Assuntos
Pustulose Exantematosa Aguda Generalizada , Antimaláricos , Malária Falciparum , Malária , Pustulose Exantematosa Aguda Generalizada/diagnóstico , Pustulose Exantematosa Aguda Generalizada/tratamento farmacológico , Pustulose Exantematosa Aguda Generalizada/etiologia , Antimaláricos/uso terapêutico , Atovaquona/efeitos adversos , Combinação de Medicamentos , Humanos , Malária/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Proguanil/efeitos adversosAssuntos
Proguanil , Atovaquona , Combinação de Medicamentos , Feminino , Humanos , Lactente , Gravidez , Proguanil/efeitos adversos , Estudos RetrospectivosAssuntos
Proguanil , Atovaquona , Combinação de Medicamentos , Feminino , Humanos , Lactente , Gravidez , Proguanil/efeitos adversos , Estudos RetrospectivosRESUMO
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 terapêuticoRESUMO
BACKGROUND: Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence of adverse outcomes after atovaquone-proguanil (AP) exposure during pregnancy. METHODS: Following PRISMA guidelines, the authors searched PubMed, MEDLINE, and the Malaria in Pregnancy Consortium Library to identify relevant literature including infant outcomes after exposure to atovaquone, proguanil, or AP in pregnancy. Two authors independently screened the titles, abstracts, and full texts, and extracted data into an EpiInfo database. Overall proportions and 95% confidence intervals of adverse outcomes were determined by pooling data across studies. RESULTS: Of 455 records identified, 16 studies were included: ten AP studies and six proguanil studies. The overall proportions and 95% confidence intervals (CI) of adverse outcomes reported for the 446 women exposed to AP include miscarriage (8.08% CI: 5.07, 12.08%), stillbirth (1.05% CI: 0.03, 5.73%), early neonatal death (0% CI: 0, 7.4%), and congenital anomalies (2.56% CI: 1.28, 4.53%). CONCLUSIONS: The limited available data suggest that outcomes following AP exposure during pregnancy are similar to expected rates in similar populations. AP may be a promising option for pregnant women, but further data are needed on its safety in pregnancy.
Assuntos
Antimaláricos/efeitos adversos , Atovaquona/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Complicações Parasitárias na Gravidez/tratamento farmacológico , Complicações Parasitárias na Gravidez/prevenção & controle , Proguanil/uso terapêutico , Aborto Espontâneo/induzido quimicamente , Antimaláricos/uso terapêutico , Atovaquona/efeitos adversos , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Recém-Nascido , Malária Falciparum/tratamento farmacológico , Gravidez , Proguanil/efeitos adversos , Natimorto , ViagemAssuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Malária/prevenção & controle , Proguanil/uso terapêutico , Aminoquinolinas/efeitos adversos , Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Quimioprevenção , Combinação de Medicamentos , Quimioterapia Combinada , Humanos , Proguanil/efeitos adversos , ViagemRESUMO
BACKGROUND: Malaria during pregnancy increases the risk of maternal and foetal complications. There are very limited options for prophylaxis in pregnant travellers. Atovaquone-Proguanil (AP or Malarone®) is an effective and well-tolerated antimalarial medication, but is not recommended for use in pregnancy due to limited data on safety. Passively reported adverse event data may provide additional information on the safety of AP during pregnancy. METHODS: We analysed adverse event data on pregnancy and birth outcomes following accidental exposures to AP during pregnancy, which were passively reported to GlaxoSmithKline LLC (GSK) between 13 May 1997 and 15 August 2017. Birth outcomes of interest included live birth, miscarriage, and stillbirth. Adverse outcomes of interest were defined as any of the following: small for gestational age (SGA), low birth weight (LBW, <2500 gm), congenital anomalies, and a composite 'poor live birth outcome,' including preterm birth (PTB), LBW or SGA. RESULTS: Among 198 women who received AP during pregnancy or breastfeeding, 96.5% occurred in women taking malaria prophylaxis, and 79.8% of exposures occurred in the first trimester. Among 195 with available birth outcome data, 18.5% resulted in miscarriage and 11.8% were elective terminations. Available adverse outcomes included SGA in 3.5% (3/85), LBW in 7.0% of infants (6/86), and the composite 'poor live birth outcome' in 13.7% (14/102). Congenital anomalies were reported in 30/124 (24.2%), with no specific pattern to suggest an effect related to AP. CONCLUSIONS: These data provide a description of outcomes in the pregnancies reported to this dataset, and it should be noted that there is likely a bias towards reporting cases resulting in poor outcomes. While there was no specific signal to suggest a teratogenic effect of AP, AP data during pregnancy were too limited to determine AP's safety with confidence. As inadvertent exposures are not infrequent, better data are needed.
