RESUMO
Despite the overall decline in malaria cases in Thailand, continuous surveillance in endemic areas remains crucial. This retrospective analysis examined Plasmodium falciparum samples from Tak province, Thailand, collected in 1998, 1999, and 2001, to investigate the prevalence and evolution of antimalarial genotypic drug resistance. The study revealed a high prevalence of drug-resistant P. falciparum, particularly to mefloquine and sulfadoxine/pyrimethamine, with significant mutations in genes associated with resistance. Notably, mutations indicative of artemisinin resistance, such as those in the kelch13 gene, were detected at low frequencies, suggesting an evolving resistance pattern. The underlying cause of these resistance mutations appears to be the historical and widespread use of these antimalarial drugs, which exerted selective pressure on the parasite population. These findings underscore the necessity of ongoing surveillance and adaptive control strategies to manage drug resistance, guide treatment policies, and prevent potential outbreaks, even as malaria cases decrease. Continuous monitoring and research are imperative to sustain malaria elimination efforts and address the dynamic challenges posed by evolving drug-resistant strains.
Assuntos
Antimaláricos , Resistência a Medicamentos , Malária Falciparum , Mutação , Plasmodium falciparum , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Tailândia/epidemiologia , Resistência a Medicamentos/genética , Malária Falciparum/parasitologia , Malária Falciparum/epidemiologia , Malária Falciparum/tratamento farmacológico , Humanos , Estudos Retrospectivos , Prevalência , Mefloquina/farmacologia , Mefloquina/uso terapêutico , Animais , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Pirimetamina/farmacologia , Pirimetamina/uso terapêutico , Sulfadoxina/farmacologia , Sulfadoxina/uso terapêutico , Combinação de MedicamentosRESUMO
Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multi-drug resistance protein 1 (Pfmrp1) gene have previously been reported to confer resistance to Artemisinin-based Combination Therapies (ACTs) in Southeast Asia. A total of 300 samples collected from six sites between 2008 and 2019 under an ongoing malaria drug sensitivity patterns in Kenya study were evaluated for the presence of SNPs at Pfmrp1 gene codons: H191Y, S437A, I876V, and F1390I using the Agena MassARRAY® platform. Each isolate was further tested against artemisinin (ART), lumefantrine (LU), amodiaquine (AQ), mefloquine (MQ), quinine (QN), and chloroquine (CQ) using malaria the SYBR Green I-based method to determine their in vitro drug sensitivity. Of the samples genotyped, polymorphism at Pfmrp1 codon I876V was the most frequent, with 59.3% (163/275) mutants, followed by F1390I, 7.2% (20/278), H191Y, 4.0% (6/151), and S437A, 3.3% (9/274). A significant decrease in median 50% inhibition concentrations (IC50s) and interquartile range (IQR) was noted; AQ from 2.996 ng/ml [IQR = 2.604-4.747, n = 51] in 2008 to 1.495 ng/ml [IQR = 0.7134-3.318, n = 40] (P<0.001) in 2019, QN from 59.64 ng/ml [IQR = 29.88-80.89, n = 51] in 2008 to 18.10 ng/ml [IQR = 11.81-26.92, n = 42] (P<0.001) in 2019, CQ from 35.19 ng/ml [IQR = 16.99-71.20, n = 30] in 2008 to 6.699 ng/ml [IQR = 4.976-9.875, n = 37] (P<0.001) in 2019, and ART from 2.680 ng/ml [IQR = 1.608-4.857, n = 57] in 2008 to 2.105 ng/ml [IQR = 1.266-3.267, n = 47] (P = 0.0012) in 2019, implying increasing parasite sensitivity to the drugs over time. However, no significant variations were observed in LU (P = 0.2692) and MQ (P = 0.0939) respectively, suggesting stable parasite responses over time. There was no statistical significance between the mutation at 876 and parasite sensitivity to selected antimalarials tested, suggesting stable sensitivity for the parasites with 876V mutations. These findings show that Kenyan parasite strains are still sensitive to AQ, QN, CQ, ART, LU, and MQ. Despite the presence of Pfmrp1 mutations in parasites among the population.
