RESUMEN
HIV is a major public health issue, and infection of CD4(+) T lymphocytes is one of its key features. Whereas several cellular proteins have been identified that facilitate viral infection and replication, the role of hemichannels in these processes has not been fully characterized. We now show that the HIV isolates, R5 and X4, induced a transient-early (5-30 min) and a later, persistent (48-120 h) opening of Panx1 hemichannels, which was dependent on the binding of HIV to CD4 and CCR5/CXCR4 receptors. Blocking Panx1 hemichannels by reducing their opening or protein expression inhibited HIV replication in CD4(+) T lymphocytes. Thus, our findings demonstrate that Panx1 hemichannels play an essential role in HIV infection.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Conexinas/fisiología , VIH/fisiología , Proteínas del Tejido Nervioso/fisiología , Conexina 43/fisiología , Humanos , Receptores CCR5/fisiología , Receptores CXCR4/fisiología , Replicación ViralRESUMEN
BACKGROUND: Although mucosal leishmaniasis is a prominent disease, it has been studied only to a limited extent. It is classically treated with parenteral antimony or, as a last resort, amphotericin B. METHODS: We treated Bolivian mucosal leishmaniasis due to Leishmania braziliensis with the oral agent miltefosine, 2.5 mg/kg/day for 28 days, and followed-up for 12 months. RESULTS: Seventy-two patients were evaluable. The cure rate for the 36 patients who had "mild" disease (i.e., affecting nasal skin and nasal mucosa) was 83%. The cure rate for the 36 patients who had more extensive disease (involving the palate, pharynx, and larynx) was 58%. Patients refused to be randomized to parenteral agents, but the cure rate for an almost contemporary group who was receiving amphotericin B (45 mg/kg over 90 days) was 7 (50%) of 14. CONCLUSIONS: In this unrandomized trial, oral miltefosine was at least as effective as heroic doses of parenteral amphotericin B. The cure rate for miltefosine was approximately equivalent to historical cure rates using parenteral pentavalent antimony for mild and extensive disease in neighboring Peru. Although gastrointestinal side reactions do occur with miltefosine, its toxicity profile is superior to that of antimony and far superior to that of amphotericin B--in part because of the inherent attractiveness of oral versus parenteral agents. Our results suggest that miltefosine should be the treatment of choice for mucosal disease in North and South America.
Asunto(s)
Antiprotozoarios/administración & dosificación , Leishmania braziliensis/efectos de los fármacos , Leishmaniasis Mucocutánea/tratamiento farmacológico , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Animales , Antiprotozoarios/efectos adversos , Bolivia , Femenino , Humanos , Masculino , Fosforilcolina/administración & dosificación , Fosforilcolina/efectos adversos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Miltefosine (2.5 mg/kg/day for 28 days) was investigated for treatment of New World cutaneous leishmaniasis in Colombia and Guatemala. The data from a controlled study was remarkably similar to the data of a prior uncontrolled pilot study. In the controlled study, the per-protocol 6-month cure rate for Leishmania panamensis disease was 91% compared with a concomitant placebo cure rate of 38%. In Guatemala, the cure rate for L. braziliensis and L. mexicana disease was approximately 50% compared with approximately 20% for placebo. In both countries, nausea but not 'motion sickness' and vomiting but not diarrhoea were experienced by approximately 30% more miltefosine patients than placebo patients. Mild elevation of creatinine, but not of aspartate aminotransferase or alanine aminotransferase, was also more frequently seen in the miltefosine group than in the placebo group. Miltefosine was well tolerated, and as effective as historic values of antimony for treatment of L. panamensis disease.
Asunto(s)
Antiprotozoarios/administración & dosificación , Leishmaniasis Cutánea/tratamiento farmacológico , Fosforilcolina/análogos & derivados , Administración Oral , Adulto , Antiprotozoarios/efectos adversos , Ensayos Clínicos como Asunto , Método Doble Ciego , Evaluación de Medicamentos , Humanos , Estudios Multicéntricos como Asunto , Fosforilcolina/administración & dosificación , Fosforilcolina/efectos adversos , Proyectos Piloto , Resultado del TratamientoRESUMEN
Two hundred twenty-six consecutive adult patients with cutaneous leishmaniasis in Colombia were treated with Glucantime and 81% were cured. The 19% who failed treatment had received a statistically significant lower total amount of antimony (354 mg/kg) than those who were cured (405 mg/kg) (P = 0.002). Thirty-nine of the failures were re-treated with Glucantime and 59% were cured. This large experience on initial and re-treatment cure rates probably represents the values found in clinical practice. In this series, parasite resistance may have been induced by the relatively low initial dose of antimony administered to some patients.