Assuntos
Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Complicações Parasitárias na Gravidez/prevenção & controle , Proguanil/uso terapêutico , Aborto Espontâneo/induzido quimicamente , Adolescente , Adulto , Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Resultado da Gravidez , Nascimento Prematuro , Proguanil/efeitos adversos , Viagem , Adulto JovemRESUMO
BACKGROUND: Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous, internet-based survey was disseminated to describe outcomes of pregnancies accidentally exposed to AP. Outcomes of interest included miscarriage (defined as pregnancy loss before 20 weeks), stillbirth (defined as pregnancy loss at or after 20 weeks), preterm birth or live birth prior to 37 weeks, and the presence of congenital anomalies. RESULTS: A total of 487 women responded and reported on 822 pregnancies. Of the 807 pregnancies with information available on exposure and outcomes, 10 (1.2%) had atovaquone-proguanil exposure, all in the first trimester, and all resulted in term births with no birth defects. CONCLUSIONS: Use of an anti-malarial not recommended in pregnancy is likely to occur before the woman knows of her pregnancy. This study adds to the limited evidence of the safety of AP in pregnancy. Further study on use of AP in pregnancy should be a high priority, as an alternative option for the prevention of malaria in pregnancy in non-immune travellers is urgently needed.
Assuntos
Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Quimioprevenção/efeitos adversos , Cloroquina/efeitos adversos , Mefloquina/efeitos adversos , Resultado da Gravidez/epidemiologia , Proguanil/efeitos adversos , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Aborto Espontâneo/induzido quimicamente , Aborto Espontâneo/epidemiologia , Adulto , Combinação de Medicamentos , Feminino , Humanos , Nascido Vivo/epidemiologia , Pessoa de Meia-Idade , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Natimorto/epidemiologia , Estados Unidos/epidemiologia , Adulto JovemAssuntos
Anticoagulantes/efeitos adversos , Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Malária Falciparum/complicações , Fenindiona/análogos & derivados , Proguanil/efeitos adversos , Anticoagulantes/uso terapêutico , Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Malária Falciparum/tratamento farmacológico , Pessoa de Meia-Idade , Fenindiona/efeitos adversos , Fenindiona/uso terapêutico , Proguanil/uso terapêutico , Trombose/prevenção & controle , ViagemRESUMO
BACKGROUND: Mefloquine is one of four antimalarial agents commonly recommended for preventing malaria in travellers to malaria-endemic areas. Despite its high efficacy, there is controversy about its psychological side effects. OBJECTIVES: To summarize the efficacy and safety of mefloquine used as prophylaxis for malaria in travellers. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published on the Cochrane Library; MEDLINE; Embase (OVID); TOXLINE (https://toxnet.nlm.nih.gov/newtoxnet/toxline.htm); and LILACS. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) for trials in progress, using 'mefloquine', 'Lariam', and 'malaria' as search terms. The search date was 22 June 2017. SELECTION CRITERIA: We included randomized controlled trials (for efficacy and safety) and non-randomized cohort studies (for safety). We compared prophylactic mefloquine with placebo, no treatment, or an alternative recommended antimalarial agent. Our study populations included all adults and children, including pregnant women. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and risk of bias of trials, extracted and analysed data. We compared dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). Prespecified adverse outcomes are included in 'Summary of findings' tables, with the best available estimate of the absolute frequency of each outcome in short-term international travellers. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 20 RCTs (11,470 participants); 35 cohort studies (198,493 participants); and four large retrospective analyses of health records (800,652 participants). Nine RCTs explicitly excluded participants with a psychiatric history, and 25 cohort studies stated that the choice of antimalarial agent was based on medical history and personal preference. Most RCTs and cohort studies collected data on self-reported or clinician-assessed symptoms, rather than formal medical diagnoses. Mefloquine efficacyOf 12 trials comparing mefloquine and placebo, none were performed in short-term international travellers, and most populations had a degree of immunity to malaria. The percentage of people developing