RESUMO
There are no recognized orally administered treatments for any of the leishmaniases. The 8-aminoquinoline WR6026 is an orally administered analog of primaquine that cured 50% of patients with kala-azar in Kenya at a dose of 1 mg/kg/day for 28 days. A further phase 2, open-label, dose-escalating safety and efficacy study was performed for kala-azar in Brazil. Cure rates for Brazilian patients treated for 28 days were as follows: 1 mg/kg/day: 0 of 4 (0%); 1.5 mg/kg/day: 1 of 6 (17%); 2.0 mg/kg/day: 4 of 6 (67%); 2.5 mg/kg/day: 1 of 5 (20%); and 3.25 mg/kg/day: 0 of 1 (0%). Nephrotoxicity that was not anticipated from preclinical animal studies or from phase 1 studies was seen at 2.5 mg/kg/day in 2 patients and in the single patient administered 3.25 mg/kg/day. WR6026 demonstrated the unusual clinical features of lack of increased efficacy against Brazilian kala-azar with increased dosing above 2 mg/kg/day and toxicity that was not present in previous investigations.
Assuntos
Aminoquinolinas/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Aminoquinolinas/efeitos adversos , Aminoquinolinas/sangue , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/sangue , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Nefropatias/induzido quimicamente , Leishmania/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Malaria represents one of the most important infectious disease threats to deployed military forces; most personnel from developed countries are nonimmune personnel and are at high risk of infection and clinical malaria. This is especially true for forces deployed to highly-endemic areas in Africa and Southeast Asia where drug-resistant malaria is common. METHODS: We conducted an outbreak investigation of malaria cases in Angola where a total of 439 nonimmune Brazilian troops were deployed for a 6-month period in 1995-1996. A post-travel medical evaluation was also performed on 338 (77%) of the 439 soldiers upon return to Brazil. Questionnaire, medical record, thick/thin smear, and serum anti-Plasmodium falciparum antibody titer (by IFA) data were obtained. Peak serum mefloquine (M) and methylmefloquine (MM) metabolite levels were measured in a subsample of 66 soldiers (42 cases, 24 nonmalaria controls) who were taking weekly mefloquine prophylaxis (250 mg). RESULTS: Seventy-eight cases of malaria occurred among the 439 personnel initially interviewed in Angola (attack rate = 18%). Four soldiers were hospitalized, and 3 subsequently died of cerebral malaria. Upon return to Brazil, 63 (19%) of 338 soldiers evaluated were documented to have had clinical symptoms and a diagnosis of malaria while in Angola. In addition, 37 (11%) asymptomatically infected individuals were detected upon return (< 1% parasitemia). Elevated, post-travel anti-P. falciparum IFA titers (> or = 1:64) were seen in 101 (35%) of 292 soldiers tested, and was associated with a prior history of malaria in-country (OR = 3.67, 95% CI 1.98-6.82, p <.001). Noncompliance with weekly mefloquine prophylaxis (250 mg) was associated with a malaria diagnosis in Angola (OR = 3.75, 95% CI 0.97-17.41, p =.03) but not with recent P. falciparum infection (by IFA titer). Mean peak levels (and ratios) of serum M and MM were also found to be lower in those who gave a history of malaria while in Angola. CONCLUSIONS: Malaria was a significant cause of morbidity among Brazilian Army military personnel deployed to Angola. Mefloquine prophylaxis appeared to protect soldiers from clinical, but not subclinical, P. falciparum infections. Mefloquine noncompliance and an erratic chemoprophylaxis prevention policy contributed to this large outbreak in nonimmune personnel. This report highlights the pressing need for development of newer, more efficacious and practical, prophylactic drug regimens that will reduce the malaria threat to military forces and travelers.