Asunto(s)
Antiprotozoarios/uso terapéutico , Leishmaniasis Cutánea/tratamiento farmacológico , Meglumina/uso terapéutico , Compuestos Organometálicos/uso terapéutico , Adulto , Humanos , Antimoniato de Meglumina , Resultado del TratamientoRESUMEN
The cost of generic pentavalent antimony (generic stibogluconate) is approximately one-sixth that of branded pentavalent antimony (stibogluconate in the form of Pentostam or meglumine antimoniate in the form of Glucantime. We compared generic stibogluconate to Pentostam and Glucantime for the treatment of cutaneous leishmaniasis patients in Bolivia and Colombia. For all 114 patients, the per-protocol cure rates were 83-91% and the intent-to-treat cure rates were 75-83%. The highest values were in the generic stibogluconate group. The incidence of pancreatic enzyme abnormalities was 48-88% and the incidence of liver enzyme abnormalities was 48-87%. The lowest incidences were in the generic stibogluconate group. The efficacy and tolerance of inexpensive generic stibogluconate appears comparable to branded formulations for the treatment of cutaneous leishmaniasis in these endemic regions.
Asunto(s)
Gluconato de Sodio Antimonio/administración & dosificación , Antiprotozoarios/administración & dosificación , Leishmaniasis Cutánea/tratamiento farmacológico , Adolescente , Adulto , Anciano , Gluconato de Sodio Antimonio/efectos adversos , Antiprotozoarios/efectos adversos , Bolivia , Colombia , Método Doble Ciego , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Femenino , Humanos , Leishmaniasis Cutánea/patología , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The oral agent miltefosine has demonstrated a >95% cure rate in Indian visceral leishmaniasis. We performed a large, placebo-controlled study of miltefosine therapy (2.5 mg/kg per day orally for 28 days) against cutaneous leishmaniasis in Colombia and Guatemala. In regions in Colombia where Leishmania vianna panamensis is common, the per-protocol cure rates for miltefosine and placebo were 91% (40 of 44 patients) and 38% (9 of 24). These values are similar to historic values for the antimony standard of care and placebo. In regions in Guatemala where L. v. braziliensis and L. mexicana mexicana are common, the per-protocol cure rates were 53% (20 of 38) for miltefosine and 21% (4 of 19) for placebo. The miltefosine rate was lower than historic antimony cure rates of >90%. Miltefosine was well tolerated. Miltefosine is a useful oral agent against cutaneous leishmaniasis due to L. v. panamensis in Colombia but not against leishmaniasis due to L. v. braziliensis in Guatemala.
Asunto(s)
Antiprotozoarios/uso terapéutico , Leishmaniasis Cutánea/tratamiento farmacológico , Cooperación del Paciente , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapéutico , Administración Oral , Adulto , Animales , Antiprotozoarios/efectos adversos , Colombia , Método Doble Ciego , Tolerancia a Medicamentos , Femenino , Guatemala , Humanos , Leishmania/efectos de los fármacos , Masculino , Fosforilcolina/efectos adversos , Resultado del TratamientoRESUMEN
There is no recognized oral treatment for American cutaneous leishmaniasis. A rising-dose, open-label phase I/II trial of the oral agent miltefosine against Colombian cutaneous leishmaniasis was conducted. Seventy-two male Colombian soldiers (mean weight, 67 kg) received miltefosine at 50-100 mg/day for 3 weeks (for 32 evaluable patients) or at 133-150 mg/day for 3-4 weeks (for 32 evaluable patients). The per-protocol cure rate for 50-100 mg/day was 21 (66%) of 32 patients. The per-protocol cure rate for 133-150 mg/day was 30 (94%) of 32 patients (P =.01, by use of Fisher's exact test). The historic per-protocol cure rate for standard injections of antimony is 93%. "Motion sickness" that did not interfere with normal duties was experienced by 40% of patients and was dose related. Vomiting and diarrhea were reported on approximately 2% of treatment days. In this uncontrolled study of oral miltefosine for treatment of patients with American cutaneous leishmaniasis, a dosage of approximately 2.25 mg/kg/day for 3-4 weeks was effective and tolerated.
