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1.
Lakartidningen ; 1172020 04 23.
Artigo em Sueco | MEDLINE | ID: mdl-32365215

RESUMO

Hydroxychloroquine and chloroquine are currently being evaluated as treatment against COVID-19. These drugs are associated with some potential harms, including QTc-interval prolongation, hypoglycaemia, severe skin reactions and psychiatric effects. Use of hydroxychloroquine or chloroquine should be reserved to current indications or clinical trials, as recommended by several governmental medical products agencies.


Assuntos
Aminoquinolinas/efeitos adversos , Antivirais/efeitos adversos , Cloroquina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Pneumonia Viral/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Antimaláricos/efeitos adversos , Betacoronavirus , Humanos , Pandemias
2.
Orv Hetil ; 161(17): 689-691, 2020 04 01.
Artigo em Húngaro | MEDLINE | ID: mdl-32324363

RESUMO

Hydroxychloroquine is an immunomodulatory drug that has been used to treat malaria and autoimmune diseases such as systemic lupus erythematosus and inflammatory arthritis. The authors conclude the proarrhytmic effects of hydroxychloroquine and the most important signs of drug-induced long QT syndrome. This article is especially relevant and timely due to the more frequent (currently not evidence-based) use of the drug during the 2019­2020 coronavirus pandemic. Orv Hetil. 2020; 161(17): 689­691.


Assuntos
Antivirais , Infecções por Coronavirus/tratamento farmacológico , Coronavirus , Hidroxicloroquina/efeitos adversos , Síndrome do QT Longo , Pneumonia Viral/tratamento farmacológico , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Betacoronavirus , Eletrocardiografia , Humanos , Hidroxicloroquina/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , Pandemias , Risco
5.
Emerg Microbes Infect ; 9(1): 830-832, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32338155

RESUMO

The current pandemic coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) calls urgently for effective therapies. Anti-malarial medicine chloroquine (CQ) and particularly its chemical analogue hydroxychloroquine (HCQ) have been recommended as promising candidate therapeutics that are now under either compassionate off-label use or clinical trials for the treatment of COVID-19 patients. However, there are public concerns and disputes about both the safety and efficacy of CQ and HCQ for this new application. Given the fact that for decades HCQ has been approved as an immunomodulatory drug for the long term treatment of chronic rheumatic diseases, as experienced rheumatologists, we would like to share our thoughts in this regard and trigger a brainstorm among clinical care providers for exchanging their diverse opinions on this urgent topic.


Assuntos
Antimaláricos , Antirreumáticos , Antivirais , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina , Pneumonia Viral/tratamento farmacológico , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Comunicação Interdisciplinar , Pandemias , Pneumonia Viral/epidemiologia , Reumatologistas
6.
J Toxicol Environ Health B Crit Rev ; 23(4): 177-181, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32281481

RESUMO

As a result of the 2019 coronavirus disease pandemic (COVID-19), there has been an urgent worldwide demand for treatments. Due to factors such as history of prescription for other infectious diseases, availability, and relatively low cost, the use of chloroquine (CQ) and hydroxychloroquine (HCQ) has been tested in vivo and in vitro for the ability to inhibit the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, even though investigators noted the therapeutic potential of these drugs, it is important to consider the toxicological risks and necessary care for rational use of CQ and HCQ. This study provides information on the main toxicological and epidemiological aspects to be considered for prophylaxis or treatment of COVID-19 using CQ but mainly HCQ, which is a less toxic derivative than CQ, and was shown to produce better results in inhibiting proliferation of SARS-CoV-2 based upon preliminary tests.


Assuntos
Antimaláricos/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antimaláricos/efeitos adversos , Antirreumáticos/efeitos adversos , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Humanos , Hidroxicloroquina/efeitos adversos , Pandemias
10.
N Z Med J ; 133(1508): 123-126, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31945049

RESUMO

Methotrexate monotherapy is a common management strategy in rheumatoid arthritis (RA). Treatment with immunosuppression can lead to opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP). The treatment options for PJP include cotrimoxazole, clindamycin-primaquine and dapsone. Though these drugs are generally well tolerated, they can result in potentially severe adverse effects. Sometimes several undesired events may occur in a single patient, reminding us of Murphy's law. Herein, we report a case which exemplifies this adage. A 50-year-old female developed PJP, while on methotrexate therapy for RA and was treated with cotrimoxazole. The latter resulted in painful peripheral neuropathy, which improved after cotrimoxazole was stopped. Salvage therapy for PJP with primaquine-clindamycin, lead to another serious adverse event, methemoglobinemia. Withdrawing the offending drug resulted in dramatic improvement.


