RESUMO
Therapies for human African trypanosomiasis and Chagas disease, caused by Trypanosoma brucei and Trypanosoma cruzi, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated in silico and by phenotypic studies using in vitro and in vivo models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. In vitro screens against bloodstream forms of T. cruzi demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (EC50s) of <3 µM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 µM) against amastigotes, showing EC50s ranging from 0.6 to 0.1 µM. All quinolines were also highly active in vitro against African trypanosomes, showing EC50s of ≤0.25 µM. The most potent and highly selective candidates for each parasite species were tested in in vivo models. Results for DB2186 were promising in mice with T. cruzi and T. brucei infections, reaching a 70% reduction of the parasitemia load for T. cruzi, and it cured 2 out of 4 mice infected with T. brucei DB2217 was also active in vivo and cured all 4 mice (100% cure rate) with T. brucei infection.
Assuntos
Doença de Chagas/tratamento farmacológico , Quinolinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Animais , Células CACO-2 , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Mamíferos , Camundongos , Parasitemia/tratamento farmacológico , RatosRESUMO
We enrolled 427 consecutive patients with tuberculosis diagnosed in Cité Soleil, Haiti in a trial of short-course intermittent therapy. All patients received supervised therapy with isoniazid, rifampin, pyrazinamide, and ethambutol thrice weekly for 8 wk, followed by isoniazid and rifampin thrice weekly for 18 wk. At entry, the 177 human immunodeficiency virus (HIV)-infected patients (42%) were found significantly more likely to have extrapulmonary tuberculosis and negative tuberculin skin tests (p < 0.05). Treatment was well tolerated by both groups of patients, and adherence to the treatment regimen was over 90%. Among patients with pulmonary or intrathoracic tuberculosis, 9% of HIV-seropositive and 1% of HIV-seronegative patients died during therapy (p < 0.001), whereas 81% and 87%, respectively, of those in the two groups were cured. Relapses occurred in 5.4% of HIV-seropositive and 2.8% of HIV-seronegative patients who completed treatment (p = 0.36). Survival after tuberculosis was poorer in HIV-seropositive patients, whose probability of dying was 33% at 18 mo after diagnosis as compared with 3% for HIV-seronegative patients (p < 0.001). HIV-seropositive patients who died had significantly lower median CD4 lymphocyte counts than did HIV-seropositive patients who survived (p < 0.001). Treatment of tuberculosis with short-course, thrice-weekly, supervised therapy in the setting of a developing country is highly efficacious in both HIV-seropositive and -seronegative patients.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antituberculosos/uso terapêutico , Infecções por HIV/complicações , Tuberculose Pulmonar/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Adulto , Antituberculosos/administração & dosagem , Estudos de Casos e Controles , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/mortalidade , Soronegatividade para HIV , Soropositividade para HIV , Haiti/epidemiologia , Humanos , Masculino , Cooperação do Paciente , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/mortalidadeRESUMO
Antibody responses following vaccination usually are analysed by comparing geometric mean concentrations across levels of relevant covariates and by comparing the proportions of vaccinees responding. In the regression setting, the analyses are done on log-transformed concentrations, estimating geometric mean responses conditional on a vector of covariates. More detailed analyses examining the relationship of covariates to different parts of the response distribution may be performed through the application of asymmetric least squares estimation of regression percentiles. We present a method for accounting for correlation in percentile regression analyses of longitudinal antibody response data. We illustrate the procedures with measles antibody response data from Haitian children who participated in a randomized trial of high titre vaccines. The strongest dose and strain effects were seen in the low end of the antibody concentration distributions.
Assuntos
Formação de Anticorpos , Modelos Estatísticos , Análise de Regressão , Vacinação , Fatores Etários , Anticorpos Antivirais/biossíntese , Relação Dose-Resposta a Droga , Feminino , Haiti , Humanos , Esquemas de Imunização , Lactente , Estudos Longitudinais , Masculino , Vacina contra Sarampo/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Fatores Sexuais , Fatores de TempoRESUMO
Much of the research on determinants of health service utilization has focused on economic and cognitive variables which influence preventative health behavior. Our ethnographic study of maternal perceptions of the barriers and incentives to immunization use in Haiti underscores the importance of 'hidden' social and psychological costs of utilization, such as embarrassment, fear, child care difficulties, and competing demands on maternal time. Findings from focus group interviews with mothers, individual interviews with health care providers, and observation at health posts identified five categories of maternal factors (competing priorities, low motivation, socioeconomic constraints, fears about health or social consequences, knowledge and folk beliefs) and five categories of system factors (accessibility, acceptability, availability, accommodation, affordability) which can deter immunization completion. The discussion focuses on how these factors influence maternal decision-making regarding use of preventive child health services. More attention is needed on the psychosocial costs of health behavior in developing country settings.