a malaria episode in the control arm varied from 1% to 82% (median 22%) and 0% to 13% in the mefloquine group (median 1%).In four RCTs that directly compared mefloquine, atovaquone-proguanil and doxycycline in non-immune, short-term international travellers, only one clinical case of malaria occurred (4 trials, 1822 participants). Mefloquine safety versus atovaquone-proguanil Participants receiving mefloquine were more likely to discontinue their medication due to adverse effects than atovaquone-proguanil users (RR 2.86, 95% CI 1.53 to 5.31; 3 RCTs, 1438 participants; high-certainty evidence). There were few serious adverse effects reported with mefloquine (15/2651 travellers) and none with atovaquone-proguanil (940 travellers).One RCT and six cohort studies reported on our prespecified adverse effects. In the RCT with short-term travellers, mefloquine users were more likely to report abnormal dreams (RR 2.04, 95% CI 1.37 to 3.04, moderate-certainty evidence), insomnia (RR 4.42, 95% CI 2.56 to 7.64, moderate-certainty evidence), anxiety (RR 6.12, 95% CI 1.82 to 20.66, moderate-certainty evidence), and depressed mood during travel (RR 5.78, 95% CI 1.71 to 19.61, moderate-certainty evidence). The cohort studies in longer-term travellers were consistent with this finding but most had larger effect sizes. Mefloquine users were also more likely to report nausea (high-certainty evidence) and dizziness (high-certainty evidence).Based on the available evidence, our best estimates of absolute effect sizes for mefloquine versus atovaquone-proguanil are 6% versus 2% for discontinuation of the drug, 13% versus 3% for insomnia, 14% versus 7% for abnormal dreams, 6% versus 1% for anxiety, and 6% versus 1% for depressed mood. Mefloquine safety versus doxycyclineNo difference was found in numbers of serious adverse effects with mefloquine and doxycycline (low-certainty evidence) or numbers of discontinuations due to adverse effects (RR 1.08, 95% CI 0.41 to 2.87; 4 RCTs, 763 participants; low-certainty evidence).Six cohort studies in longer-term occupational travellers reported our prespecified adverse effects; one RCT in military personnel and one cohort study in short-term travellers reported adverse events. Mefloquine users were more likely to report abnormal dreams (RR 10.49, 95% CI 3.79 to 29.10; 4 cohort studies, 2588 participants, very low-certainty evidence), insomnia (RR 4.14, 95% CI 1.19 to 14.44; 4 cohort studies, 3212 participants, very low-certainty evidence), anxiety (RR 18.04, 95% CI 9.32 to 34.93; 3 cohort studies, 2559 participants, very low-certainty evidence), and depressed mood (RR 11.43, 95% CI 5.21 to 25.07; 2 cohort studies, 2445 participants, very low-certainty evidence). The findings of the single cohort study reporting adverse events in short-term international travellers were consistent with this finding but the single RCT in military personnel did not demonstrate a difference between groups in frequencies of abnormal dreams or insomnia.Mefloquine users were less likely to report dyspepsia (RR 0.26, 95% CI 0.09 to 0.74; 5 cohort studies, 5104 participants, low certainty-evidence), photosensitivity (RR 0.08, 95% CI 0.05 to 0.11; 2 cohort studies, 1875 participants, very low-certainty evidence), vomiting (RR 0.18, 95% CI 0.12 to 0.27; 4 cohort studies, 5071 participants, very low-certainty evidence), and vaginal thrush (RR 0.10, 95% CI 0.06 to 0.16; 1 cohort study, 1761 participants, very low-certainty evidence).Based on the available evidence, our best estimates of absolute effect for mefloquine versus doxycyline were: 2% versus 2% for discontinuation, 12% versus 3% for insomnia, 31% versus 3% for abnormal dreams, 18% versus 1% for anxiety, 11% versus 1% for depressed mood, 4% versus 14% for dyspepsia, 2% versus 19% for photosensitivity, 1% versus 5% for vomiting, and 2% versus 16% for vaginal thrush.Additional analyses, including comparisons of mefloquine with chloroquine, added no new information. Subgroup analysis by study design, duration of travel, and military versus non-military participants, provided no conclusive findings. AUTHORS' CONCLUSIONS: The absolute risk of malaria during short-term travel appears low with all three established antimalarial agents (mefloquine, doxycycline, and atovaquone-proguanil).The choice of antimalarial agent depends on how individual travellers assess the importance of specific adverse effects, pill burden, and cost. Some travellers will prefer mefloquine for its once-weekly regimen, but this should be balanced against the increased frequency of abnormal dreams, anxiety, insomnia, and depressed mood.
Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/prevenção & controle , Mefloquina/uso terapêutico , Doença Relacionada a Viagens , Adulto , Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Atovaquona/uso terapêutico , Criança , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Doxiciclina/efeitos adversos , Doxiciclina/uso terapêutico , Combinação de Medicamentos , Resistência a Medicamentos , Quimioterapia Combinada/métodos , Humanos , Mefloquina/efeitos adversos , Primaquina/efeitos adversos , Primaquina/uso terapêutico , Proguanil/efeitos adversos , Proguanil/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoAssuntos
Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Cloroquina/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Plasmodium malariae/efeitos dos fármacos , Proguanil/uso terapêutico , Viagem , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Proteína C-Reativa/análise , Combinação de Medicamentos , Quimioterapia Combinada/efeitos adversos , Eritrócitos/parasitologia , Humanos , Malária/diagnóstico , Malária/parasitologia , Masculino , Países Baixos , Plasmodium malariae/genética , Plasmodium malariae/isolamento & purificação , Plasmodium malariae/parasitologia , Profilaxia Pré-Exposição , Proguanil/efeitos adversos , Recidiva , Trombocitopenia/sangue , Falha de Tratamento , UgandaRESUMO
BACKGROUND: The UK deployed a task force to Sierra Leone to assist in ending the 2014/15 Ebola outbreak. Malaria protection was based on existing Defence Policy which saw a wide range of bite prevention measures deployed. Atovaquone/Proguanil ("A/P"), Doxycycline ("D") and Mefloquine ("M") were the chemoprophylactic medications that were prescribed. A survey was undertaken to audit the Adverse Effect (AE) burden experienced by the population. METHOD: A questionnaire based survey was administered that sought information on individuals' experiences with malaria chemoprophylaxis. RESULTS: 337 personnel were eligible to take part and 151 (46.3%) individuals returned questionnaires. The reported AE rates for the three drugs were "A/P" 28% of the respondents, "D" 25% and "M" 23.1%. 24 individuals (15.9%) reported 1 AE while 34 (22.5%) reported multiple AEs. Eight (5.3%) individuals changed medication (Five "A/P", two "M" and one "D") because of unacceptable AE but no significant neuro/psychological conditions were reported. The malaria attack rate for the deployed population was 0.4 cases per thousand person weeks which is very low when compared to other military deployments to the West African Area. CONCLUSION: UK Defence policy is effective in the way it balances the risk of malaria with that of AE due to chemoprophylaxis. "M" remains an acceptable chemoprophylactic agent for a section of the population.
Assuntos
Antimaláricos/efeitos adversos , Quimioprevenção/efeitos adversos , Doença pelo Vírus Ebola/epidemiologia , Malária/prevenção & controle , Militares , Viagem , Adulto , Antimaláricos/administração & dosagem , Atovaquona/administração & dosagem , Atovaquona/efeitos adversos , Surtos de Doenças/prevenção & controle , Surtos de Doenças/estatística & dados numéricos , Doxiciclina/administração & dosagem , Doxiciclina/efeitos adversos , Combinação de Medicamentos , Doença pelo Vírus Ebola/virologia , Humanos , Malária/epidemiologia , Malária/parasitologia , Mefloquina/administração & dosagem , Mefloquina/efeitos adversos , Proguanil/administração & dosagem , Proguanil/efeitos adversos , Serra Leoa/epidemiologia , Inquéritos e Questionários , Reino UnidoRESUMO
BACKGROUND: Chlorproguanil-dapsone (CD) has been linked to hemolysis in symptomatic glucose-6-phosphate dehydrogenase deficient (G6PDd) children. Few studies have explored the effects of G6PD status on hemolysis in children treated with Intermittent Preventive Treatment in infants (IPTi) antimalarial regimens. We sought to examine the joint effects of G6PD status and IPTi antimalarial treatment on incidence of hemolysis in asymptomatic children treated with CD, sulfadoxine-pyrimethamine (SP), and mefloquine (MQ). METHODS: A secondary analysis of data from a double-blind, placebo-controlled trial of IPTi was conducted. Hemoglobin (Hb) measurements were made at IPTi doses, regular follow-up and emergency visits. G6PD genotype was determined at 9 months looking for SNPs for the A- genotype at coding position 202. Multivariable linear and logistic regression models were used to examine hemolysis among children with valid G6PD genotyping results. Hemolysis was defined as the absolute change in Hb or as any post-dose Hb <8 g/dL. These outcomes were assessed using either a single follow-up Hb on day 7 after an IPTi dose or Hb obtained 1 to 14 or 28 days after each IPTi dose. FINDINGS: Relative to placebo, CD reduced Hb by approximately 0.5 g/dL at day 7 and within 14 days of an IPTi dose, and by 0.2 g/dL within 28 days. Adjusted declines in the CD group were larger than in the MQ and SP groups. At day 7, homo-/hemizygous genotype was associated with higher odds of Hb <8 g/dL (adjusted odds ratio = 6.7, 95% CI 1.7 to 27.0) and greater absolute reductions in Hb (-0.6 g/dL, 95% CI -1.1 to 0.003). There was no evidence to suggest increased reductions in Hb among homo-/hemizygous children treated with CD compared to placebo, SP or MQ. CONCLUSIONS: While treatment with CD demonstrated greater reductions in Hb at 7 and 14 days after an IPTi dose compared to both SP and MQ, there was no evidence that G6PD deficiency exacerbated the adverse effects of CD, despite evidence for higher hemolysis risk among G6PDd infants.
