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2.
Malar J ; 18(1): 277, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429785

RESUMO

BACKGROUND: HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Dihydroartemisinin-piperaquine (DPQ) is recommended for treatment of Plasmodium falciparum malaria, but its efficacy and safety has not been evaluated in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events were assessed in HIV-infected individuals on non-nucleoside reverse transcriptase inhibitor-based ART (efavirenz and nevirapine) with uncomplicated P. falciparum malaria treated with dihydroartemisinin-piperaquine. METHODS: An open label single arm clinical trial was conducted in Malawi (Blantyre and Chikhwawa districts) and Mozambique (Manhiça district) involving patients aged 15-65 years with uncomplicated P. falciparum malaria who were on efavirenz-based or nevirapine-based ART. They received a directly-observed 3-day standard treatment of DPQ and were followed up until day 63 for malaria infection and adverse events. Day-42 PCR-corrected-ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat (ITT) population. RESULTS: The study enrolled 160 and 61 patients on efavirenz and nevirapine-based ART, with a baseline geometric mean (95% CI) parasite density of 2681 (1964-3661) and 9819 (6606-14,593) parasites/µL, respectively. The day-42 PCR-corrected ACPR (95% CI) was 99.4% (95.6-99.9%) in the efavirenz group and 100% in the nevirapine group. Serious adverse events occurred in 5.0% (8/160) and 3.3% (2/61) of the participants in the efavirenz and nevirapine group, respectively, but none were definitively attributable to DPQ. Cases of prolonged QT interval (> 60 ms from baseline) occurred in 31.2% (48/154) and 13.3% (8/60) of the patients on the efavirenz and nevirapine ART groups, respectively. These were not clinically significant and resolved spontaneously over time. As this study was not designed to compare the efficacy and safety of DPQ in the two ART groups, no formal statistical comparisons were made between the two ART groups. CONCLUSIONS: DPQ was highly efficacious and safe for the treatment of malaria in HIV-infected patients concurrently taking efavirenz- or nevirapine-based ART, despite known pharmacokinetic interactions between dihydroartemisinin-piperaquine and efavirenz- or nevirapine-based ART regimens. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013, https://pactr.samrc.ac.za/Search.aspx.


Assuntos
Antirretrovirais/uso terapêutico , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Malária Falciparum/prevenção & controle , Quinolinas/efeitos adversos , Adolescente , Adulto , Benzoxazinas/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Malaui , Masculino , Pessoa de Meia-Idade , Moçambique , Nevirapina/uso terapêutico , Plasmodium falciparum/fisiologia , Adulto Jovem
3.
Anesth Analg ; 129(2): 515-519, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31314746

RESUMO

BACKGROUND: Malaria is a common problem throughout the world, particularly in sub-Saharan Africa, where 90% of all deaths in the world from malaria occur. While many studies on malaria are available in the medical literature, few publications have addressed the problems of managing malaria during surgery and anesthesia. At a newly opened hospital in Niger, we initiated further studies to evaluate our process of managing malaria when we had a number of problems in our first group of pediatric patients having elective cleft lip and palate repairs. Many patients had fevers during and soon after surgery and were found to have clinical malaria, despite recent treatment. METHODS: In our first group of 16 patients (group A), 4 initially tested positive for malaria by light microscopy and were treated before arrival at our hospital. On arrival at our hospital, we retested all the patients for malaria. Three of the original 4 were still positive. Six additional patients also tested positive, for a total of 9 of 16 in group A. Despite treatment, 6 of these 16 patients still had fevers in the operating rooms and postoperative period requiring further treatment for clinical malaria (6/16 or 38% incidence of perioperative malaria; 95% CI, 15%-65%).We then changed our diagnostic and management strategies for subsequent patients: all patients were tested for malaria 3-7 days before surgery at our hospital rather than before arrival. We decided to universally treat all patients coming for surgery for presumed malaria due to the number of problems encountered in the first group and the high prevalence of malaria in our population. We changed the source of the malaria medications used for all subsequent patients. We included rapid diagnostic tests for falciparum and nonfalciparum malaria species. RESULTS: After the change in protocols, no children in the second group of patients (group B, n = 53) developed clinical malaria or fever during or after surgery (P < .0001, comparing 6/16 vs 0/53, using Fisher exact test). During the first 4 months after the implementation of rapid diagnostic tests for malaria testing, we tested 283 patients, of whom 73 were found to be positive for malaria by light microscopy and/or rapid diagnostic test. Of the 73 malarias, 24.6% were nonfalciparum malarias (95% CI, 14.7%-34.5%), much higher than the 1%-5% incidence that international and local health officials told us to expect. CONCLUSIONS: Pediatric patients in many areas of the world often present with a high risk for malaria in the perioperative time frame. Treatment with artemisinin-based therapy 3-7 days before elective surgeries may be an effective method to reduce the risks of febrile episodes and clinical malaria during and after surgery in areas of high transmission. However, these results may be limited by (1) the presence of nonfalciparum malarias, some of which may require prolonged treatment for hepatic cryptogenic malaria; (2) the potential for complications related to counterfeit medications; and (3) international efforts at malaria eradication, especially when considering the use of malaria medications that have the potential to develop drug resistance.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Países em Desenvolvimento , Recursos em Saúde , Malária/tratamento farmacológico , Procedimentos Cirúrgicos Bucais , Adolescente , Fatores Etários , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Criança , Pré-Escolar , Fenda Labial/diagnóstico , Fenda Labial/epidemiologia , Fissura Palatina/diagnóstico , Fissura Palatina/epidemiologia , Protocolos Clínicos , Esquema de Medicação , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Incidência , Lactente , Malária/diagnóstico , Malária/epidemiologia , Malária/transmissão , Masculino , Nigéria/epidemiologia , Procedimentos Cirúrgicos Bucais/efeitos adversos , Assistência Perioperatória , Prevalência , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
4.
Pol J Vet Sci ; 22(2): 297-304, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31269339