Assuntos
Aplicação da Lei/métodos , Metemoglobinemia/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Pneumonia por Pneumocystis/tratamento farmacológico , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Clindamicina/efeitos adversos , Clindamicina/uso terapêutico , Dapsona/efeitos adversos , Dapsona/uso terapêutico , Quimioterapia Combinada/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Pneumonia por Pneumocystis/complicações , Primaquina/efeitos adversos , Primaquina/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Suspensão de Tratamento
11.
PLoS One ; 14(12): e0225882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856172

RESUMO

BACKGROUND: The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial drugs is a key component of malaria control and elimination. The published randomized trials that assessed comparisons of ACTs for treating uncomplicated falciparum malaria reported conflicting results in treatment efficacy. A network meta-analysis is an extension of pairwise meta-analysis that can synthesize evidence simultaneously from both direct and indirect treatment comparisons. The objective was to synthesize evidence on the comparative efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region. METHODS: Relevant randomized trials that assessed efficacy of antimalarial drugs for patients having uncomplicated falciparum malaria in Asian region were searched in health-related databases. We evaluated the methodological quality of the included studies with the Cochrane risk of bias tool. Main outcome was treatment success at day 28 as determined by the absence of parasiteamia. We performed network meta-analysis of the interventions in the trials, and assessed the overall quality of evidence using the GRADE approach. RESULTS: Seventeen randomized trials (n = 5043) were included in this network meta-analysis study. A network geometry was formed with 14 antimalarial treatment options such as artemether-lumefantrine (AL), artemisinin-piperaquine, artesunate-amodiaquine, artesunate-mefloquine (ASMQ), artesunate-chloroquine, artesunate-mefloquine home treatment, artesunate-mefloquine 2-day course, artesunate plus sulfadoxine-pyrimethamine, chloroquine, dihydroartemisinin-piperaquine (DHP), dihydroartemisinin-piperaquine home treatment, dihydroartemisinin-piperaquine 4-day course, dihydroartemisinin-piperaquine and added artesunate, sulfadoxine-pyrimethamine. A maximum number of trials included was DHP compared to ASMQ (n = 5). In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8). There is low certainty evidence due to limited number of studies and small trials. DISCUSSION/ CONCLUSIONS: The findings suggest the superiority of DHP (3-day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. For substantiation, well-designed larger trials from endemic countries are needed. In the light of benefit versus harm concept, future analysis with safety information is recommended.


Assuntos
Antimaláricos/uso terapêutico , Bases de Dados Factuais , Resistência a Medicamentos/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Antimaláricos/efeitos adversos , Ásia , Humanos , Malária Falciparum/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
PLoS Negl Trop Dis ; 13(11): e0007890, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751347

RESUMO

Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM-1.14 µM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at study day 3 from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.


Assuntos
Antimaláricos/administração & dosagem , Antivirais/administração & dosagem , Doença pelo Vírus Ebola/prevenção & controle , Naftiridinas/administração & dosagem , Animais , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Antivirais/efeitos adversos , Antivirais/farmacocinética , Citocinas/imunologia , Reposicionamento de Medicamentos , Ebolavirus/efeitos dos fármacos , Ebolavirus/genética , Ebolavirus/fisiologia , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naftiridinas/efeitos adversos , Naftiridinas/farmacocinética
13.
Malar J ; 18(1): 340, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31590661