Asunto(s)
Antiprotozoarios/uso terapéutico , Leishmaniasis Cutánea/tratamiento farmacológico , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapéutico , Administración Oral , Adulto , Antiprotozoarios/efectos adversos , Colombia , Humanos , Masculino , Personal Militar , Fosforilcolina/efectos adversos , Resultado del TratamientoRESUMEN
Chloroquine-resistant Plasmodium vivax has been the subject of numerous case reports and prospective studies from Oceania and Asia. In contrast, only case reports exist from the Americas. We performed a prospective study with 28-day follow-up of clinical responses to chloroquine in 2 P. vivax-endemic regions of Colombia. Three (11%) of 27 patients failed to respond to treatment with the standard regimen of chloroquine (1,500 mg of base over 3 days). One patient demonstrated RI resistance on Day 26; one patient demonstrated RI resistance due to recrudescence of blood stages on Day 11; and one patient demonstrated RII resistance of blood stages by never displaying clearing of peripheral parasitemia. All patients were successfully treated with primaquine, which has some blood stage efficacy against P. vivax, combined with a second course of chloroquine. Clinical resistance of P. vivax to chloroquine is present in Colombia and should be monitored in the Americas.
Asunto(s)
Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Malaria Vivax/tratamiento farmacológico , Plasmodium vivax/efectos de los fármacos , Animales , Colombia , Quimioterapia Combinada , Humanos , Masculino , Parasitemia , Plasmodium vivax/aislamiento & purificación , Primaquina/uso terapéutico , Insuficiencia del TratamientoRESUMEN
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.
Asunto(s)
Aminoquinolinas/administración & dosificación , Antiprotozoarios/administración & dosificación , Leishmaniasis Visceral/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Aminoquinolinas/efectos adversos , Aminoquinolinas/sangre , Animales , Antiprotozoarios/efectos adversos , Antiprotozoarios/sangre , Niño , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Enfermedades Renales/inducido químicamente , Leishmania/aislamiento & purificación , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The safety and immunogenicity of an intramuscular (i.m.) and intradermal (ID) formulation of autoclaved Leishmania (Leishmania) amazonensis vaccine was evaluated in 296 volunteers in a randomized, placebo-controlled, double-blind trial in Colombia. There were 4 vaccination groups: i.m. vaccine, i.m. placebo, ID vaccine, and ID placebo. The ID formulations were mixed with BCG as adjuvant at the time of injection. For each group, 3 vaccinations were given with a 20-day interval between injections, and adverse events were monitored at 20 min, and at 2, 7 and 21 days after each injection. BCG-induced adverse reactions resulted in cancellation of the third vaccine administration in the ID groups. Antibody titres did not differ significantly between the groups. Montenegro skin-test conversion was achieved by 86.4% and 90% of the i.m. vaccine group and by 25% and 5% of the i.m. placebo group 80 days and 1 year after vaccination, respectively. A significant increase in mean Leishmania-antigen lymphocyte proliferation indexes was observed after i.m. vaccine immunization, but not after i.m. placebo immunization, 80 days and 1 year after vaccination. Significant levels of IFN gamma but not IL-10 were observed 1 year after vaccination in the i.m. vaccine group compared to the i.m. placebo group. The good safety profile and evidence of Th1 immune reactions due to i.m. vaccination in this phase-I/II study suggest that a population-based phase-III efficacy trial of the i.m. vaccine should be initiated.