RESUMO

Artemisinin is a powerful antimalarial drug, useful in the treatment of many diseases, including chickens coccidiosis. Its toxic effects have been well studied in humans and experimental animals, but not sufficiently in broiler chickens. Therefore, in the present study, we aimed to assess the side effects of artemisinin in chickens, by measuring the serum level of proteins and enzymes (ALT, AST, GGT, ALP, CK), by histopathological examination and by the evaluation of relative weight of organs (liver, kidney, heart). Artemisinin was administered in the standard feed for chickens in three different concentrations: 5, 50 and 500 ppm. Each concentration of artemisinin increased the total serum proteins, gamma-globulins and the serum activity of CK and decreased the serum ALP level. The values of ALT and GGT were higher in the chickens treated with 50 and 500 ppm of artemisinin. Multifocal liver necrosis and inflammatory infiltrate were detected in the chickens that received the 50 and 500 ppm dosage of artemisinin. Minimal tubular necrosis, renal tubular epithelium vacuolation, multifocal interstitial nephritis and mild uric nephrosis were detected in chickens treated with the drug. Artemisinin administration produced no significant changes in the organs relative weight. Artemisinin, at a concentration of 5 mg/kg of feed is well tolerated by broiler chickens, but the concentrations of 50 and 500 mg/ kg feed can produce toxic effects.


Assuntos
Ração Animal/análise , Artemisininas/efeitos adversos , Galinhas , Dieta/veterinária , Doenças das Aves Domésticas/induzido quimicamente , Fenômenos Fisiológicos da Nutrição Animal , Animais , Artemisininas/administração & dosagem , Artemisininas/sangue , Relação Dose-Resposta a Droga , Feminino , Masculino , Distribuição Aleatória
5.
Rev Soc Bras Med Trop ; 52: e20180453, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31141053

RESUMO

INTRODUCTION: Concern regarding the cardiotoxicity of antimalarials has been renewed because of their potential to cause QT/QTc interval prolongation related to torsade de pointes (TdP). Artemisinin-piperaquine (AP) is considered an effective artemisinin-based combination therapy (ACT) for malaria. METHODS: This study involved a retrospective analysis of clinical data of 93 hospitalized malaria patients who had received AP orally. Electrocardiograms (ECGs) were obtained at specific time points in the original study. RESULTS: Some cases of QT prolongation were observed. However, no TdP was found. CONCLUSIONS: AP may cause QT interval prolongation in some malaria patients but may not lead to TdP.


Assuntos
Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Malária Falciparum/tratamento farmacológico , Quinolinas/efeitos adversos , Adulto , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Quimioterapia Combinada , Eletrocardiografia , Feminino , Humanos , Síndrome do QT Longo/diagnóstico , Masculino , Pessoa de Meia-Idade , Quinolinas/uso terapêutico , Estudos Retrospectivos
6.
Phytomedicine ; 57: 49-56, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30668322

RESUMO

BACKGROUND AND OBJECTIVE: Prior small-scale clinical trials showed that Artemisia annua and Artemisia afra infusions, decoctions, capsules, or tablets were low cost, easy to use, and efficient in curing malaria infections. In a larger-scale trial in Kalima district, Democratic Republic of Congo, we aimed to show A. annua and/or A. afra infusions were superior or at least equivalent to artesunate-amodiaquine (ASAQ) against malaria. METHODS: A double blind, randomized clinical trial with 957 malaria-infected patients had two treatment arms: 472 patients for ASAQ and 471 for Artemisia (248 A. annua, 223 A. afra) remained at end of the trial. ASAQ-treated patients were treated per manufacturer posology, and Artemisia-treated patients received 1 l/d of dry leaf/twig infusions for 7 d; both arms had 28 d follow-up. Parasitemia and gametocytes were measured microscopically with results statistically compared among arms for age and gender. RESULTS: Artemisinin content of A. afra was negligible, but therapeutic responses of patients were similar to A. annua-treated patients; trophozoites cleared after 24  h, but took up to 14 d to clear in ASAQ-treated patients. D28 cure rates defined as absence of parasitemia were for pediatrics 82, 91, and 50% for A. afra, A. annua and ASAQ; while for adults cure rates were 91, 100, and 30%, respectively. Fever clearance took 48  h for ASAQ, but 24  h for Artemisia. From D14-28 no Artemisia-treated patients had microscopically detectable gametocytes, while 10 ASAQ-treated patients remained gametocyte carriers at D28. More females than males were gametocyte carriers in the ASAQ arm but were unaffected in the Artemisia arms. Hemoglobin remained constant at 11 g/dl for A. afra after D1, while for A. annua and ASAQ it decreased to 9-9.5  g/dl. Only 5.0% of Artemisia-treated patients reported adverse effects, vs. 42.8% for ASAQ. CONCLUSION: A. annua and A. afra infusions are polytherapies with better outcomes than ASAQ against malaria. In contrast to ASAQ, both Artemisias appeared to break the cycle of malaria by eliminating gametocytes. This study merits further investigation for possible inclusion of Artemisia tea infusions as an alternative for fighting and eradicating malaria.


Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Artemisia , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Preparações de Plantas/uso terapêutico , Adolescente , Adulto , Amodiaquina/efeitos adversos , Artemisia annua , Artemisininas/efeitos adversos , Criança , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Febre/tratamento farmacológico , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Parasitemia/tratamento farmacológico , Preparações de Plantas/efeitos adversos , Plantas Medicinais , Resultado do Tratamento
7.
Cochrane Database Syst Rev ; 1: CD006404, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30620055

RESUMO

BACKGROUND: The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum (P falciparum) malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine-artesunate is a novel ACT. OBJECTIVES: To evaluate the efficacy of pyronaridine-artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine-artesunate and other pyronaridine treatments compared to alternative treatments. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform Search Portal, and the International Standard Randomized Controlled Trial Number (ISRCTN) registry for ongoing or recently completed trials. The date of the last search was 8 May 2018. SELECTION CRITERIA: Efficacy analysis: randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria.Safety analysis: RCTs of pyronaridine-artesunate or pyronaridine for treating P falciparum or P vivax malaria. DATA COLLECTION AND ANALYSIS: For this update, two review authors independently re-extracted all data and assessed certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons. MAIN RESULTS: We included 10 relevant studies. Seven studies were co-funded by Shin Poong Pharmaceuticals which manufactures the drug. Three studies were funded by government agencies.For efficacy analysis we identified five RCTs with 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. It included 541 children aged less than five years.For polymerase chain reaction (PCR)-adjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence), artesunate-amodiaquine (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence), and mefloquine plus artesunate (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence).For unadjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence), and probably has fewer failures compared to artesunate-amodiaquine (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence) and mefloquine plus artesunate (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence).For PCR-adjusted failures at day 42, pyronaridine-artesunate may make little or no difference compared to artemether-lumefantrine (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence) and artesunate-amodiaquine (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence), but may have higher failures than mefloquine plus artesunate (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Overall, pyronaridine-artesunate had a PCR-adjusted treatment failure rate of less than 5%.For unadjusted failures at day 42, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence), may make little or no difference compared to mefloquine plus artesunate (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence), and probably makes little or no difference compared to artesunate-amodiaquine (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence).For the safety analysis of severe adverse events and liver function, we identified eight RCTs with 6614 participants comparing pyronaridine-artesunate to other antimalarials, four of which were not in the previous version of this review. A further two RCTs, comparing pyronaridine alone to other treatments, contributed to the synthesis of all adverse events.Raised alanine aminotransferase (ALT) greater than five times the upper limit of normal (> 5 x ULN) is more frequent with pyronaridine-artesunate compared to other antimalarials (RR 3.34, 95% CI 1.63 to 6.84; 8 RCTS, 6581 participants, high-certainty evidence). There is probably little or no difference for raised bilirubin > 2.5 x ULN between pyronaridine-artesunate and other antimalarials (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate-certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin, meeting criteria for moderate drug-induced liver injury. No study reported severe drug-induced liver injury. Electrocardiograph (ECG) abnormalities were less common with pyronaridine-artesunate compared to other antimalarials. We identified no other safety concerns. AUTHORS' CONCLUSIONS: Pyronaridine-artesunate was efficacious against uncomplicated P falciparum malaria, achieved a PCR-adjusted treatment failure rate of less than 5% at days 28 and 42, and may be at least as good as, or better than other marketed ACTs.Pyronaridine-artesunate increases the risk of episodes of raised ALT > 5 x ULN. This meets criteria for mild drug-induced liver injury. On one instance this was linked to raised bilirubin, indicating moderate drug-induced liver injury. No episodes of severe drug-induced liver injury were reported. The findings of this review cannot fully inform a risk-benefit assessment for an unselected population. Readers should remain aware of this uncertainty when considering use of pyronaridine-artesunate in patients with known or suspected pre-existing liver dysfunction, and when co-administering with other medications which may cause liver dysfunction.


Assuntos
Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Malária Falciparum/tratamento farmacológico , Naftiridinas/uso terapêutico , Adulto , Amodiaquina/efeitos adversos , Amodiaquina/uso terapêutico , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Artemisininas/uso terapêutico , Artesunato/efeitos adversos , Criança , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lumefantrina/efeitos adversos , Lumefantrina/uso terapêutico , Mefloquina/efeitos adversos , Mefloquina/uso terapêutico , Naftiridinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Drugs R D ; 19(1): 1-14, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30656608

RESUMO

INTRODUCTION: Artemisinin-based combination therapies (ACTs) are the first-line antimalarial drugs used to treat uncomplicated Plasmodium falciparum alaria in many endemic countries worldwide. The present work reviewed the therapeutic efficacy of ACT in Cameroon more than 10 years after the initial change in national drug policy in 2004. METHODS: A PubMed literature search was performed to analyse clinical trials conducted in Cameroon from 2001 to May 2017. Clinical studies that evaluated ACT for the treatment of uncomplicated falciparum malaria in children or adults, and reported efficacy and/or safety, were included. In addition, a small network meta-analysis (NMA) with a frequentist approach was performed. RESULTS: Six papers were selected from 48 articles screened and were full-text reviewed. The efficacy of both artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) ranged from moderate to high, with polymerase chain reaction-corrected cure rates ranging from 96.7 to 100% and 88.2 to 100%, respectively, in per-protocol analysis, and 86.2 to 96.7% and 74.0 to 90.6%, respectively, in intention-to-treat analysis. The malaria evidence network suggested that AL and ASAQ efficacies were comparable. The highest day 3 parasite positivity rate was 8.2% for ASAQ and 4% for AL. A novel ACT, artesunate-atovaquoneproguanil (ASATPG) was tested once and showed a cure rate of 100%. Based on an ITT approach, the NMA revealed that AL was more efficacious than ASAQ, but the difference was not statistical significant (706 participants, three randomised clinical trials (RCT); OR 1.25, 95%CI 0.78-2.00). Adverse events ranged from mild to moderate severity but were not directly attributed to drug intake. CONCLUSION: ACTs are still effective and safe in Cameroon; however, there are insufficient data on their efficacy, safety and tolerability, therefore more RCTs should be conducted, including novel ACTs.


