RESUMEN
Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated Plasmodium falciparum malaria. Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each ferroquine dose and N = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).
Asunto(s)
Aminoquinolinas/uso terapéutico , Amodiaquina/uso terapéutico , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Quimioterapia Combinada , Compuestos Ferrosos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Artesunato , Relación Dosis-Respuesta a Droga , Gabón , Humanos , Kenia , Masculino , Metalocenos , Persona de Mediana EdadRESUMEN
Resistance to efavirenz and nevirapine has not been associated with mutations at position 138 of reverse transcriptase. In an evaluation of virologic suppression rates in PEPFAR (President's Emergency Plan For AIDS Relief) clinics in Kenya among patients on first-line therapy (RV288), 63% (617/975) of randomly selected patients on antiretroviral therapy were suppressed (HIV RNA<400âcopies/ml). Among those with non-nucleoside reverse transcriptase inhibitor resistance (nâ=â101), 14 (13.8%) had substitutions at 138 (A, G, K or Q), mutations selected only by etravirine and rilpivirine in subtype B viruses. All 14 patients received efavirenz or nevirapine, not etravirine or rilpivirine, and were predominantly subtype A1. This may be the first report of efavirenz and nevirapine selecting these mutations in these subtypes.