Assuntos
Dapsona/administração & dosagem , Deficiência de Glucosefosfato Desidrogenase/genética , Hemólise/efeitos dos fármacos , Malária/tratamento farmacológico , Mefloquina/administração & dosagem , Proguanil/análogos & derivados , Pirimetamina/administração & dosagem , Sulfadoxina/administração & dosagem , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Estudos de Coortes , Dapsona/efeitos adversos , Dapsona/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Genótipo , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/metabolismo , Hemoglobinas/análise , Humanos , Lactente , Modelos Logísticos , Malária/prevenção & controle , Masculino , Mefloquina/uso terapêutico , Análise Multivariada , Razão de Chances , Distribuição de Poisson , Polimorfismo de Nucleotídeo Único , Proguanil/administração & dosagem , Proguanil/efeitos adversos , Proguanil/uso terapêutico , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , TanzâniaAssuntos
Antimaláricos/uso terapêutico , Malária Falciparum/prevenção & controle , Viagem , Adulto , Antimaláricos/efeitos adversos , Atovaquona/efeitos adversos , Atovaquona/uso terapêutico , Criança , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Doxiciclina/efeitos adversos , Doxiciclina/uso terapêutico , Combinação de Medicamentos , Resistência a Medicamentos , Quimioterapia Combinada/métodos , Humanos , Mefloquina/efeitos adversos , Mefloquina/uso terapêutico , Primaquina/efeitos adversos , Primaquina/uso terapêutico , Proguanil/efeitos adversos , Proguanil/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Atovaquone (ATO) and proguanil hydrochloride (PROG) is the fixed combination for the prevention and treatment of Plasmodium falciparum malaria. As safe and effective antimalarial drugs are needed in both the treatment and the prophylaxis of malaria, this study was performed to investigate their possible cyto/genotoxic potential towards human lymphocytes and the possible mechanism responsible for it. Two different concentrations of ATO and PROG were used with and without S9 metabolic activation. The concentrations used were those found in human plasma when a fixed-dose combination of ATO and PROG was used: 2950/130 ng/mL after prophylactic treatment and 11 800/520 ng/mL after treatment of malaria, respectively. Possible cellular and DNA-damaging effects were evaluated by cell viability and alkaline comet assays, while oxidative stress potential was evaluated by formamidopyrimidine-DNA glycosylase (Fpg)-modified comet assay, in addition to measuring malondialdehyde and glutathione levels. According to our results, the ATO/PROG combination displayed only weak cyto/genotoxic potential towards human lymphocytes with no impact on oxidative stress parameters, suggesting that oxidative stress is not implicated in their mechanism of action towards human lymphocytes. Given that the key portion of the damaging effects was induced after S9 metabolic activation, it is to presume that the principal metabolite of PROG, cycloguanil, had the greatest impact. The obtained results indicate that the ATO/PROG combination is relatively safe for the consumption from the aspect of cyto/genotoxicity, especially if used for prophylactic treatment. Nevertheless, further cytogenetic research and regular patient monitoring are needed to minimize the risk of adverse events especially among frequent travellers.