Assuntos
Amodiaquina/efeitos adversos , Amodiaquina/uso terapêutico , Combinação Arteméter e Lumefantrina/efeitos adversos , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/efeitos adversos , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Camarões , Combinação de Medicamentos , Humanos , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos
9.
J Infect Dis ; 219(7): 1112-1120, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30418593

RESUMO

BACKGROUND: In Uganda, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ) showed excellent treatment efficacy for uncomplicated malaria in prior trials. Because the frequency of resistance to artemisinins and piperaquine is increasing in Southeast Asia and the prevalence of Plasmodium falciparum polymorphisms associated with resistance has changed, we reassessed treatment efficacies at 3 sites in Uganda. METHODS: For this randomized, single-blinded clinical trial, children aged 6-59 months with uncomplicated falciparum malaria were assigned treatment with AL or DHA-PQ and followed for 42 days. Primary end points were risks of recurrent parasitemia, either unadjusted or adjusted to distinguish recrudescence from new infection. We assessed selection by study regimens of relevant P. falciparum genetic polymorphisms associated with drug resistance. RESULTS: Of 599 patients enrolled, 578 completed follow-up. There were no early treatment failures. The risk of recurrent parasitemia was lower with DHA-PQ as compared to AL at all 3 sites at 42 days (26.0% vs 47.0%; P < .001). Recrudescent infections were uncommon in both the DHA-PQ and AL arms (1.1% and 2.2%, respectively; P = .25). Neither regimen selected for pfcrt or pfmdr1 polymorphisms associated with drug resistance. CONCLUSIONS: AL and DHA-PQ remain effective for the treatment of malaria in Uganda. Neither regimen selected for genetic polymorphisms associated with drug resistance. CLINICAL TRIALS REGISTRATION: ISRCTN15793046.


Assuntos
Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Quinolinas/uso terapêutico , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/efeitos adversos , Artemisininas/efeitos adversos , Pré-Escolar , Pesquisa Comparativa da Efetividade , Combinação de Medicamentos , Resistência a Medicamentos/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Parasitemia/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Quinolinas/efeitos adversos , Recidiva , Método Simples-Cego , Uganda
10.
Trials ; 19(1): 610, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400934

RESUMO

BACKGROUND: Children hospitalised with severe anaemia in malaria endemic areas in Africa are at high risk of readmission or death within 6 months post-discharge. Currently, no strategy specifically addresses this period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment courses of artemether-lumefantrine given at discharge and at 1 and 2 months prevented 30% of all-cause readmissions by 6 months post-discharge. Another efficacy trial is needed before a policy of malaria chemoprevention can be considered for the post-discharge management of severe anaemia in children under 5 years of age living in malaria endemic areas. OBJECTIVE: We aim to determine if 3 months of PMC with monthly 3-day treatment courses of dihydroartemisinin-piperaquine is safe and superior to a single 3-day treatment course with artemether-lumefantrine provided as part of standard in-hospital care in reducing all-cause readmissions and deaths (composite primary endpoint) by 6 months in the post-discharge management of children less than 5 years of age admitted with severe anaemia of any or undetermined cause. METHODS/DESIGN: This is a multi-centre, two-arm, placebo-controlled, individually randomised trial in children under 5 years of age recently discharged following management for severe anaemia. Children in both arms will receive standard in-hospital care for severe anaemia and a 3-day course of artemether-lumefantrine at discharge. At 2 weeks after discharge, surviving children will be randomised to receive either 3-day courses of dihydroartemisinin-piperaquine at 2, 6 and 10 weeks or an identical placebo and followed for 26 weeks through passive case detection. The trial will be conducted in hospitals in malaria endemic areas in Kenya and Uganda. The study is designed to detect a 25% reduction in the incidence of all-cause readmissions or death (composite primary outcome) from 1152 to 864 per 1000 child years (power 80%, α = 0.05) and requires 520 children per arm (1040 total children). RESULTS: Participant recruitment started in May 2016 and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02671175 . Registered on 28 January 2016.


Assuntos
Anemia/tratamento farmacológico , Artemisininas/administração & dosagem , Malária/prevenção & controle , Quinolinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Artemisininas/efeitos adversos , Quimioprevenção , Pré-Escolar , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Lactente , Recém-Nascido , Quênia , Estudos Multicêntricos como Assunto , Quinolinas/efeitos adversos , Tamanho da Amostra , Uganda
11.
Expert Opin Drug Saf ; 17(11): 1129-1144, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30351243

RESUMO

INTRODUCTION: Malaria in pregnancy and postpartum cause maternal mortality and adverse fetal outcomes. Efficacious and safe antimalarials are needed to treat and prevent such serious consequences. However, because of the lack of evidence on fetal safety, quinine, an old and less efficacious drug has long been recommended for pregnant women. Uncertainty about safety in relation to breastfeeding leads to withholding of efficacious treatments postpartum or cessation of breastfeeding. Areas covered: A search identified literature on humans in three databases (MEDLINE, Embase and Global health) using pregnancy or lactation, and the names of antimalarial drugs as search terms. Adverse reactions to the mother, fetus or breastfed infant were summarized together with efficacies. Expert opinion: Artemisinins are more efficacious and well-tolerated than quinine in pregnancy. Furthermore, the risks of miscarriage, stillbirth or congenital abnormality were not higher in pregnancies exposed to artemisinin derivatives for treatment of malaria than in pregnancies exposed to quinine or in the comparable background population unexposed to any antimalarials, and this was true for treatment in any trimester. Assessment of safety and efficacy of antimalarials including dose optimization for pregnant women is incomplete. Resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum and long unprotected intervals between intermittent treatment doses begs reconsideration of current preventative recommendations in pregnancy. Data remain limited on antimalarials during breastfeeding; while most first-line drugs appear safe, further research is needed.


