiaRESUMO
Imidazolium salts are privileged compounds in organic chemistry, and have valuable biological properties. Recent studies show that symmetric imidazolium salts with bulky moieties can display antiparasitic activity against T. cruzi. After developing a facile methodology for the synthesis of tetrasubstituted imidazolium salts from propargylamines and isocyanides, we screened a small library of these adducts against the causative agents of African and American trypanosomiases. These compounds display nanomolar activity against T. brucei and low (or sub) micromolar activity against T. cruzi, with excellent selectivity indexes and favorable molecular properties, thereby emerging as promising hits for the treatment of Chagas disease and sleeping sickness.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Mioblastos/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Ratos , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologiaRESUMO
The reported toxicities of current antitrypanosomal drugs and the emergence of drug resistant trypanosomes underscore the need for the development of new antitrypanosomal agents. We report herein the synthesis and antitrypanosomal activity of 24 new amide derivatives of 3-aminoquinoline, bearing substituted benzenesulphonamide. Nine of the new derivatives showed comparable antitrypanosomal activities at IC50 range of 1-6 nM (melarsoprol 5 nM). Compound 11n and 11v are more promising antitrypanosomal agents with IC50 1.0 nM than the rest of the reported derivatives. The novel compounds showed satisfactory predicted physico-chemical properties including oral bioavailability, permeability and transport properties.