Asunto(s)
Leishmania mexicana/inmunología , Leishmaniasis Cutánea/prevención & control , Vacunas de Productos Inactivados , Adyuvantes Inmunológicos , Animales , Formación de Anticuerpos , Método Doble Ciego , Estudios de Seguimiento , Humanos , Leishmaniasis Cutánea/inmunologíaRESUMEN
To improve upon the efficacy of primaquine prophylaxis for malaria (94%, Plasmodium falciparum malaria; 85%, Plasmodium vivax malaria), we administered chloroquine (300 mg weekly) in combination with primaquine (30 mg daily) to nonimmune Colombian soldiers during 16 weeks of patrol in a region of endemicity and for a further 1 week in base camp. The occurrence of symptomatic parasitemia was determined during those 17 weeks and during a further 3 weeks in base camp. The protective efficacy for the chloroquine/primaquine treatment group of 100 subjects, compared with that for the placebo treatment group of 51 subjects, was 88% (95% confidence interval [CI], 76-94) against all types of malaria, 89% (95% CI, 61-97) against P. falciparum malaria, and 88% (95% CI, 58-93) against P. vivax malaria. Two chloroquine/primaquine recipients had severe gastrointestinal distress. Comparison of these data with data from a previous study indicates that the addition of chloroquine did not increase the prophylactic efficacy of primaquine.
Asunto(s)
Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Malaria/prevención & control , Personal Militar , Primaquina/uso terapéutico , Cloroquina/efectos adversos , Colombia , Método Doble Ciego , Humanos , Malaria Falciparum/prevención & control , Malaria Vivax/prevención & control , Primaquina/efectos adversosRESUMEN
Mucosal leishmaniasis is arguably the most morbid sequelae of cutaneous leishmaniasis. The importance of early diagnosis for effective therapy, coupled with the difficulty of diagnosing the disease parasitologically, prompted this investigation of humoral immune markers of mucosal disease. Promastigote soluble antigens of Leishmania braziliensis, isolated from cutaneous and mucosal lesions, were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis; antigens were identified by immunoblotting with parasite-specific IgG antibody-positive sera of patients with mucosal disease (n = 18) and cutaneous disease (n = 23). For antigens of the cutaneous parasite WR 2095, mucosal sera generally reacted intensely to antigens of 75, 66, and 45 kDa and weakly to 48-50-kDa antigens, whereas cutaneous sera generally detected weakly the first 3 antigens and intensely the latter doublet. The data suggest that the transition from the cutaneous antigenic profile to a mucosal antigenic profile could be used to predict mucosal disease in approximately half of mucosal patients. An additional finding was that antibodies present in the sera of patients with mucosal disease labeled a 66-kDa peptide of normal human lip mucosa more intensely than did cutaneous sera. Autoimmune processes stimulated by the reaction of IgG, originally directed against the 66-kDa of L. braziliensis, to the 66-kDa antigen of mucosal tissue may contribute to the clinical presentation of mucosal leishmaniasis.
Asunto(s)
Anticuerpos Antiprotozoarios/biosíntesis , Leishmania braziliensis/inmunología , Leishmaniasis Cutánea/inmunología , Leishmaniasis Mucocutánea/inmunología , Adolescente , Adulto , Anciano , Animales , Antígenos de Protozoos/inmunología , Western Blotting , Reacciones Cruzadas , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Interacciones Huésped-Parásitos , Humanos , Inmunoglobulina G/análisis , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Primaquine had a prophylactic efficacy of 90% to 95% against infection with Plasmodium falciparum and P. vivax in Indonesian settlers. OBJECTIVE: To evaluate the efficacy of primaquine prophylaxis for protecting nonimmune persons from malaria. DESIGN: Randomized, double-blind, placebo-controlled field study. SETTING: A malaria-endemic area in Colombia. PATIENTS: 176 healthy, young, nonimmune adult male soldiers. INTERVENTION: Primaquine, 30 mg/d, or matching placebo during 15 weeks of patrol in the endemic area and 1 week afterward. MEASUREMENTS: Symptomatic parasitemia was determined over the 16-week intervention period and for 3 weeks in base camp. RESULTS: Protective efficacy in the primaquine group (122 participants) was 89% (95% CI, 75% to 96%) against all types of malaria, 94% (CI, 78% to 99%) against P. falciparum malaria, and 85% (CI, 57% to 95%) against P. vivax malaria. Six primaquine recipients had mild to moderate gastrointestinal distress, and three had severe distress. CONCLUSIONS: For prophylaxis against P. falciparum malaria, primaquine has an efficacy and toxicity competitive with those of standard agents. A potential advantage of primaquine is that prophylaxis may be discontinued 1 week after the recipient has left the endemic area.
