RESUMO
BACKGROUND: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. METHODS: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. RESULTS: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. CONCLUSIONS: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.
Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Sangue/parasitologia , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Plasmodium falciparum/isolamento & purificação , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Resistência a Medicamentos , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. METHODS: We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHO's Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. FINDINGS: The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30.3% (95% CI 19.8-39.4, p<0.0001) against clinical malaria, 21.3% (8.2-32.5, p=0.002) against the risk of anaemia, 38.1% (12.5-56.2, p=0.007) against hospital admissions associated with malaria parasitaemia, and 22.9% (10.0-34.0, p=0.001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1.05, 95% CI 0.72-1.54, p=0.79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. INTERPRETATION: IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. FUNDING: Bill & Melinda Gates Foundation.
Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/prevenção & controle , Pirimetamina/uso terapêutico , Segurança , Sulfadoxina/uso terapêutico , África/epidemiologia , Anemia/epidemiologia , Antimaláricos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Seguimentos , Humanos , Esquemas de Imunização , Incidência , Lactente , Mortalidade Infantil , Malária Falciparum/epidemiologia , Admissão do Paciente/estatística & dados numéricos , Pirimetamina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Projetos de Pesquisa , Fatores de Risco , Sulfadoxina/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Sulphadoxine-pyrimethamine (SP) is the only single dose therapy for uncomplicated malaria, but there is widespread resistance. At the time of this study, artemether-lumefantrine (AL) and chlorproguanil-dapsone (CPD), both multi-dose regimes, were considered possible alternatives to SP in Malawi. The aim of this study was to investigate the impact of poor adherence on the effectiveness of AL and CPD. METHODS: Children > or =12 months and adults with uncomplicated malaria were randomized to receive AL, CPD or SP. Adherence was measured using a questionnaire and electronic monitoring devices, MEMS, pill bottles that recorded the date and time of opening. Day-7 plasma dapsone or lumefantrine concentrations were measured to examine their relationship with adherence and clinical response. RESULTS: 841 patients were recruited. The day-28 adequate clinical and parasitological response (ACPR) rates, using intention to treat analysis (missing data treated as failure), were AL 85.2%, CPD 63.7% and SP 50%. ACPR rates for AL were higher than CPD or SP on days 28 and 42 (p < or = 0.002 for all comparisons). CPD was more effective than SP on day-28 (p = 0.01), but not day-42.Very high adherence was reported using the questionnaire, 100% for AL treated patients and 99.2% for the CPD group. Only three CPD participants admitted missing any doses. 164/181 (90.6%) of CPD treated patients took all their doses out of the MEMS container and they were more likely to have a day-28 ACPR than those who did not take all their medication out of the container, p = 0.024. Only 7/87 (8%) AL treated patients did not take all of their doses out of their MEMS container and none had treatment failure.Median day-7 dapsone concentrations were higher in CPD treated patients with ACPR than in treatment failures, p = 0.012. There were no differences in day-7 dapsone or lumefantrine concentrations between those who took all their doses from the MEMS container and those who did not. A day-7 lumefantrine concentration reported to be predictive of AL treatment failure in Thailand was not useful in this population; only one of 16 participants with a concentration below this threshold (175 ng/ml) had treatment failure. CONCLUSION: This study provides reassurance of the effectiveness of AL, even with unsupervised dosing, as it is rolled out across sub-Saharan Africa. Self-reported adherence appears to be an unreliable measure of adherence in this population.
Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Dapsona/uso terapêutico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Malária/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Plasma/química , Proguanil/análogos & derivados , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Adolescente , Adulto , Combinação Arteméter e Lumefantrina , Criança , Pré-Escolar , Combinação de Medicamentos , Feminino , Humanos , Lactente , Malaui , Masculino , Proguanil/uso terapêutico , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Chlorproguanil (CPG)-dapsone (DDS)-artesunate was in development for the treatment of uncomplicated Plasmodium falciparum malaria. The pharmacokinetics of CPG, DDS, artesunate and their metabolites chlorcycloguanil (CCG), monoacetyl dapsone (MADDS) and dihydroartemisinin (DHA) were investigated in patients with P. falciparum given CPG-DDS alone or plus artesunate. METHODS: Adult patients from Malawi and The Gambia taking part in a phase II clinical trial were randomised to receive a 3-day treatment of CPG-DDS alone (2/2.5 mg/kg/day) or plus 1, 2 or 4 mg/kg/day artesunate. Blood samples for pharmacokinetic analysis were collected up to 24 h post-first dose. RESULTS: The pharmacokinetic analysis included 115 patients. For CPG, there was no significant effect of artesunate on C(max) or AUC(0-24), except the 90% confidence interval (CI) for AUC(0-24) for the 4 mg/kg artesunate dose was slightly below that for the standard bioequivalence range (90% CI 0.78, 1.11); this was not considered clinically relevant. Artesunate increased the CCG AUC(0-24) by 6-17% and C(max) by 0-16%. Artesunate had no significant effect on the rate or extent of absorption of DDS. For MADDS, artesunate increased the AUC(0-24) by 13-47% and C(max) by 8-45%. For 1, 2 and 4 mg/kg artesunate dosing, artesunate AUC(0-infinity) was 64.6, 151 and 400 ng.h/ml and C(max) 48.9, 106 and 224 ng/ml respectively; DHA AUC(0-infinity) was 538, 1,445 and 3,837 ng.h/ml and C(max) 228, 581 and 1,414 ng/ml respectively. Using a power model, the point estimates of slope were greater than 1 for artesunate AUC(0-t) by 16% and C(max) by 5% and for DHA by 39 and 21% respectively. CONCLUSION: Artesunate did not significantly affect CPG or DDS pharmacokinetics. For CCG and MADDS, small to moderate increases in exposure with artesunate dosing were observed. There was a greater than proportional increase in artesunate and DHA exposure with increasing artesunate dose. These effects are not considered to be clinically relevant. It should be noted that the CPG-DDS-artesunate programme has now been stopped following unacceptable haematological toxicity in patients with glucose-6-phosphate dehydrogenase deficiency during a phase III trial. In addition, the CPG-DDS combination has been withdrawn from clinical use.
Assuntos
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Dapsona/farmacocinética , Malária Falciparum/metabolismo , Proguanil/análogos & derivados , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/sangue , Área Sob a Curva , Artemisininas/administração & dosagem , Artemisininas/sangue , Artesunato , Dapsona/administração & dosagem , Dapsona/sangue , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Gâmbia , Humanos , Malária Falciparum/tratamento farmacológico , Malaui , Masculino , Pessoa de Meia-Idade , Testes de Sensibilidade Parasitária , Proguanil/administração & dosagem , Proguanil/sangue , Proguanil/farmacocinética , Fatores de TempoRESUMO
The Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme is the target of pyrimethamine, a component of the antimalarial pyrimethamine-sulfadoxine. Resistance to this drug is associated primarily with mutations in the Pfdhfr gene. The I164L mutant allele is of particular interest, because strains possessing this mutation are highly resistant to pyrimethamine and to chlorproguanil, a component of chlorproguanil-dapsone. A recent study from Malawi reported this mutation at a prevalence of 4.7% in parasites from human immunodeficiency virus-positive pregnant women by using a real-time PCR method. These observations have huge implications for the use of pyrimethamine-sulfadoxine, chlorproguanil-dapsone, and future antifolate-artemisinin combinations in Africa. It was imperative that this finding be rigorously tested. We identified a number of critical limitations in the original genotyping strategy. Using a refined and validated real-time PCR strategy, we report here that this mutation was absent in 158 isolates from Malawi and 42 isolates from Zambia collected between 2003 and 2005.
Assuntos
Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/genética , Mutação Puntual , Tetra-Hidrofolato Desidrogenase/genética , Adulto , Alelos , Animais , Antimaláricos/farmacologia , Sequência de Bases , Pré-Escolar , Primers do DNA/genética , DNA de Protozoário/análise , DNA de Protozoário/genética , Resistência a Medicamentos/genética , Feminino , Antagonistas do Ácido Fólico/farmacologia , Frequência do Gene , Genes de Protozoários , Infecções por HIV/complicações , Humanos , Malária Falciparum/complicações , Malaui , Masculino , Plasmodium falciparum/efeitos dos fármacos , Reação em Cadeia da Polimerase/métodos , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Complicações Parasitárias na Gravidez/parasitologia , Pirimetamina/farmacologia , Tailândia , ZâmbiaRESUMO
Malaria claims over one million lives a year in some of the poorest countries of the world. Affected populations and governments cannot afford to pay for expensive new therapies. Most antimalarial treatments are purchased from local shops and administered in the home. These factors make for a complex set of requirements for any new treatment for malaria if a substantial reduction in mortality is ever to be achieved. Thankfully there are several treatments being developed, mostly within public-private partnerships. Typically, the goal of public-private partnerships is the granting of a product license, so work plans end after phase III trials. As these drugs will ultimately be used unsupervised, malaria control programme managers will require further data on safety and whether the drug is as efficacious when used outside of controlled clinical trials before allowing widespread use of these new products. These data need to be collected in highly specific phase IV programmes. We explain why public-private partnerships should extend their development plans well beyond drug registration, and set out the requirements of such a programme. We aim to generate debate and discussion so that guidelines that are internationally accepted and adhered to can be developed not only for antimalarials but for all drugs that are being developed specifically for use in resource-poor settings.