Assuntos
Antimaláricos , Combinação Arteméter e Lumefantrina , Malária Falciparum , Plasmodium falciparum , Polimorfismo de Nucleotídeo Único , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Humanos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Combinação Arteméter e Lumefantrina/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Quênia , Mefloquina/farmacologia , Mefloquina/uso terapêutico , Amodiaquina/farmacologia , Amodiaquina/uso terapêutico , Resistência a Medicamentos/genética , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Quinina/farmacologia , Quinina/uso terapêutico , Masculino , FemininoRESUMO
A middle-aged man with progressive multifocal leukoencephalopathy (PML) in a human T-cell lymphotropic virus type-1 (HTLV-1) carrier on haemodialysis presented with mild dysarthria and ataxia. Brain MRI revealed asymmetric T2-hyperintense lesions in the cerebral white matter, cerebellum and brainstem. A small amount of JC virus (JCV) genome in cerebrospinal fluid was detected by PCR and cerebellar biopsy demonstrated JCV-DNA presence. Pathological findings showed demyelinating lesions and glial cells with mildly enlarged nuclei, accompanied by T-lymphocytes, neutrophils and plasma cell infiltration. The CD4+/CD8+ratio was 0.83. High-dose corticosteroid therapy was effective for inflammatory PML lesions, and the administration of mefloquine combined with mirtazapine led to favourable outcome. The encephalitis in this case is considered to have occurred secondarily to JCV infection in the presence of HTLV-1 infection. Therefore, it is crucial to investigate the presence of HTLV-1 in order to understand the aetiology of this brain inflammation.
Assuntos
Coinfecção , Infecções por HTLV-I , Vírus Linfotrópico T Tipo 1 Humano , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Mirtazapina , Humanos , Leucoencefalopatia Multifocal Progressiva/virologia , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Masculino , Infecções por HTLV-I/complicações , Infecções por HTLV-I/tratamento farmacológico , Infecções por HTLV-I/diagnóstico , Pessoa de Meia-Idade , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Vírus JC/isolamento & purificação , Mirtazapina/uso terapêutico , Imageamento por Ressonância Magnética , Mefloquina/uso terapêuticoRESUMO
Capillary samples offer practical benefits compared with venous samples for the measurement of drug concentrations, but the relationship between the two measures varies between different drugs. We measured the concentrations of lumefantrine, mefloquine, piperaquine in 270 pairs of venous plasma and concurrent capillary plasma samples collected from 270 pregnant women with uncomplicated falciparum or vivax malaria. The median and range of venous plasma concentrations included in this study were 447.5 ng/mL (8.81-3,370) for lumefantrine (day 7, n = 76, median total dose received 96.0 mg/kg), 17.9 ng/mL (1.72-181) for desbutyl-lumefantrine, 1,885 ng/mL (762-4,830) for mefloquine (days 3-21, n = 90, median total dose 24.9 mg/kg), 641 ng/mL (79.9-1,950) for carboxy-mefloquine, and 51.8 ng/mL (3.57-851) for piperaquine (days 3-21, n = 89, median total dose 52.2 mg/kg). Although venous and capillary plasma concentrations showed a high correlation (Pearson's correlation coefficient: 0.90-0.99) for all antimalarials and their primary metabolites, they were not directly interchangeable. Using the concurrent capillary plasma concentrations and other variables, the proportions of venous plasma samples predicted within a ±10% precision range was 34% (26/76) for lumefantrine, 36% (32/89) for desbutyl-lumefantrine, 74% (67/90) for mefloquine, 82% (74/90) for carboxy-mefloquine, and 24% (21/89) for piperaquine. Venous plasma concentrations of mefloquine, but not lumefantrine and piperaquine, could be predicted by capillary plasma samples with an acceptable level of agreement. Capillary plasma samples can be utilized for pharmacokinetic and clinical studies, but caution surrounding cut-off values is required at the individual level.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT01054248.