Assuntos
Surtos de Doenças , Malária Falciparum/epidemiologia , Militares , Angola/epidemiologia , Animais , Anticorpos Antiprotozoários/sangue , Antimaláricos/uso terapêutico , Brasil , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/prevenção & controle , Mefloquina/uso terapêutico , Cooperação do Paciente , Plasmodium falciparum/imunologiaRESUMO
The prevalence and severity of drug-resistant malaria is emerging rapidly in the Amazon basin of Brazil. In support of clinical trials using the new antimalarial drug combination of atovaquone and proguanil, we performed in vitro drug sensitivities, molecular characterization of parasite populations using the circumsporozoite protein, merozoite surface antigen-1 (MSA-1), and MSA-2 markers, and an analysis of the Plasmodium falciparum multidrug resistance (pfmdr1) gene sequence and copy number in 26 isolates of P. falciparum obtained in a gold-mining endemic area in Peixoto de Azevedo, Mato Grosso State. All 26 isolates were found to be resistant to chloroquine (50% inhibitory concentration [IC50] = 100-620 nM) and sensitive to mefloquine (IC50 < 23 nM) and halofantrine (IC50 < 6 nM). The isolates also show reduced susceptibility to quinine (IC50 = 48-280 nM). Sequence analysis of the pfmdr1 gene revealed Asn, Phe, Cys, Asp, and Tyr in positions 86, 184, 1034, 1042, and 1246, respectively. These point mutations were similar to that previously described in other Brazilian isolates. Southern blot analysis revealed no amplification of the pfmdr1 gene. These results suggest that three different mechanisms for drug resistance exist for chloroquine, mefloquine, and quinine.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Antimaláricos/farmacologia , DNA de Protozoário/análise , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/genética , Animais , Brasil/epidemiologia , Resistência a Medicamentos , Resistência a Múltiplos Medicamentos/genética , Quimioterapia Combinada , Genes de Protozoários/genética , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/metabolismo , Mefloquina/farmacologia , Plasmodium falciparum/classificação , Plasmodium falciparum/isolamento & purificação , Mutação Puntual , Quinina/farmacologiaRESUMO
The purpose of this study was to compare an experimental regimen of atovaquone plus proguanil with the standard regimen of quinine plus tetracycline for the treatment of uncomplicated falciparum malaria. The study was designed as an open, randomized study of men presenting with symptoms of uncomplicated malaria and thick-smear slide confirmation of parasitemia (1000-100,000 ring forms/microL). Subjects were hospitalized for 28 days to insure medication compliance and to rule out the possibility of reinfections. With 77 patients in each group, the cure rates were 98.7% and 100% for atovaquone plus proguanil and quinine plus tetracycline, respectively. The parasite clearance times (mean, 56 h) and fever clearance times (mean, 19 h) were significantly shorter in the atovaquone plus proguanil group, and there were significantly fewer side effects in the atovaquone plus proguanil group. Atovaquone plus proguanil is an efficacious, easily administered, safe regimen for the treatment of uncomplicated, multidrug-resistant falciparum malaria in Brazil.
Assuntos
Antimaláricos/administração & dosagem , Malária/tratamento farmacológico , Naftoquinonas/administração & dosagem , Proguanil/administração & dosagem , Adolescente , Adulto , Idoso , Antimaláricos/efeitos adversos , Atovaquona , Brasil , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Naftoquinonas/efeitos adversos , Proguanil/efeitos adversos , Quinina/administração & dosagem , Quinina/efeitos adversos , Tetraciclina/administração & dosagem , Tetraciclina/efeitos adversosRESUMO
This is the first report of serologic evidence of hepatitis E infection in Brazil. During a community-based survey of healthy individuals, six of 97 gold miners in the Amazon region of Mato Grosso had antibody to the virus. The mining camps have poor sanitation with a great potential for fecal-oral transmission of disease. Since levels of hepatitis E antibodies may quickly wane, studies to directly measure the incidence of seroconversion are planned to determine the intensity of transmission in this area.
Assuntos
Hepatite E/epidemiologia , Mineração , Doenças Profissionais/epidemiologia , Adulto , Brasil/epidemiologia , Feminino , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite E/imunologia , Humanos , MasculinoRESUMO
Two antimalarial quassinoids, gutolactone [1] and simalikalactone D [2], have been characterized by bioactivity-directed fractionation from the bark of Simaba guianensis collected near Manaus, Brazil. Compound 2 was previously isolated from Simaba multiflora and Quassia africana and shown to be an active antimalarial in vitro. This is the first occurrence of 1. The structure of the novel quassinoid was established by spectral methods including 2D nmr spectroscopy.
Assuntos
Antimaláricos/isolamento & purificação , Compostos Bicíclicos com Pontes/isolamento & purificação , Glaucarubina/análogos & derivados , Plantas Medicinais/química , Quassinas , Animais , Antimaláricos/farmacologia , Brasil , Compostos Bicíclicos com Pontes/farmacologia , Cromatografia em Camada Fina , Glaucarubina/isolamento & purificação , Glaucarubina/farmacologia , Espectroscopia de Ressonância Magnética , Extratos Vegetais/análise , Extratos Vegetais/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Espectrofotometria UltravioletaRESUMO
During 1983, a multinational military intervention took place on Grenada. After deployment, troops from several U.S. Army units noted signs and symptoms consistent with soil-transmitted helminthic infection. Of 684 soldiers screened five to seven weeks post-deployment, over 20% reported abdominal pain and/or diarrhea during or after the action. Eosinophilia of at least 10% was observed in 119 (22.5%) of 529 soldiers evaluated further; eosinophilia of 5-9% was documented in another 126 (23.8%) of the 529 soldiers. Stool examinations confirmed hookworm infection in 35 soldiers. One case of strongyloidiasis was also documented. Infection was attributed to ground exposure near homes with compromised sanitation. Units that joined the operation after the initial assault phase were at low risk of hookworm infection.