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1.
Am J Trop Med Hyg ; 97(3): 702-711, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28749773

RESUMO

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [N = 3]) and primaquine (-1.25 to -3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.


Assuntos
Aminoquinolinas/efeitos adversos , Antimaláricos/efeitos adversos , Regulação Enzimológica da Expressão Gênica , Deficiência de Glucosefosfato Desidrogenase/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Heterozigoto , Adolescente , Adulto , Aminoquinolinas/administração & dosagem , Antimaláricos/administração & dosagem , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Pessoa de Meia-Idade , Adulto Jovem
2.
J Clin Pharmacol ; 54(9): 995-1005, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24700490

RESUMO

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18-65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine-QTcF concentration-effect relationship demonstrated a shallow slope (0.5 ms/µg mL(-1) ) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization.


Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Adolescente , Adulto , Idoso , Aminoquinolinas/efeitos adversos , Aminoquinolinas/sangue , Aminoquinolinas/farmacocinética , Antimaláricos/efeitos adversos , Antimaláricos/sangue , Antimaláricos/farmacocinética , Eletrocardiografia/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Método Simples-Cego , Adulto Jovem
3.
Br J Clin Pharmacol ; 76(6): 858-67, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23701202

RESUMO

AIMS: The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. METHODS: Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. RESULTS: The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. CONCLUSIONS: No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.


Assuntos
Aminoquinolinas , Antimaláricos , Cloroquina , Administração Oral , Adolescente , Adulto , Aminoquinolinas/administração & dosagem , Aminoquinolinas/efeitos adversos , Aminoquinolinas/farmacocinética , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Área Sob a Curva , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Cloroquina/farmacocinética , Método Duplo-Cego , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
4.
Proc Natl Acad Sci U S A ; 110(10): E861-8, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23404707

RESUMO

We present an unconventional approach to antiviral drug discovery, which is used to identify potent small molecules against rabies virus. First, we conceptualized viral capsid assembly as occurring via a host-catalyzed biochemical pathway, in contrast to the classical view of capsid formation by self-assembly. This suggested opportunities for antiviral intervention by targeting previously unappreciated catalytic host proteins, which were pursued. Second, we hypothesized these host proteins to be components of heterogeneous, labile, and dynamic multi-subunit assembly machines, not easily isolated by specific target protein-focused methods. This suggested the need to identify active compounds before knowing the precise protein target. A cell-free translation-based small molecule screen was established to recreate the hypothesized interactions involving newly synthesized capsid proteins as host assembly machine substrates. Hits from the screen were validated by efficacy against infectious rabies virus in mammalian cell culture. Used as affinity ligands, advanced analogs were shown to bind a set of proteins that effectively reconstituted drug sensitivity in the cell-free screen and included a small but discrete subfraction of cellular ATP-binding cassette family E1 (ABCE1), a host protein previously found essential for HIV capsid formation. Taken together, these studies advance an alternate view of capsid formation (as a host-catalyzed biochemical pathway), a different paradigm for drug discovery (whole pathway screening without knowledge of the target), and suggest the existence of labile assembly machines that can be rendered accessible as next-generation drug targets by the means described.


Assuntos
Antivirais/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Vírus da Raiva/efeitos dos fármacos , Vírus da Raiva/fisiologia , Proteínas Virais/fisiologia , Sequência de Aminoácidos , Animais , Sistema Livre de Células , Chlorocebus aethiops , Descoberta de Drogas , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/fisiologia , Domínios e Motivos de Interação entre Proteínas , Vírus da Raiva/genética , Células Vero , Proteínas Virais/química , Proteínas Virais/genética , Montagem de Vírus/efeitos dos fármacos
5.
Am J Trop Med Hyg ; 81(6): 969-78, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19996424

RESUMO

This multi-center, randomized, parallel-group, double-blind, double-dummy study compared the efficacy and safety of chlorproguanil-dapsone-artesunate (CDA) and chlorproguanil-dapsone (CPG-DDS) in the treatment of falciparum malaria in Africa (Burkina Faso, Ghana, Mali, Nigeria). Six hundred patients (>or= 1 year of age) received CDA 2.0/2.5/4.0 mg/kg, and 292 CPG-DDS 2.0/2.5 mg/kg, once daily for 3 days. Day 28 parasitologic cure rate (polymerase chain reaction [PCR]-corrected, per-protocol population) was 89.1% (416/467) for CDA, non-inferior but also superior to CPG-DDS, 83.0% (176/212) (treatment difference 6.1%; 95% confidence interval [CI] 0.3, 11.9). Glucose-6-phosphate dehydrogenase (G6PD) genotype was available for 844/892 (95%) patients. Occurrences of a composite hemoglobin safety endpoint (hemoglobin drop >or= 40 g/L or >or= 40% versus baseline, hemoglobin < 50 g/L, or blood transfusion) were CDA 13/44 (30%), CPG-DDS 7/24 (29%) in G6PD-deficient patients versus CDA 4/448 (< 1%), CPG-DDS 6/221 (3%) in G6PD-normal patients. No deaths occurred. CDA was more efficacious than CPG-DDS. However, the hemolytic potential in G6PD-deficient patients does not support further development of CDA.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Dapsona/uso terapêutico , Malária Falciparum/tratamento farmacológico , Proguanil/análogos & derivados , Adolescente , Adulto , África Subsaariana/epidemiologia , Animais , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Artesunato , Criança , Pré-Escolar , Dapsona/administração & dosagem , Dapsona/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Doença de Depósito de Glicogênio Tipo I/genética , Hemólise , Humanos , Masculino , Plasmodium falciparum/genética , Proguanil/administração & dosagem , Proguanil/efeitos adversos , Proguanil/uso terapêutico , Fatores de Tempo
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