RESUMO

BACKGROUND: G6PD enzyme deficiency is a common enzymatic X-linked disorder. Deficiency of the G6PD enzyme can cause free radical-mediated oxidative damage to red blood cells, leading to premature haemolysis. Treatment of Plasmodium vivax malaria with primaquine poses a potential risk of mild to severe acute haemolytic anaemia in G6PD deficient people. In this study, the prevalence and distribution of G6PD mutations were investigated across broad areas of Ethiopia, and tested the association between G6PD genotype and phenotype with the goal to provide additional information relevant to the use of primaquine in malaria treatment. METHODS: This study examined G6PD mutations in exons 3-11 for 344 febrile patient samples collected from seven sites across Ethiopia. In addition, the G6PD enzyme level of 400 febrile patient samples from Southwestern Ethiopia was determined by the CareStart™ biosensor. The association between G6PD phenotype and genotype was examined by Fisher exact test on a subset of 184 samples. RESULTS: Mutations were observed at three positions of the G6PD gene. The most common G6PD mutation across all sites was A376G, which was detected in 21 of 344 (6.1%) febrile patients. Thirteen of them were homozygous and eight were heterozygous for this mutation. The G267+119C/T mutation was found in 4 (1.2%) individuals in South Ethiopia, but absent in other sites. The G1116A mutation was also found in 4 (1.2%) individuals from East and South Ethiopia. For the 400 samples in the south, 17 (4.25%) were shown to be G6PD-deficient. G6PD enzyme level was not significantly different by age or gender. Among a subset of 202 febrile patients who were diagnosed with malaria, 11 (5.45%) were G6PD-deficient. These 11 infected samples were diagnosed with Plasmodium vivax by microscopy. Parasitaemia was not significantly different between the G6PD-deficient and G6PD-normal infections. CONCLUSIONS: The prevalence of G6PD deficiency is modest among febrile patients in Ethiopia. G6PD deficiency testing is thus recommended before administrating primaquine for radical cure of P. vivax infected patients. The present study did not indicate a significant association between G6PD gene mutations and enzyme levels.


Assuntos
Antimaláricos/uso terapêutico , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Malária Vivax/prevenção & controle , Primaquina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimaláricos/efeitos adversos , Criança , Pré-Escolar , Etiópia/epidemiologia , Feminino , Genótipo , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Primaquina/efeitos adversos , Adulto Jovem
14.
Rev Soc Bras Med Trop ; 52: e20190163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618306

RESUMO

Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated malaria. Currently, there appears to be a downward trend in the efficacy of ACT in some parts of sub-Saharan Africa because some patients have been positive for Plasmodium parasite 3 days after artemether-lumefantrine treatment. We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.


Assuntos
Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Adulto , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Tratamento , Adulto Jovem
15.
BMC Vet Res ; 15(1): 314, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477120

RESUMO

BACKGROUND: Malarone® is a drug used for the treatment of malaria in humans. This drug is also particularly effective in the treatment of canine Babesia gibsoni infections. Malarone® is rarely used in dogs, and its adverse effects have not been widely reported. Its mechanism of action is related to the inhibition of cytochrome b and electron transport in the cell. This is the first known report of the development of acute pancreatitis and alopecia in a dog following the administration of Malarone®. CASE PRESENTATION: A 3-year-old, intact, female Maltese was referred to our clinic with intermittent vomiting and sudden, generalized alopecia. Two months previously, the dog had been prescribed Malarone® for the treatment of a suspected B. gibsoni infection. The dog was evaluated using hematology, radiography, ultrasonography, a PCR for Babesia detection, and a canine pancreatic lipase immunoreactivity (cPLI) assay. The result of the PCR test was negative, whereas the cPLI assay yielded a positive result. Dermatologic examination revealed bacterial infection with hair cycle arrest. CONCLUSIONS: Based on these findings, drug-induced acute pancreatitis and alopecia with superficial pyoderma were diagnosed. Malarone® may induce severe adverse reactions in dogs. Therefore, careful monitoring for adverse effects is required when using Malarone® in dogs.


Assuntos
Alopecia/veterinária , Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Doenças do Cão/induzido quimicamente , Pancreatite/veterinária , Proguanil/efeitos adversos , Alopecia/induzido quimicamente , Animais , Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Babesiose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Cães , Combinação de Medicamentos , Feminino , Pancreatite/induzido quimicamente , Proguanil/uso terapêutico
16.
Malar J ; 18(1): 260, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362736