Asunto(s)
Antimaláricos/efectos adversos , Antimaláricos/uso terapéutico , Malaria Falciparum/prevención & control , Malaria Vivax/prevención & control , Personal Militar , Primaquina/efectos adversos , Primaquina/uso terapéutico , Adolescente , Adulto , Colombia , Método Doble Ciego , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Masculino , Cooperación del Paciente , Pacientes Desistentes del TratamientoRESUMEN
Reported are the results of a study to determine the efficacy and safety of liposomal amphotericin B (AmBisome) for treating visceral leishmaniasis (kala-azar) in several developing countries where the disease is endemic (Brazil, India, and Kenya). At each study site, sequential cohorts of 10 patients each were treated with AmBisome at a dose of 2 mg.kg-1.day-1 (2 MKD). The first cohort received regimen 1:2 MKD on days 1-6 and day 10 (total dose: 14 mg/kg). If the efficacy with this regimen was satisfactory, a second cohort received regimen 2:2 MKD on days 1-4 and 10 (total dose: 10 mg/kg); and a third cohort received regimen 3:2 MKD on days 1, 5, and 10 (total dose: 6 mg/kg). In India, regimens 1, 2, and 3 (which were studied concurrently) each cured 100% of 10 patients. In Kenya, regimen 1 cured all 10 patients, regimen 2 cured 90% of 10 patients, but regimen 3 cured only 20% of 5 patients. In Brazil, regimen 1 was only partially curative: 5 of 13 patients (62%). Therefore, 15 patients were administered regimen 4 (2 MKD for 10 consecutive days; total dose, 20 mg/kg) and 13 patients were cured (83%). These results suggest that for the treatment of kala-azar the following doses of AmBisome should be administered: in India and Kenya, 2 mg/kg on days 1-4 and day 10; and in Brazil, 2 mg/kg on days 1-10.
PIP: The efficacy and safety of liposomal amphotericin B (AmBisome) for the treatment of visceral leishmaniasis (kala-azar) were evaluated in a phase II clinical trial conducted in Brazil, India, and Kenya--countries where kala-azar is endemic. At each study site, sequential cohorts of 10 patients each received three different dosage regimens of AmBisome. The first cohort received 2 mg/kg/day (MKD) on days 1-6 and day 10 (total dose, 14 mg/kg). If the efficacy of this regimen was satisfactory, the second cohort received 2 MKD on days 1-4 and day 10 (total dose, 10 mg/kg) and a third cohort was administered 2 MKD on days 1, 5, and 10 (total dose, 6 mg/kg). In India, all three regimens (studied concurrently) cured 100% of the total of 30 patients. In Kenya, the first regimen cured all 10 patients (100%), the second cured 9 of 10 patients (90%), and the third cured only 1 of 5 patients (20%). In Brazil, since the first regimen cured only 5 of 13 patients (62%), the next 15 patients were given 2 MKD for 10 consecutive days (total dose, 20 mg/kg); this intensified regimen cured 13 of the 15 patients (83%). Adverse effects were minor, primarily fever and chills associated with infusion and irregular pulse. These findings suggest that leishmaniasis patients in India and Kenya should receive 2 mg/kg of AmBisome on days 1-4 and day 10, while those in Brazil should be given 2 mg/kg on days 1-10. AmBisome treatment is especially recommended for those for whom standard agents are likely to be ineffective, toxic, or difficult to administer.
Asunto(s)
Anfotericina B/uso terapéutico , Antiprotozoarios/uso terapéutico , Países en Desarrollo , Enfermedades Endémicas , Leishmaniasis Visceral/tratamiento farmacológico , Adolescente , Adulto , Brasil , Niño , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , India , Kenia , Leishmaniasis Visceral/epidemiología , Resultado del TratamientoRESUMEN
We determined the efficacy of the combination of the topical formulation 15% paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate.