Assuntos
Antimaláricos/administração & dosagem , Malária/tratamento farmacológico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Antimaláricos/efeitos adversos , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Aleitamento Materno , Feminino , Humanos , Recém-Nascido , Lactação , Malária/complicações , Malária/prevenção & controle , Gravidez , Quinina/administração & dosagem , Quinina/efeitos adversos
12.
Trials ; 19(1): 558, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30326952

RESUMO

BACKGROUND: Malaria remains a critical public health problem in Southeast Asia despite intensive containment efforts. The continued spread of multi-drug-resistant Plasmodium falciparum has led to calls for malaria elimination on the Thai-Cambodian border. However, the optimal approach to elimination in difficult-to-reach border populations, such as the Military, remains unclear. METHODS/DESIGN: A two-arm, cluster-randomized controlled, open-label pilot study is being conducted in military personnel and their families at focal endemic areas on the Thai-Cambodian border. The primary objective is to compare the effectiveness of monthly malaria prophylaxis (MMP) with dihydroartemisinin-piperaquine and weekly primaquine for 12 weeks compared with focused screening and treating (FSAT) following current Cambodian national treatment guidelines. Eight separate military encampments, making up approximately 1000 military personnel and their families, undergo randomization to the MMP or FSAT intervention for 3 months, with an additional 3 months' follow-up. In addition, each treatment cluster of military personnel and civilians is also randomly assigned to receive either permethrin- or sham (water)-treated clothing in single-blind fashion. The primary endpoint is risk reduction for malaria infection in geographically distinct military encampments based on their treatment strategy. Monthly malaria screening in both arms is done via microscopy, PCR, and rapid diagnostic testing to compare both the accuracy and cost-effectiveness of diagnostic modalities to detect asymptomatic infection. Universal glucose-6-phosphate dehydrogenase (G6PD) deficiency screening is done at entry, comparing the results from a commercially available rapid diagnostic test, the fluorescence spot test, and quantitative testing for accuracy and cost-effectiveness. The comparative safety of the interventions chosen is also being evaluated. DISCUSSION: Despite the apparent urgency, the key operational elements of proposed malaria elimination strategies in Southeast Asian mobile and migrant populations, including the Military, have yet to be rigorously tested in a well-controlled clinical study. Here, we present a protocol for the primary evaluation of two treatment paradigms - monthly malaria prophylaxis and focused screening and treatment - to achieve malaria elimination in a Cambodian military population. We will also assess the feasibility and incremental benefit of outdoor-biting vector intervention - permethrin-treated clothing. In the process, we aim to define the cost-effectiveness of the inputs required for success including a responsive information system, skilled human resource and laboratory infrastructure requirements, and quality management. Despite being a relatively low transmission area, the complexities of multi-drug-resistant malaria and the movement of vulnerable populations require an approach that is not only technically sound, but simple enough to be achievable. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02653898 . Registered on 13 January 2016.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Erradicação de Doenças/métodos , Malária Falciparum/prevenção & controle , Programas de Rastreamento/métodos , Medicina Militar , Militares , Plasmodium falciparum/efeitos dos fármacos , Primaquina/administração & dosagem , Quinolinas/administração & dosagem , Adolescente , Adulto , Idoso , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Camboja , Criança , Pré-Escolar , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Inseticidas , Malária Falciparum/diagnóstico , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Masculino , Pessoa de Meia-Idade , Controle de Mosquitos/métodos , Projetos Piloto , Plasmodium falciparum/patogenicidade , Valor Preditivo dos Testes , Primaquina/efeitos adversos , Roupa de Proteção , Quinolinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
13.
Malar J ; 17(1): 369, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30333022

RESUMO

BACKGROUND: Artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment of uncomplicated malaria in most malaria endemic countries, including Tanzania. Unfortunately, there have been reports of artemisinin resistance and ACT failure from South East Asia highlighting the need to monitor therapeutic efficacy of ACT in these countries as recommended by World Health Organization. METHODS: Open-label single arm studies in mainland Tanzania were conducted in nine sentinel sites in 2011, 2012 and 2015 to assess the efficacy and safety of artemether/lumefantrine (AL) and artesunate/amodiaquine (ASAQ) using 28 days follow-up and dihydroartemisinin/piperaquine (DHAPQ) using 42 days follow-up. Mutations in the propeller domain of the Plasmodium falciparum kelch 13 (k13) gene and amplification of the P. falciparum plasmepsin 2 (pm2) gene, associated with artemisinin and piperaquine (PQ) resistance, were also investigated. RESULTS: Of the 428 patients enrolled, 328 patients provided study endpoint. For AL, the PCR corrected per-protocol analysis showed adequate clinical and parasitological response (ACPR) of 90.3% (n = 28; 95% CI 74.2-98.0) in Kyela 2012, 95.7% (n = 22; 95% CI 78.1-99.0) in Chamwino, 100% in Muheza (n = 29; 95% CI 88.1-100), 100% in Nagaga (n = 39; 95% CI 91.0-100) and Kyela 2015 (n = 60; 95% CI 94.0-100). For ASAQ, PCR corrected ACPR of 98% (n = 49; 95% CI 89.4-99.9) and 100% (n = 25; 95% CI 86.3-100) were observed in 2011 in Ujiji and Kibaha, respectively. For DHAPQ, the ACPR was 100% (n = 71; 95% CI 94.9-100). Of the 235 samples with genetic interpretable results, only 7 (3%) had non-synonymous k13 mutations. None of these are candidate or validated markers of artemisinin resistance and all patients carrying these alleles cleared the parasites on day 3. Of the DHAPQ group, 10% (3/29) of the samples with interpretable results had pm2 multiple copies and none of them was associated with treatment failure. CONCLUSION: All the tested ACT in mainland Tanzania were highly efficacious and none of validated k13 mutants associated with artemisinin resistance was observed. However, three isolates with multiple copy numbers of pm2 gene associated with PQ resistance among the limited samples tested successfully calls for further investigation. Trial registration Number ACTRN12615000159550. Registered 18th February 2015, https://www.anzctr.org.au/trial/MyTrial.aspx.


Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/prevenção & controle , Quinolinas/uso terapêutico , Adolescente , Amodiaquina/efeitos adversos , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/efeitos adversos , Artemisininas/efeitos adversos , Criança , Pré-Escolar , Combinação de Medicamentos , Feminino , Humanos , Lactente , Masculino , Plasmodium falciparum/efeitos dos fármacos , Estudos Prospectivos , Quinolinas/efeitos adversos , Tanzânia
14.
Artigo em Inglês | MEDLINE | ID: mdl-30249696

RESUMO

Mass drug administration (MDA) of sequential rounds of antimalarial drugs is being considered for use as a tool for malaria elimination. As an effective and long-acting antimalarial, dihydroartemisinin-piperaquine (DHA-PQP) appears to be suitable as a candidate for MDA. However, the absence of cardiac safety data following repeated administration hinders its use in the extended schedules proposed for MDA. We conducted an interventional study in Lihir Island, Papua New Guinea, using healthy individuals age 3 to 60 years who received a standard 3-day course of DHA-PQP on 3 consecutive months. Twelve-lead electrocardiography (ECG) readings were conducted predose and 4 h after the final dose of each month. The primary safety endpoint was QT interval correction (QTc using Fridericia's correction [QTcF]) prolongation from baseline to 4 h postdosing. We compared the difference in prolongations between the third course postdose and the first course postdose. Of 84 enrolled participants, 69 (82%) participants completed all treatment courses and ECG measurements. The average increase in QTcF was 19.6 ms (standard deviation [SD], 17.8 ms) and 17.1 ms (SD, 17.1 ms) for the first-course and third-course postdosing ECGs risk difference, -2.4 (95% confidence interval [95% CI], -6.9 to 2.1; P = 0.285), respectively. We recorded a QTcF prolongation of >60 ms from baseline in 3 (4.3%) and 2 (2.9%) participants after the first course and third course (P = 1.00), respectively. No participants had QTcF intervals of >500 ms at any time point. Three consecutive monthly courses of DHA-PQP were as safe as a single course. The absence of cumulative cardiotoxicity with repeated dosing supports the use of monthly DHA-PQP as part of malaria elimination strategies.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Síndrome do QT Longo/diagnóstico , Malária Falciparum/prevenção & controle , Malária Vivax/prevenção & controle , Malária/prevenção & controle , Quinolinas/administração & dosagem , Adolescente , Adulto , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Criança , Pré-Escolar , Esquema de Medicação , Combinação de Medicamentos , Eletrocardiografia , Feminino , Voluntários Saudáveis , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Masculino , Administração Massiva de Medicamentos , Pessoa de Meia-Idade , Papua Nova Guiné , Segurança do Paciente , Estudos Prospectivos , Quinolinas/efeitos adversos
15.
Curr Rheumatol Rep ; 20(9): 55, 2018 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-30056574

RESUMO

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a complex, potentially fatal autoimmune disease with no complete cure. Current treatments for SLE are limited by suboptimal efficacy and increased risk of infections and malignancies, and cannot meet the clinical demands of patients with SLE. Artemisinin and its derivatives (artemisinins), a new class of anti-malarial drugs, have recently been reported to have an immunosuppressive effect on lupus patients. In this review, we evaluate the therapeutic properties and potential mechanisms of artemisinins for the treatment of SLE. RECENT FINDINGS: Both clinical and animal studies suggest that artemisinins have potential beneficial effects for SLE. The beneficial effects associated with artemisinin treatment include improving symptoms, reducing level of antibodies and proteinuria, ameliorating renal damage, and diminishing the dosage of prednisone use. Animal studies suggest that mechanisms of action of artemisinins may include regulating T cell subsets, inhibiting activation of B cells and production of inflammatory cytokines, as well as blocking the NF-κB signal transduction pathway, thus playing a role in anti-inflammation and immunomodulation. Artemisinin family drugs are a promising potential new medication that may challenge the current treatment paradigms available for SLE.