Assuntos
Antimaláricos/uso terapêutico , Ensaios Clínicos Fase IV como Assunto , Malária/tratamento farmacológico , África , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Custos de Medicamentos , Feminino , Humanos , Malária/epidemiologia , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológicoRESUMO
Most malaria control strategies today depend on safe and effective drugs, as they have done for decades. But sensitivity to chloroquine, hitherto the workhorse of malaria chemotherapy, has rapidly declined throughout the tropics since the 1980s, and this drug is now useless in many high-transmission areas. New options for resource-constrained governments are few, and there is growing evidence that the burden from malaria has been increasing, as has malaria mortality in Africa. In this chapter, we have tried to outline the main pharmacological properties of current drugs, and their therapeutic uses and limitations. We have summarised the ways in which these drugs are employed, both in the formal health sector and in self-medication. We have briefly touched on the limitations of current drug development, but have tried to pick out a few promising drugs that are under development. Given that Plasmodium falciparum is the organism that kills, and that has developed multi-drug resistance, we have tended to focus upon it. Similarly, given that around 90% of global mortality from malaria occurs in Africa, there is the tendency to dwell on this continent. We give no apology for placing our emphasis upon the use of antimalarial drugs in endemic populations rather than their use for prophylaxis in travellers.
Assuntos
Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , África , Animais , Antimaláricos/efeitos adversos , Gerenciamento Clínico , Desenho de Fármacos , Feminino , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológicoRESUMO
Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalarial drug, is associated with selection of point mutations in dihydrofolate reductase and dihydropteroate synthase. Among these mutations, the leucine 164 dihydrofolate reductase mutation (Leu-164) is associated with higher levels of SP resistance; this mutation is also associated with a decrease in the efficacy of chlorproguanil/dapsone, a newly developed antifolate antimalarial drug. Leu-164 has been detected in Southeast Asia and South America, regions where SP is no longer effective. Surprisingly, this mutation has not yet been detected in Africa, using the standard protocol based on PCR-RFLP, despite high SP resistance. In this paper, we discuss briefly the reasons why Leu-164 has not yet been selected in Africa and we propose a means that may slow down the selection of this mutation.
Assuntos
Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Plasmodium falciparum/genética , Mutação Puntual , Tetra-Hidrofolato Desidrogenase/genética , África , Animais , Combinação de Medicamentos , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/transmissão , Plasmodium falciparum/efeitos dos fármacos , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêuticoRESUMO
Plasmodium falciparum parasites resistant to the combination sulfadoxine-pyrimethamine are spreading in Africa, particularly in East Africa. This is a matter of concern because there are no other affordable drugs available. This article provides the evidence indicating that sulfadoxine-pyrimethamine resistance can be reversed in vitro and discusses how this information might be exploited to extend the therapeutic lifetime of sulfadoxine-pyrimethamine in vivo.
Assuntos
Antimaláricos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Probenecid/farmacologia , Pirimetamina/farmacologia , Sulfadoxina/farmacologia , Animais , Antimaláricos/uso terapêutico , Combinação de Medicamentos , Resistência a Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Ácido Fólico/efeitos dos fármacos , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/metabolismo , Probenecid/uso terapêutico , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêuticoRESUMO
Africa carries the greatest burden of disease caused by Plasmodium falciparum, and we can expect this burden to rise in the near future, mainly because of drug resistance. Although effective drugs are available (such as artemether-lumefantrine, mefloquine, atovaquone-proguanil and halofantrine) they are uniformly too expensive for routine use. Affordable options include chloroquine plus sulfadoxine-pyrimethamine (SP), amodiaquine (alone or in combination with SP) and chlorproguanil-dapsone. Artemisinin combination therapy may offer considerable advantages over alternative therapies, but its introduction faces considerable logistic difficulty.
Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária/tratamento farmacológico , Malária/epidemiologia , Plasmodium falciparum/efeitos dos fármacos , África/epidemiologia , Animais , Antimaláricos/farmacocinética , Antimaláricos/provisão & distribuição , Antimaláricos/uso terapêutico , Culicidae , Vetores de Doenças , Política de Saúde/economia , Política de Saúde/legislação & jurisprudência , Humanos , Programas Nacionais de Saúde/economia , Programas Nacionais de Saúde/legislação & jurisprudência , Plasmodium falciparum/genética , Organização Mundial da SaúdeRESUMO
Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC(50) = 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED(50) activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.