Asunto(s)
Antiprotozoarios/administración & dosificación , Bencetonio/análogos & derivados , Leishmaniasis Cutánea/tratamiento farmacológico , Meglumina/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Paromomicina/administración & dosificación , Bencetonio/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Humanos , Antimoniato de MegluminaRESUMEN
A randomized, open, controlled clinical trial was designed to evaluate the efficacy, tolerance, and safety of sodium stibogluconate plus allopurinol and sodium stibogluconate alone as treatment of patients with mucocutaneous leishmaniasis. In phase 1 of the study, all 22 patients with severe disease had improvement of their lesions, but only two had clinical cure (both of these patients received sodium stibogluconate alone). In phase 2, which included 59 patients with moderate disease, the cure rate among sodium stibogluconate recipients was 75% (21 of 28) compared with 63.6% (14 of 22) among the sodium stibogluconate plus allopurinol recipients. The rates of clinical adverse events were similar among both groups. Thrombocytopenia was more frequent in the sodium stibogluconate plus allopurinol recipients, but the difference was not statistically significant. Eight patients (two sodium stibogluconate recipients and six sodium stibogluconate plus allopurinol recipients) withdrew from the study because of severe thrombocytopenia. In this study, the addition of allopurinol to sodium stibogluconate provided no clinical benefit as treatment of mucocutaneous leishmaniasis.
Asunto(s)
Alopurinol/administración & dosificación , Gluconato de Sodio Antimonio/administración & dosificación , Antiprotozoarios/administración & dosificación , Leishmaniasis Mucocutánea/tratamiento farmacológico , Adulto , Alopurinol/efectos adversos , Gluconato de Sodio Antimonio/efectos adversos , Antiprotozoarios/efectos adversos , Quimioterapia Combinada , Tolerancia a Medicamentos , Humanos , Masculino , SeguridadRESUMEN
BACKGROUND: Hundreds of thousands of cases of cutaneous leishmaniasis occur each year worldwide. Available therapies are parenteral, moderately toxic, and costly. OBJECTIVE: To determine the efficacy of and tolerance for oral allopurinol as monotherapy for cutaneous leishmaniasis. DESIGN: Randomized, controlled trial. SETTING: Outpatient clinics in 11 regions of Colombia in which cutaneous leishmaniasis is endemic. PATIENTS: 187 otherwise healthy adults with cutaneous leishmaniasis. Eighty-four percent of patients were infected with or were from regions with Leishmania panamensis; 16% were infected or were from regions with L. braziliensis. INTERVENTION: Patients were randomly assigned to one of three treatment groups. The first group received allopurinol, three 100-mg tablets four times daily (20 mg/kg of body weight per day) for 28 days. The second group received three placebo tablets four times daily for 28 days. The third group received Glucantime, 20 mg of intramuscular antimony/kg per day for 20 days. MEASUREMENT: Complete cure was defined as complete clinical reepithelialization of all lesions at 3 months and no relapse during 12 months of follow-up. RESULTS: Of 182 patients whose data could be analyzed, 157 (86%) were evaluated. In the allopurinol group, 18 of 55 (33% [95% CI, 21% to 47%]) patients were cured; in the placebo group, 17 of 46 patients (37% [CI, 23% to 52%]) were cured (difference, 4% [CI, -14% to 22%]; P = 0.68); and in the Glucantime group, 52 of 56 patients (93% [CI, 83% to 98%]) were cured (P < 0.001 compared with the allopurinol and placebo groups combined). In most cases, therapy was considered to have failed because the lesion did not reepithelialize by 1.5 months after the end of therapy. Three cases of relapse (two in the allopurinol group and one in the placebo group) at the nasal mucosa (mucosal leishmaniasis) had occurred by the end of 12 months of follow-up. CONCLUSIONS: Allopurinol monotherapy has no effect on Colombian cutaneous disease primarily caused by L. panamensis and therefore is unlikely to be effective against cutaneous leishmaniasis in other endemic regions.