Assuntos
Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Atovaquona/efeitos adversos , Atovaquona/uso terapêutico , Linfócitos/efeitos dos fármacos , Proguanil/efeitos adversos , Proguanil/uso terapêutico , Adulto , Sobrevivência Celular/efeitos dos fármacos , Citogenética/métodos , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Glutationa/metabolismo , Humanos , Linfócitos/metabolismo , Malária Falciparum/tratamento farmacológico , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Triazinas/uso terapêuticoRESUMO
BACKGROUND: Although malaria can be prevented with prophylaxis, it is diagnosed in over 100 Africa-region Peace Corps Volunteers annually. This suggests that prophylaxis non-adherence is a problem in these non-immune travelers. METHODS: We investigated Volunteers' knowledge, attitudes, and practices regarding prophylaxis using an internet-based survey during August 19-September 30, 2013. Adherence was defined as taking doxycycline or atovaquone-proguanil daily, or taking mefloquine doses no more than 8 days apart. RESULTS: The survey was sent to 3248 Volunteers. Of 781 whose responses were analyzed, 514 (73%) reported adherence to prophylaxis. The most common reasons for non-adherence were forgetting (n = 530, 90%); fear of long-term adverse effects (LTAEs; n = 316, 54%); and experiencing adverse events that Volunteers attributed to prophylaxis (n = 297, 51%). Two hundred fourteen (27%) Volunteers reported not worrying about malaria. On multivariate analysis controlling for sex and experiencing adverse events Volunteers attributed to prophylaxis, the factor most strongly associated with non-adherence was being prescribed mefloquine (OR 5.4, 95% confidence interval 3.2-9.0). CONCLUSIONS: We found moderate adherence and a prevailing fear of LTAEs among Volunteers. Strategies to improve prophylaxis adherence may include medication reminders, increasing education about prophylaxis safety and malaria risk, and promoting prompt management of prophylaxis side effects.
Assuntos
Antimaláricos/uso terapêutico , Malária/prevenção & controle , Adesão à Medicação , Peace Corps , Profilaxia Pré-Exposição , Voluntários , África , Atovaquona/efeitos adversos , Atovaquona/uso terapêutico , Coleta de Dados , Doxiciclina/efeitos adversos , Doxiciclina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Internet , Masculino , Mefloquina/efeitos adversos , Mefloquina/uso terapêutico , Proguanil/efeitos adversos , Proguanil/uso terapêutico , Inquéritos e Questionários , Estados UnidosRESUMO
BACKGROUND: Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. METHODS: The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C ± P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. RESULTS: The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C ± P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases--model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the 'background' reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C ± P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C ± P 62613, Dx 61923, Mq 59973, AP 58059; increasing the 'background' rate by 50% yielded NNPs of: C ± P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2.3% decrease in estimated infections. The number of travellers experiencing moderate adverse events (AE) or those requiring medical attention or drug withdrawal per case prevented is as follows: C ± P 170, Mq 146, Dx 114, AP 103. CONCLUSIONS: The model correctly predicted the number of malaria deaths, providing a robust and reliable estimate of the number of imported malaria cases in the UK, and giving a measure of benefit derived from chemoprophylaxis use against the likely adverse events generated. Overall numbers needed to prevent a malaria infection are comparable among the four options and are sensitive to changes in the background infection rates. Only a limited impact on the number of infections can be expected if Mq is substituted by AP.
Assuntos
Antimaláricos/uso terapêutico , Quimioprevenção , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária/epidemiologia , Malária/prevenção & controle , Viagem , Atovaquona/efeitos adversos , Atovaquona/uso terapêutico , Quimioprevenção/métodos , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Doxiciclina/efeitos adversos , Doxiciclina/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Uso de Medicamentos/estatística & dados numéricos , Humanos , Malária/mortalidade , Malária Falciparum/mortalidade , Mefloquina/efeitos adversos , Mefloquina/uso terapêutico , Modelos Estatísticos , Proguanil/efeitos adversos , Proguanil/uso terapêutico , Estudos Retrospectivos , Risco , Reino UnidoRESUMO
Phototoxic reaction has not been reported previously as an adverse reaction to the combination of atovaquone and proguanil (AP) (Malarone) used for antimalarial prophylaxis and therapy. We report here a 32-year-old patient treated with AP who presented with clinical manifestations of photosensitivity. AP-induced phototoxicity in this patient was further supported by phototesting. Malarone is not known to photosensitize and render the skin more susceptible to severe sunburn-like reactions. That it may do so, as in this case, is of importance especially as this drug is used predominantly by those travelling to sunnier climes. A notification of potential phototoxic effects of AP should be published for the choice of prophylaxis made by tourists traveling in malarial areas.