Assuntos
Antimaláricos , Lumefantrina , Malária Falciparum , Malária Vivax , Mefloquina , Piperazinas , Quinolinas , Humanos , Feminino , Mefloquina/sangue , Mefloquina/uso terapêutico , Mefloquina/farmacocinética , Antimaláricos/sangue , Antimaláricos/uso terapêutico , Antimaláricos/farmacocinética , Gravidez , Quinolinas/sangue , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Lumefantrina/uso terapêutico , Lumefantrina/sangue , Malária Falciparum/tratamento farmacológico , Malária Falciparum/sangue , Adulto , Malária Vivax/tratamento farmacológico , Malária Vivax/sangue , Adulto Jovem , Etanolaminas/sangue , Etanolaminas/farmacocinética , Etanolaminas/uso terapêutico , Fluorenos/sangue , Fluorenos/uso terapêutico , Fluorenos/farmacocinética , AdolescenteRESUMO
BACKGROUND: Ferroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy have not been elucidated. METHODS: Cytotoxicity assays, colony formation assays, flow cytometry and animal experiments were used to evaluate the effects of mefloquine (Mef) on survival and ferroptosis in melanoma and lung cancer. RNA sequencing, Real-time quantitative PCR (qRT-PCR), western blotting, chromatin immunoprecipitation-qPCR and flow cytometry were used to determine the molecular mechanisms by which Mef regulates lysophosphatidylcholine acyltransferase 3 (LPCAT3). The relationship between LPCAT3 and the efficacy of anti-PD-1 immunotherapy was verified via a clinical database and single-cell RNA sequencing (ScRNA-Seq). RESULTS: In this study, we discovered that Mef induces ferroptosis. Furthermore, treatment with Mef in combination with T-cell-derived interferon-γ (IFN-γ) enhanced tumor ferroptosis and sensitized melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef upregulated the expression of LPCAT3, a key gene involved in lipid peroxidation, by activating IFN-γ-induced STAT1-IRF1 signaling, and knocking down LPCAT3 impaired the induction of ferroptosis by Mef+IFN-γ. Clinically, analysis of the transcriptome and single-cell sequencing results in patients with melanoma showed that LPCAT3 expression was significantly lower in patients with melanoma than in control individuals, and LPCAT3 expression was positively correlated with the efficacy of anti-PD-1 immunotherapy. CONCLUSIONS: In conclusion, our study demonstrated a novel mechanism by which LPCAT3 is regulated, and demonstrated that Mef is a highly promising new target that can be utilized to enhance the efficacy of anti-PD-1 immunotherapy.
Assuntos
Ferroptose , Neoplasias Pulmonares , Melanoma , Animais , Humanos , Melanoma/tratamento farmacológico , Mefloquina/farmacologia , Mefloquina/uso terapêutico , Interferon gama/metabolismo , Linhagem Celular Tumoral , Neoplasias Pulmonares/genética , Imunoterapia , Fator de Transcrição STAT1/metabolismo , Fator Regulador 1 de Interferon/genética , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferase/farmacologiaRESUMO
Malaria is a longstanding global health challenge that continues to afflict over 90 countries located in tropical and subtropical regions of the globe. The rise of drug-resistant malarial parasites has curtailed the therapeutic efficacy of a number of once-effective anti-malarials, including mefloquine. In the present study, we have taken advantage of drug encapsulation approach to elevate the anti-malarial potential of mefloquine. Encouragingly, our findings unveil that liposomal formulations of mefloquine outperform equivalent doses of free mefloquine, both in laboratory cultures and in a murine model of malaria. Intriguingly, a cationic liposomal mefloquine formulation, administered at four successive doses of 3 mg/kg body weight, achieves complete resolution of cerebral malaria in the murine model while avoiding noticeable toxic repercussions. Altogether, our study furnishes pre-clinical validation for a therapeutic strategy that can remarkably enhance the drug efficacy, offering a revitalizing solution for failing anti-malarials.