Asunto(s)
Alopurinol/uso terapéutico , Antimetabolitos/uso terapéutico , Antiprotozoarios/uso terapéutico , Leishmaniasis Cutánea/tratamiento farmacológico , Adulto , Alopurinol/efectos adversos , Antimetabolitos/efectos adversos , Antimonio/uso terapéutico , Antiprotozoarios/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Meglumina/uso terapéutico , Antimoniato de Meglumina , Compuestos Organometálicos/uso terapéutico , Insuficiencia del TratamientoRESUMEN
The most extensive investigations of treatment of New World cutaneous leishmaniasis have been performed against L. panamensis disease in Colombia, and the relative value of regimens shown there may be instructive for disease from other areas. In Colombia, a 90-95% cure rate was achieved with three different drug regimens: The standard regimen of pentavalent antimony (20 mg/ kg/day for 20 days parenterally) A short course of pentamidine (3 mg/kg every other day for four injections intramuscularly The marketed combination of topical paromomycin (15%)-MBCl (12%) for 10 days, plus antimony (20 mg/kg/day parenterally) for 7 days. My view is that all these regimens could be chosen as first-line therapy for cutaneous disease in Colombia. The antimony regimen has the advantage of established use; the disadvantages are cost, requirement for injections each day for 20 days, and considerable morbidity in the last two weeks of therapy. The pentamidine regimen has the advantage of a short time course; the disadvantages are lack of experience with this new regimen and frequent, although moderate, morbidity. The combined topical-parenteral regimen has the advantage of requiring few and nontoxic injections; the primary disadvantage is that the regimen is novel and its efficacy has not been confirmed. It would be expected that cases of lesions in other areas caused by L. braziliensis complex would respond in a similar manner to these regimens. To date, however, only the efficacy of the standard antimonial regimen has been confirmed. In certain regions of Central America, other regimens may be effective. Thus, ketoconazole appears to be effective for the more rapidly self-curing forms of disease (cutaneous disease caused by L. mexicana and L. panamensis from Central America), and a short course of antimony may be effective against L. braziliensis in Guatemala.
Asunto(s)
Antiprotozoarios/uso terapéutico , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Mucocutánea/tratamiento farmacológico , Administración Cutánea , Administración Oral , Animales , Antimonio/administración & dosificación , Antimonio/uso terapéutico , Antiprotozoarios/administración & dosificación , América Central , Protocolos Clínicos , Colombia , Combinación de Medicamentos , Guatemala , Humanos , Inyecciones Intramusculares , Cetoconazol/administración & dosificación , Cetoconazol/uso terapéutico , Leishmania/efectos de los fármacos , Leishmania braziliensis/efectos de los fármacos , Leishmania mexicana/efectos de los fármacos , Paromomicina/administración & dosificación , Paromomicina/uso terapéutico , Pentamidina/administración & dosificación , Pentamidina/uso terapéuticoRESUMEN
We determined the efficacy of the use of permethrin-impregnated uniforms for prevention of malaria and leishmaniasis in a double-blind, randomized study of Colombian soldiers on patrol. In the study of malaria, soldiers were issued impregnated uniforms (i.e., a shirt, an undershirt, pants, socks, and a hat) or uniforms washed in water; the soldiers wore the uniforms day and night for a mean of 4.2 weeks and were observed for an additional 4 weeks. Three (3%) of 86 soldiers wearing impregnated uniforms contracted malaria, whereas 12 (14%) of 86 soldiers wearing control uniforms contracted malaria (P = .015). In the study of leishmaniasis (soldiers were in the area of endemicity for 6.6 weeks and were observed for 12 weeks thereafter), 4 (3%) of 143 soldiers wearing impregnated uniforms and 18 (12%) of 143 soldiers wearing control uniforms acquired disease (P = .002). In the leishmaniasis study, and presumably in the malaria study, breakthrough infections in the treated group were primarily due to bites in unclothed regions of the body (face and hands). Permethrin-treated uniforms were virtually nontoxic (there were only two cases of mild skin irritation among 229 subjects), and impregnation is quick and inexpensive. Impregnation of clothing with permethrin is suggested for nonimmune populations who are likely to be exposed to malaria or leishmaniasis over a period of 1-2 months.