Assuntos
Serviços de Saúde da Criança/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Imunização , Adulto , Antropologia Cultural , Criança , Haiti , Humanos , Imunização/psicologia , Imunização/estatística & dados numéricosRESUMO
Mortality was evaluated in 1972 children who had received measles vaccines at 6-11 months of age that were 10-fold (medium titer) or 100-fold (high titer) greater than standard titer. Mortality among boys did not differ by vaccine titer and was similar to mortality in children who received standard-titer vaccine. Girl recipients of high-titer vaccine had somewhat greater mortality than girls who received medium-titer vaccine (risk ratio = 1.71, 95% confidence interval = 0.91-3.24). Increased mortality was associated with high-titer vaccine for girls but not for boys (P = .04). There was no evidence of selection bias or preferential health care by sex that might explain the differential mortality. This mortality pattern has been noted in two other populations with high background infant and childhood mortality. The biologic basis for this effect on mortality has not been determined. Data from this and other studies have resulted in discontinuation of the use of high-titer measles vaccines.
Assuntos
Vacina contra Sarampo/efeitos adversos , Sarampo/prevenção & controle , Caracteres Sexuais , Vacinação/mortalidade , Demografia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Haiti/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Sarampo/epidemiologia , Vacina contra Sarampo/administração & dosagem , Estado Nutricional , População Suburbana , Análise de Sobrevida , Vacinação/estatística & dados numéricosRESUMO
OBJECTIVE: To determine whether deaths among Haitian infants born to HIV-1-seronegative women could be distinguished from deaths among children born to HIV-1-seropositive women using the verbal autopsy technique. METHODS: Mothers of 315 Haitian children who died were interviewed about events leading to the child's death. Three physicians independently reviewed interview data and determined the probable cause of death without knowledge of maternal HIV-1 status or hospital records. The underlying causes of death assigned to the infants were analyzed to determine whether maternal HIV status could be predicted. RESULTS: There was good agreement among the physicians (kappa = 0.62) and 90% agreement between hospital records and the verbal autopsy diagnosis. Compared with children born to HIV-1-seronegative women, deaths in children born to HIV-1-seropositive mothers were more likely to be ascribed to a presumptive diagnosis of AIDS (37 versus 21%; P = 0.01). The sensitivity and specificity of verbal autopsies for identifying deaths associated with maternal HIV-1 infection ranged from 37 to 59% and from 69 to 79%, respectively, depending on the classification system used. The predictive positive value of a death believed to be consistent with pediatric HIV-1 infection was 26-30% and the predictive negative value was 85-90%. CONCLUSION: Verbal autopsies may be useful for distinguishing certain causes of death, but have limited utility for distinguishing deaths associated with maternal HIV-1 infection from deaths among children born to HIV-1-seronegative women.
Assuntos
Síndrome da Imunodeficiência Adquirida/mortalidade , Síndrome da Imunodeficiência Adquirida/patologia , Autopsia/métodos , Causas de Morte , Pré-Escolar , Feminino , Soropositividade para HIV , Haiti/epidemiologia , Humanos , Lactente , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Sensibilidade e EspecificidadeRESUMO
Antibodies to herpes simplex virus type 2 (HSV-2), antibodies to hepatitis B virus (HBV) core antigen (anti-HBc), and VDRL antibodies (serologic evidence of syphilis) were evaluated in women known to be infected with human immunodeficiency virus type 1 (HIV-1) (n = 95) or human T lymphotropic virus type I (HTLV-I) (n = 45) and controls (n = 89). HIV-1-seropositive women were more likely than controls to have antibodies to HSV-2 (88% vs. 54%; P less than .001), anti-HBc (67% vs. 43%; P = .008), and VDRL antibodies (21% vs. 8%; P = .02). Similarly, HTLV-I-seropositive women were more likely than controls to have antibodies to HSV-2 (82% vs. 54%; P = .003) and anti-HBc (67% vs. 43%; P = .008). There was no evidence that HIV-1 or HTLV-I predisposed to chronic hepatitis B virus infection. The stronger associations between HIV-1 and HTLV-I with HSV-2 than the associations with syphilis or HBV are consistent with the hypothesis that recurrent disruptions of mucous membranes caused by HSV-2 infections predispose to sexual transmission of HIV-1 and HTLV-I.