Assuntos
Artemisininas/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Artemisininas/efeitos adversos , Artesunato/efeitos adversos , Artesunato/uso terapêutico , Modelos Animais de Doenças , Humanos , Imunossupressores/efeitos adversos , Camundongos
16.
PLoS Med ; 15(7): e1002606, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30016328

RESUMO

BACKGROUND: Intermittent preventive treatment of malaria in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) has been shown to reduce the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (IPTp-SP). However, limited data exist on how IPTp regimens impact malaria risk during infancy. We conducted a double-blinded randomized controlled trial (RCT) to test the hypothesis that children born to mothers given IPTp-DP would have a lower incidence of malaria during infancy compared to children born to mothers who received IPTp-SP. METHODS AND FINDINGS: We compared malaria metrics among children in Tororo, Uganda, born to women randomized to IPTp-SP given every 8 weeks (SP8w, n = 100), IPTp-DP every 8 weeks (DP8w, n = 44), or IPTp-DP every 4 weeks (DP4w, n = 47). After birth, children were given chemoprevention with DP every 12 weeks from 8 weeks to 2 years of age. The primary outcome was incidence of malaria during the first 2 years of life. Secondary outcomes included time to malaria from birth and time to parasitemia following each dose of DP given during infancy. Results are reported after adjustment for clustering (twin gestation) and potential confounders (maternal age, gravidity, and maternal parasitemia status at enrolment).The study took place between June 2014 and May 2017. Compared to children whose mothers were randomized to IPTp-SP8w (0.24 episodes per person year [PPY]), the incidence of malaria was higher in children born to mothers who received IPTp-DP4w (0.42 episodes PPY, adjusted incidence rate ratio [aIRR] 1.92; 95% CI 1.00-3.65, p = 0.049) and nonsignificantly higher in children born to mothers who received IPT-DP8w (0.30 episodes PPY, aIRR 1.44; 95% CI 0.68-3.05, p = 0.34). However, these associations were modified by infant sex. Female children whose mothers were randomized to IPTp-DP4w had an apparently 4-fold higher incidence of malaria compared to female children whose mothers were randomized to IPTp-SP8w (0.65 versus 0.20 episodes PPY, aIRR 4.39, 95% CI 1.87-10.3, p = 0.001), but no significant association was observed in male children (0.20 versus 0.28 episodes PPY, aIRR 0.66, 95% CI 0.25-1.75, p = 0.42). Nonsignificant increases in malaria incidence were observed among female, but not male, children born to mothers who received DP8w versus SP8w. In exploratory analyses, levels of malaria-specific antibodies in cord blood were similar between IPTp groups and sex. However, female children whose mothers were randomized to IPTp-DP4w had lower mean piperaquine (PQ) levels during infancy compared to female children whose mothers received IPTp-SP8w (coef 0.81, 95% CI 0.65-1.00, p = 0.048) and male children whose mothers received IPTp-DP4w (coef 0.72, 95% CI 0.57-0.91, p = 0.006). There were no significant sex-specific differences in PQ levels among children whose mothers were randomized to IPTp-SP8w or IPTp-DP8w. The main limitations were small sample size and childhood provision of DP every 12 weeks in infancy. CONCLUSIONS: Contrary to our hypothesis, preventing malaria in pregnancy with IPTp-DP in the context of chemoprevention with DP during infancy does not lead to a reduced incidence of malaria in childhood; in this setting, it may be associated with an increased incidence of malaria in females. Future studies are needed to better understand the biological mechanisms of in utero drug exposure on drug metabolism and how this may affect the dosing of antimalarial drugs for treatment and prevention during infancy. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02163447.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Malária Falciparum/prevenção & controle , Complicações Parasitárias na Gravidez/prevenção & controle , Pirimetamina/administração & dosagem , Quinolinas/administração & dosagem , Sulfadoxina/administração & dosagem , Adolescente , Adulto , Antimaláricos/efeitos adversos , Artemisininas/efeitos adversos , Pré-Escolar , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Gravidez , Complicações Parasitárias na Gravidez/epidemiologia , Complicações Parasitárias na Gravidez/parasitologia , Pirimetamina/efeitos adversos , Quinolinas/efeitos adversos , Sulfadoxina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Uganda/epidemiologia , Adulto Jovem
17.
Lancet Infect Dis ; 18(8): 913-923, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29887371

RESUMO

BACKGROUND: Dihydroartemisinin-piperaquine is an effective and well tolerated artemisinin-based combination therapy that has been assessed extensively for the prevention and treatment of malaria. Piperaquine, similar to several structurally related antimalarials currently used, can prolong cardiac ventricular repolarisation duration and the electrocardiographic QT interval, leading to concerns about its proarrhythmic potential. We aimed to assess the risk of potentially lethal iatrogenic ventricular arrhythmias in individuals receiving dihydroartemisinin-piperaquine. METHODS: We did a systematic review and Bayesian meta-analysis. We searched clinical bibliographic databases (last on May 24, 2017) for studies of dihydroartemisinin-piperaquine in human beings. Further unpublished studies were identified with the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials. We searched for articles containing "dihydroartemisinin-piperaquine" as title, abstract, or subject heading keywords, with synonyms and variant spellings as additional search terms. We excluded animal studies, but did not apply limits on language or publication date. Eligible studies were prospective, randomised, controlled trials or cohort studies in which individuals received at least one 3-day treatment course of dihydroartemisinin-piperaquine for mass drug administration, preventive therapy, or case management of uncomplicated malaria, with follow-up over at least 3 days. At least two independent reviewers screened titles, abstracts, and full texts, agreed study eligibility, and extracted information about study and participant characteristics, adverse event surveillance methodology, dihydroartemisinin-piperaquine exposures, loss-to-follow up, and any deaths after dihydroartemisinin-piperaquine treatment into a standardised database. The risk of sudden unexplained death after dihydroartemisinin-piperaquine with 95% credible intervals (CI) generated by Bayesian meta-analysis was compared with the baseline rate of sudden cardiac death. FINDINGS: Our search identified 94 eligible primary studies including data for 197 867 individuals who had received dihydroartemisinin-piperaquine: 154 505 in mass drug administration programmes; 15 188 in 14 studies of repeated courses in preventive therapies and case management of uncomplicated malaria; and 28 174 as single-course treatments of uncomplicated malaria in 76 case-management studies. There was one potentially drug-related sudden unexplained death: a healthy woman aged 16 in Mozambique who developed heart palpitations several hours after the second dose of dihydroartemisinin-piperaquine and collapsed and died on the way to hospital (no autopsy or ECG was done). The median pooled risk estimate of sudden unexplained death after dihydroartemisinin-piperaquine was 1 in 757 950 (95% CI 1 in 2 854 490 to 1 in 209 114). This risk estimate was not higher than the baseline rate of sudden cardiac death (0·7-11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835 over a 30-day risk period). The risk of bias was low in most studies and unclear in a few. INTERPRETATION: Dihydroartemisinin-piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death. Concerns about repolarisation-related cardiotoxicity need not limit its current use for the prevention and treatment of malaria. FUNDING: Wellcome Trust, UK Medical Research Council, WHO, Bill & Melinda Gates Foundation, and University of Oxford.


Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Quimioterapia Combinada/mortalidade , Malária/tratamento farmacológico , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Adolescente , Animais , Teorema de Bayes , Causas de Morte , Estudos de Coortes , Feminino , Humanos , Moçambique , Estudos Prospectivos
18.
Travel Med Infect Dis ; 24: 23-24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29715560

RESUMO

In scientific discourse, few would consider the widely used term resistance as ambiguous. The definition and usage of the term antimicrobial resistance revolves around the concept that microorganisms change in ways that render antimicrobial medications clinically ineffective. Because artemisinins have become the cornerstone for antimalarial therapy, the widely used term artemisinin resistance in scientific literature is highly alarming. Naturally, many people will assume that artemisinin resistance must essentially be the same as antimicrobial resistance, which means it is clinically ineffective. However, this is incorrect, and the WHO defines artemisinin resistance differently to antimicrobial resistance as "partial/relative resistance". This means that parasite clearance times are increased but does not automatically mean that artemisinins have become clinically inefficacious. Is the ambiguous use of the term resistance justified and appropriate, although it might be misleading biomedical researchers, the media, policy makers and possibly attending physicians? Science is also about clear and unambiguous use of terminology, so that a message is accurately communicated and understood. Ambiguity can lead to misunderstandings, and misunderstandings can cause wrong actions; unnecessarily so.


Assuntos
Antimaláricos/farmacologia , Artemisininas/efeitos adversos , Artemisininas/farmacologia , Resistência a Medicamentos , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Organização Mundial da Saúde
19.
Artigo em Inglês | MEDLINE | ID: mdl-29760133

RESUMO

There are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus-infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared the area under the concentration-time curve from 0 to 28 days (AUC0-28) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy-naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria-uninfected adults (n = 6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort (n = 25/arm) received the full regimen. In step 1, there were no safety signals or significant differences in desethylamodiaquine AUC0-28 among participants in the ritonavir-boosted lopinavir, nevirapine, and antiretroviral therapy-naive arms. In step 2, compared with those in the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC0-28, with the following geometric means (95% confidence intervals [CIs]): 23,822 (17,458 to 32,506) versus 48,617 (40,787 to 57,950) ng · h/ml (P < 0.001). No significant differences in AUC0-28 were observed between nevirapine and antiretroviral therapy-naive arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy-naive (0.0% [0/25]) arm (risk difference, 20% [95% CI, 4.3 to 35.7]; P = 0.018). The ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure, which may compromise artesunate-amodiaquine's efficacy. Coadministration of nevirapine and artesunate-amodiaquine may be associated with hepatoxicity.


Assuntos
Amodiaquina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Artemisininas/efeitos adversos , Artemisininas/farmacocinética , Infecções por HIV/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Adulto , Amodiaquina/efeitos adversos , Amodiaquina/farmacocinética , Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Lopinavir/uso terapêutico , Malaui , Masculino , Nevirapina/uso terapêutico , Ritonavir/uso terapêutico
20.
Parasite ; 25: 24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29676250

RESUMO

The use of artemisinin-based combination therapies (ACTs), which combine an artemisinin derivative with a partner drug, in the treatment of uncomplicated malaria has largely been responsible for the significant reduction in malaria-related mortality in tropical and subtropical regions. ACTs have also played a significant role in the 18% decline in the incidence of malaria cases from 2010 to 2016. However, this progress is seriously threatened by the reduced clinical efficacy of artemisinins, which is characterised by delayed parasitic clearance and a high rate of recrudescence, as reported in 2008 in Western Cambodia. Resistance to artemisinins has already spread to several countries in Southeast Asia. Furthermore, resistance to partner drugs has been shown in some instances to be facilitated by pre-existing decreased susceptibility to the artemisinin component of the ACT. A major concern is not only the spread of these multidrug-resistant parasites to the rest of Asia but also their possible appearance in Sub-Saharan Africa, the continent most affected by malaria, as has been the case in the past with parasite resistance to other antimalarial treatments. It is therefore essential to understand the acquisition of resistance to artemisinins by Plasmodium falciparum to adapt malaria treatment policies and to propose new therapeutic solutions.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Resistência a Múltiplos Medicamentos , Quimioterapia Combinada/efeitos adversos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , África ao Sul do Saara/epidemiologia , Antimaláricos/farmacologia , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Artemisininas/farmacologia , Ásia/epidemiologia , Ásia Sudeste/epidemiologia , Camboja/epidemiologia , Ensaios Clínicos como Assunto , Erradicação de Doenças/legislação & jurisprudência , Erradicação de Doenças/métodos , Humanos , Malária/tratamento farmacológico , Malária/epidemiologia , Malária/parasitologia , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia
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