Assuntos
Antimaláricos , Malária Cerebral , Animais , Camundongos , Antimaláricos/farmacologia , Mefloquina/uso terapêutico , Lipossomos , Malária Cerebral/tratamento farmacológico , Modelos Animais de DoençasRESUMO
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease characterized by severe pulmonary fibrosis, for which there is an urgent need for effective therapeutic agents. Mefloquine (Mef) is a quinoline compound primarily used for the treatment of malaria. However, high doses (>25 mg/kg) may lead to side effects such as cardiotoxicity and psychiatric disorders. Here, we found that low-dose Mef (5 mg/kg) can safely and effectively treat IPF mice. Functionally, Mef can improve the pulmonary function of IPF mice (PIF, PEF, EF50, VT, MV, PENH), alleviating pulmonary inflammation and fibrosis by inhibiting macrophage activity. Mechanically, Mef probably regulates the Jak2/Stat3 signaling pathway by binding to the 492HIS site of Potassium voltage-gated channel subfamily H member 2 (KCNH2) protein in macrophages, inhibiting the secretion of macrophage inflammatory and fibrotic factors. In summary, Mef may inhibit macrophage activity by binding to KCNH2 protein, thereby slowing down the progress of IPF.
Assuntos
Fibrose Pulmonar Idiopática , Mefloquina , Humanos , Camundongos , Animais , Mefloquina/uso terapêutico , Macrófagos/metabolismo , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/patologia , Fibrose , Transdução de Sinais , Bleomicina/farmacologia , Canal de Potássio ERG1/metabolismoRESUMO
In antimalarial drug development research, overcoming drug resistance has been a major challenge for researchers. Nowadays, several drugs like chloroquine, mefloquine, sulfadoxine, and artemisinin are used to treat malaria. But increment in drug resistance has pushed researchers to find novel drugs to tackle drug resistance problems. The idea of using transition metal complexes with pharmacophores as ligands/ligand pendants to show enhanced antimalarial activity with a novel mechanism of action has gained significant attention recently. The advantages of metal complexes include tunable chemical/physical properties, redox activity, avoiding resistance factors, etc. Several recent reports have successfully demonstrated that the metal complexation of known organic antimalarial drugs can overcome drug resistance by showing enhanced activities than the parent drugs. This review has discussed the fruitful research works done in the past few years falling into this criterion. Based on transition metal series (3d, 4d, or 5d), the antimalarial metal complexes have been divided into three broad categories (3d, 4d, or 5d metal-based), and their activities have been compared with the similar control complexes as well as the parent drugs. Furthermore, we have also commented on the potential issues and their possible solution for translating these metal-based antimalarial complexes into the clinic.
Assuntos
Antimaláricos , Complexos de Coordenação , Malária Falciparum , Malária , Humanos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Malária/tratamento farmacológico , Cloroquina/farmacologia , Mefloquina/uso terapêutico , Resistência a Medicamentos , Plasmodium falciparum , Malária Falciparum/tratamento farmacológicoRESUMO
BACKGROUND: Hair analysis to identify substance use is an established methodology. This could also be a method to monitor adherence to antimalarial drugs. We aimed to establish a methodology to determine hair concentrations of atovaquone, proguanil and mefloquine in travellers using chemoprophylaxis. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous analysis of the antimalarial drugs -atovaquone (ATQ), proguanil (PRO) and mefloquine (MQ), in human hair. The hair samples from five volunteers were used for this proof-of-concept analysis. Three volunteers were taking daily atovaquone/proguanil (ATQ/PRO) chemoprophylaxis and two volunteers were using weekly mefloquine (MQ) chemoprophylaxis. RESULTS: With this proof-of-principle analysis, we could show that ATQ/PRO and MQ are integrated into the hair matrix. Chemoprophylaxis could be quantified with the established method. In hair segments, maximal concentrations of 3.0 ng/mL/20 mg hair proguanil, 1.3 ng/mL/20 mg hair atovaquone and 78.3 ng/mL/20 mg hair mefloquine were measured. Moreover, malaria drug concentration changes correlated with the time interval since finishing the chemoprophylaxis regimen. CONCLUSIONS: The validated method was used successfully for the analysis of antimalarial-drug positive hair samples containing atovaquone, proguanil or mefloquine. This research shows that hair can be used for adherence monitoring of chemoprophylaxis and paves the way for larger studies and optimized procedures.