Assuntos
Infecções por HIV/complicações , Infecções por HTLV-I/complicações , Hepatite B/epidemiologia , Herpes Simples/epidemiologia , Sífilis/epidemiologia , Adolescente , Adulto , Fatores Etários , Anticorpos Antivirais/sangue , Feminino , Anticorpos Anti-HIV/sangue , HIV-1 , Anticorpos Anti-HTLV-I/sangue , Haiti/epidemiologia , Hepatite B/complicações , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Herpes Simples/complicações , Humanos , Prevalência , Simplexvirus/imunologia , Sífilis/complicações , Sorodiagnóstico da SífilisRESUMO
OBJECTIVE: To determine whether a previously observed association between human immunodeficiency virus type 1 (HIV-1) infection and smoking in Haitian women could be explained by confounding high-risk behaviors. DESIGN AND SETTING: A nested case-control study at a primary care health clinic in Cité Soleil, Haiti. PARTICIPANTS: Women who reported having smoked (n = 89) and randomly selected nonsmokers (n = 329) who had participated in a survey 1 to 12 months earlier evaluating risk factors for HIV-1 infection. MAIN OUTCOME MEASURES: Lifetime sexual practices, smoking, health beliefs and practices, and other factors potentially confounding the relationship between smoking and HIV-1 infection. RESULTS: Compared with nonsmokers, smokers reported higher rates of high-risk behaviors, including more lifetime sex partners (P less than .001), being less likely to be married (P less than .01), and being more likely to have visited folk healers (P less than .01). No intravenous drug use was reported, and no significant differences were noted between smokers and nonsmokers in numbers of past surgical or dental procedures or injections. Adjustment for all factors associated with HIV-1 infection and smoking in regression analyses revealed an independent association between smoking and HIV-1 infection (odds ratio [OR], 3.4; 95% confidence interval [Cl], 1.6 to 7.5). Other factors associated with HIV-1 infection included having more than two life-time sex partners (OR, 3.4; 95% Cl, 1.7 to 6.8) and lower socioeconomic status as reflected by a dirt floor in the home (OR, 8.6; 95% Cl, 3.3 to 22.0). CONCLUSIONS: Smoking is a marker for high-risk sexual behavior and is associated with an increased risk of HIV-1 infection in this population. The persistent association between smoking and HIV-1 infection after adjustment for all known risk factors suggests the possibility of a biologic effect of smoking that warrants further evaluation in other populations.
Assuntos
Infecções por HIV/epidemiologia , HIV-1 , Comportamento Sexual/estatística & dados numéricos , Fumar/epidemiologia , Adulto , Estudos de Casos e Controles , Feminino , Soropositividade para HIV/epidemiologia , Haiti/epidemiologia , Humanos , Modelos Logísticos , Fatores de Risco , Assunção de RiscosRESUMO
A group of 2097 Haitian infants 6 to 11 months of age were randomized to receive Schwarz or Edmonston-Zagreb strain measles vaccines containing 10- to 500-fold more vaccine viral particles than standard potency vaccines. No unusual adverse reactions were noted. Edmonston-Zagreb vaccines were more effective than equivalent doses of Schwarz vaccines as measured by the proportion of vaccinated children with measles antibody concentrations greater than or equal to 200 mIU/ml 2 months after vaccination and the persistence of antibody at 18 to 24 months of age. High titer Edmonston-Zagreb vaccine administered at 6 months of age induced antibody concentrations greater than or equal to 200 mIU/ml in 83% of infants by plaque reduction neutralization and 93% of infants by enzyme-linked immunosorbent assay with high rates of antibody persistence at 12 to 24 months of age. The World Health Organization recommends high titer Edmonston-Zagreb measles vaccines for routine use at 6 months of age in areas where measles is an important cause of mortality in young infants.
Assuntos
Anticorpos Antivirais/análise , Vacina contra Sarampo/imunologia , Vírus do Sarampo/imunologia , Sarampo/prevenção & controle , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Haiti , Humanos , Lactente , Masculino , Vacina contra Sarampo/administração & dosagem , Vacinação , Ensaio de Placa ViralRESUMO
Of 4588 pregnant women in a high-risk Haitian population, 443 (9.7%) were serologically positive for the human immunodeficiency virus type 1 (HIV-1). Infants born to women who were HIV-1 seropositive were more likely to be premature, of low birth weight, and malnourished at 3 and 6 months of age than were infants born to women who were HIV-1 seronegative. Increased mortality was observed in infants born to women who were HIV-1 seropositive by 3 months of age. At 12 months of age, 23.4% of the infants born to women who were HIV-1 seropositive had died compared with 10.8% of the infants born to women who were HIV-1 seronegative; at 24 months of age, the mortality rates were 31.3% and 14.2%, respectively. Maternal HIV-1 infections resulted in an 11.7% increase in the overall infant mortality rate in this population. The estimated mother-to-infant HIV-1 transmission rate in these breast-fed infants was 25%, similar to the rates reported for non-breast-fed populations in the United States and Europe.