Assuntos
Aminoquinolinas/síntese química , Amodiaquina/síntese química , Antimaláricos/síntese química , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacologia , Amodiaquina/análogos & derivados , Amodiaquina/farmacocinética , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Cristalografia por Raios X , Malária/tratamento farmacológico , Malária/metabolismo , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii , Ratos , Ratos Wistar , Relação Estrutura-AtividadeAssuntos
Antirretrovirais/uso terapêutico , Antimaláricos/uso terapêutico , Antirretrovirais/efeitos adversos , Antirretrovirais/metabolismo , Antimaláricos/efeitos adversos , Antimaláricos/metabolismo , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Malária/tratamento farmacológico , MasculinoAssuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Adulto , África , Animais , Antimaláricos/uso terapêutico , Roupas de Cama, Mesa e Banho , Administração de Caso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Inseticidas/administração & dosagem , Malária Falciparum/tratamento farmacológico , GravidezRESUMO
In light of reports of increasing resistance of parasites to amodiaquine in African countries in which Plasmodium falciparum is endemic as well as the paucity of recent in vitro sensitivity data, we assessed the in vivo and in vitro sensitivity to amodiaquine of P. falciparum isolates from 128 pediatric outpatients (0.5-10 years old) in Pingilikani, Kilifi District, Kenya, who were treated with amodiaquine (10 mg/kg/day for 3 days). The polymerase chain reaction-corrected parasitological cure rate on day 28 (by Kaplan-Meier analysis) was 82% (95% confidence interval [CI], 74%-88%). Twenty-six percent (17/66) of tested pretreatment P. falciparum field isolates had 50% in vitro growth inhibition at concentrations of N-desethyl-amodiaquine (DEAQ)-the major biologically active metabolite of amodiaquine-above the proposed resistance threshold of 60 nmol/L, but baseline median DEAQ 50% inhibitory concentration values were not associated with subsequent risk of asexual parasite recrudescence (29 nmol/L [95% CI, 23-170 nmol/L] and 34 nmol/L [95% CI, 30-46 nmol/L] for patients with and those without recrudescences, respectively). The median absolute neutrophil count dropped by 1.3 X 10(3) cells/microL (95% CI, -1.7 X 10(3) to -0.7 X 10(3) cells/microL) between days 0 and 28. The high prevalence of in vitro and in vivo resistance precludes the use of amodiaquine on its own as second-line treatment. These findings also suggest that the value of amodiaquine combinations as first- or second-line treatment in areas with similar patterns of 4-aminoquinoline resistance should be reassessed.
Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Amodiaquina/farmacologia , Animais , Antimaláricos/farmacologia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Quênia/epidemiologia , Malária/sangue , Malária/epidemiologia , Masculino , Pacientes AmbulatoriaisRESUMO
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 TempoRESUMO
BACKGROUND: Chlorproguanil-dapsone-artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether-lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients. METHODS AND FINDINGS: The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (> or =1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2:1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/379) for AL (treatment difference -3.3%, 95%CI -5.6, -0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL). CONCLUSIONS: Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa. TRIAL REGISTRATION: ClinicalTrials.Gov NCT00344006.
Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Dapsona/uso terapêutico , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Proguanil/análogos & derivados , Adolescente , África , Artemisininas/administração & dosagem , Artesunato , Criança , Dapsona/administração & dosagem , Método Duplo-Cego , Etanolaminas/administração & dosagem , Feminino , Fluorenos/administração & dosagem , Humanos , Lumefantrina , Masculino , Cooperação do Paciente , Proguanil/administração & dosagem , Proguanil/uso terapêutico , Resultado do TratamentoRESUMO
AIMS: Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria. MATERIALS & METHODS: Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated. RESULTS: All CYP2C19/CYP2C9 alleles obeyed Hardy-Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC(0-24)) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher C(max) (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071). CONCLUSION: CYP2C19*17 determines antimalarial biguanide metabolic profile at the CYP2C19/CYP2C9 locus.
Assuntos
Antimaláricos/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Proguanil/farmacocinética , Triazinas/farmacocinética , Adolescente , Adulto , Alelos , Área Sob a Curva , Biotransformação/genética , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , DNA/genética , Feminino , Gâmbia/epidemiologia , Frequência do Gene , Variação Genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.
Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Benzilaminas/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Aminoquinolinas/toxicidade , Amodiaquina/análogos & derivados , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Antimaláricos/toxicidade , Benzilaminas/síntese química , Benzilaminas/química , Benzilaminas/toxicidade , Inibidores das Enzimas do Citocromo P-450 , Cães , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Feminino , Haplorrinos , Heme/química , Humanos , Malária/tratamento farmacológico , Camundongos , Modelos Moleculares , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii , Ratos , Relação Estrutura-AtividadeRESUMO
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.