RESUMO

BACKGROUND: Despite recent strides made towards reducing the emergence of artemisinin resistance, inappropriate dispensing practices for anti-malarials in both private and public sectors affect treatment outcomes negatively. In Ghana, private retail pharmacies are the most accessible health facilities for managing diseases of common occurrence. However, there is growing concern about the number of patients harmed by dispensing errors in the management of malaria in retail pharmacies. Although considerable work has been done in this area, several questions regarding dispensing practices remain unanswered. This study, therefore, sought to investigate the predictors of appropriate dispensing practices for anti-malarials in community pharmacies in the La Nkwantanang-Madina municipality of Greater Accra, Ghana. METHODS: A cross-sectional analytic study was conducted in sixty-one randomly selected community pharmacies in the La Nkwantanang-Madina. Data from 230 clients and 106 dispensers were analysed. It was checked for internal consistency and completeness then entered and analysed using STATA I/C version 14.0. Frequencies, Chi square tests, and logistic regression analyses were conducted, accounting for clustering. RESULTS AND DISCUSSION: Of the 106 dispensers interviewed, 71.4% were medicine counter assistants. The mean age of dispensers was 30.4 years (SD 8.8). Over 88.0% of clients were advised to complete the full course of their anti-malarials. However, the 8-h loading dose principle for artemether-lumefantrine was not explained to 88.3% of the clients. More than half of the clients (52.2%) were given appropriate dispensing information on anti-malarial use. Most clients (66.1%), were dispensed anti-malarials without malaria tests. Dispensers with more than a 10-years experience were less likely to dispense artemisinin-based combinations appropriately relative to dispensers with less than 2 years experience (AOR = 0.04, 95% CI 0.002-0.802 p-value = 0.036) while pharmacy interns were about 19 times more likely (AOR = 18.5, 95% CI 1.40-245.6 p-value = 0.03) to dispense artemisinin-based combinations appropriately compared to pharmacists. CONCLUSION: Dispensing practices for anti-malarials is unsatisfactory. There is a need to enforce existing legislation with educational programmes directed towards dispensers especially those with more than 10 years experience. Specific adherence to the World Health Organization Test, Treat and Track initiative should be encouraged to ensure effective use of anti-malarials.


Assuntos
Antimaláricos/efeitos adversos , Competência Clínica/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Farmácias/estatística & dados numéricos , Farmacêuticos/psicologia , Adulto , Idoso , Estudos Transversais , Feminino , Gana , Humanos , Masculino , Pessoa de Meia-Idade , Farmacêuticos/estatística & dados numéricos , Adulto Jovem
17.
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
18.
Malar J ; 18(1): 291, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455339

RESUMO

BACKGROUND: The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice. METHODS: Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P. yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 h to 5½ months after injection. RESULTS: A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 h) and sustained (4-5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration versus time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60-80 nM). CONCLUSIONS: Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.


Assuntos
Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Plasmodium yoelii/efeitos dos fármacos , Quinolonas/efeitos adversos , Quinolonas/farmacocinética , Animais , Feminino , Camundongos , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética
19.
BMC Med ; 17(1): 151, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31366382

RESUMO

BACKGROUND: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. METHODS: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. RESULTS: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. CONCLUSIONS: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. TRIAL REGISTRATION: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.


Assuntos
Anemia Hemolítica/etiologia , Antimaláricos/efeitos adversos , Malária Vivax/complicações , Malária Vivax/tratamento farmacológico , Primaquina/efeitos adversos , Adulto , Cloroquina/uso terapêutico , Feminino , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Hemólise/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Plasmodium vivax/efeitos dos fármacos
20.
Lancet ; 394(10202): 929-938, 2019 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-31327563

RESUMO

BACKGROUND: Primaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria. METHODS: We did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics (two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivax parasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683). FINDINGS: Between July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivax malaria was 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (-0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatment were reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group). INTERPRETATION: In patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria. FUNDING: UK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404).


Assuntos
Antimaláricos/administração & dosagem , Malária Vivax/tratamento farmacológico , Primaquina/administração & dosagem , Adolescente , Adulto , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Criança , Pré-Escolar , Método Duplo-Cego , Esquema de Medicação , Estudos de Equivalência como Asunto , Feminino , Seguimentos , Humanos , Malária Vivax/parasitologia , Masculino , Adesão à Medicação/estatística & dados numéricos , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Plasmodium vivax/isolamento & purificação , Primaquina/efeitos adversos , Primaquina/uso terapêutico , Recidiva , Prevenção Secundária/métodos , Adulto Jovem
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