Assuntos
Antimaláricos , Humanos , Antimaláricos/uso terapêutico , Proguanil/uso terapêutico , Atovaquona/uso terapêutico , Mefloquina/uso terapêutico , Cromatografia Líquida , Quimioterapia Combinada , Viagem , Espectrometria de Massas em Tandem , Combinação de MedicamentosRESUMO
Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed. Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against E. multilocularis in vitro and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against E. multilocularis metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1'681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against E. multilocularis. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE.
Assuntos
Equinococose , Echinococcus multilocularis , Parasitos , Humanos , Camundongos , Animais , Cães , Mefloquina/farmacologia , Mefloquina/uso terapêutico , Equinococose/tratamento farmacológico , Equinococose/parasitologia , Antiparasitários/farmacologia , MamíferosRESUMO
BACKGROUND: Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling. METHODS: We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment. RESULTS: Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 µM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations. CONCLUSIONS: These data suggest that atovaquone would be a potential candidate for treating mpox.
Assuntos
Mefloquina , Monkeypox virus , Humanos , Atovaquona/farmacologia , Atovaquona/uso terapêutico , Mefloquina/farmacologia , Mefloquina/uso terapêutico , Monkeypox virus/efeitos dos fármacosRESUMO
BACKGROUND: Declining in susceptibility of Plasmodium falciparum to mefloquine is reported in South-East Asia. A revisiting on mefloquine pharmacokinetics-pharmacodynamics (PK/PD) could assist in finding new appropriate dosage regimens in combination with artesunate as a three-day course treatment. OBJECTIVE: This study aimed to investigate promising alternative artesunate-mefloquine combination regimens that are effective for the treatment of patients with mefloquine-sensitive and resistant P. falciparum malaria. METHODS: Data collected during 2008-2009 from 124 patients with uncomplicated P. falciparum malaria were included in the analysis, 90 and 34 patients with sensitive and recrudescence response, respectively. All patients were treated with a three-day combination of artesunate-mefloquine. Population PK-PD models were developed. The developed models were validated with clinically observed data. Simulations of clinical efficacy of alternative mefloquine regimens were performed based on mefloquine sensitivity, patients' adherence and parasite biomass. RESULTS: The developed PK/PD models well described with clinically observed data. For mefloquine-resistant P. falciparum, a three-day standard regimen of artesunate-mefloquine is suitable (>50% efficacy) only when the level of parasite sensitivity was < 1.5-fold of the cut-off level (IC50 < 36 nM). For mefloquine-sensitive parasite with IC50 < 23.19 nM (0.96-fold), all regimens provided satisfactory efficacy. In the isolates with IC50 of 24 nM, regimen-I is recommended. Curative treatment criteria for mefloquine and artesunate were C336h (>408 ng.mL-1) or Cmax/IC50 (>130.1 g.m/M), and Cmax/IC50 (>381.2 g.m/M), respectively. CONCLUSIONS: Clinical use of a three-day standard artesunate-mefloquine is suitable only when the IC50 of P. falciparum isolates is lower than 36 nM. Otherwise, other ACT regimens should be replaced. For mefloquine-sensitive parasite, a dose reduction is recommended with the IC50 is lower than 23.19 nM.
Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Sesquiterpenos , Humanos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Mefloquina/farmacologia , Mefloquina/uso terapêutico , Artesunato/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum , Quimioterapia Combinada , Sesquiterpenos/farmacologiaRESUMO
BACKGROUND: The aim of this study was to evaluate the rates of parasitaemia clearance and the prevalence of treatment failure in patients with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (AL), mefloquine (MQ), and atovaquone-proguanil (AP). METHOD: The retrospective descriptive study included adult patients with uncomplicated P. falciparum malaria treated at the University Hospital Bulovka in Prague from 2006 to 2019. Parasitaemia clearance was estimated using a linear regression model. RESULTS: The study included 72 patients with a median age of 33 years (IQR 27-45) and a male to female ratio of 3.2:1. Thirty-six patients (50.0%) were treated with AL, 27 (37.5%) with MQ and 9 (12.5%) with AP. The proportion of VFR and migrants was 22.2% with no significant differences among the three groups. The median time to the parasitaemia clearance was two days (IQR 2-3) in patients treated with AL versus four days in the MQ (IQR 3-4) and AP (IQR 3-4) groups, p < 0.001. The clearance rate constant was 3.3/hour (IQR 2.5-4.0) for AL, 1.6/hour (IQR 1.3-1.9) for MQ, and 1.9/hour (IQR 1.3-2.4) for AP, p < 0.001. Malaria recrudescence occurred in 5/36 (13.9%) patients treated with AL and in no patients treated with MQ or AP. CONCLUSIONS: The findings demonstrate the superior efficacy of AL compared to other oral antimalarials in early malaria treatment. However, we observed a higher rate of late treatment failure in patients treated with AL than previously reported. This issue warrants further investigation of possible dose adjustments, extended regimens, or alternative artemisinin-based combinations.
Assuntos
Antimaláricos , Malária Falciparum , Malária , Adulto , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Antimaláricos/efeitos adversos , Mefloquina/uso terapêutico , Mefloquina/efeitos adversos , Combinação Arteméter e Lumefantrina/uso terapêutico , Estudos Retrospectivos , Artemeter/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Combinação de Medicamentos , Malária/tratamento farmacológico , Falha de Tratamento , Plasmodium falciparum , Etanolaminas/uso terapêuticoRESUMO
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system caused by reactivation of the polyomavirus JC (JCV). Human immunodeficiency virus (HIV) infection is one of the leading causes of PML which has high morbidity and mortality due to the lack of a proven standard treatment. We found clinical and radiological improvement with the combination of high-dose methylprednisolone, mirtazapine, mefloquine, and IVIG in our patient who presented with neurological symptoms and had diagnosed concurrent acquired immunodeficiency syndrome (AIDS) and PML. To our knowledge, our case is the first HIV-associated PML which responded to this combination therapy.
Assuntos
Infecções por HIV , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Humanos , Mirtazapina/uso terapêutico , Mefloquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Infecções por HIV/complicaçõesRESUMO
The use of herbal products is booming all over the world because of being believed as safer than conventional drugs and free of side effects. However, there are untrustworthy manufacturers who adulterate herbal products by adding conventional drugs which might eventually lead to microbial resistance and herb-to-drug interactions. There is a need to develop methods for detecting adulterants in herbal products. A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneous identification and determination of conventional antimalarials (chloroquine, quinine, sulfadoxine, pyrimethamine, mefloquine, lumefantrine, amodiaquine, artemisinin, dihydroartemisinin, artesunate and artemether) in herbal products was developed. Stable isotopically labelled compounds (artemether-d3, quindine-d3, and sulfadoxine-d3) were used as internal standards (ISs) for quantitative analysis. Extraction of analytes was performed using methanol: water: formic acid (90:10:0.1, v/v) and chromatographic separation was done in a gradient mode using mobile phase A: Ultrapure water containing 0.1% formic acid and 1 mM ammonium formate and mobile phase B: Acetonitrile/methanol (50:50) containing 0.1% formic acid and 1 mM ammonium formate. The calibration curves were linear (r2 ≥ 0.991) over the range of 0.001-0.3 µg mL-1 for all compounds. The limit of detection (LOD) ranged from 0.002 to 0.02 µg mL-1 while the limit of quantification (LOQ) ranged from 0.006 to 0.08 µg mL-1. Accuracy, expressed as recovery of spiked herbal products ranged from 52 to 128%. The precision, expressed as percent relative standard deviation (%RSD) at two concentration levels, ranged from 1.0 to 13.8%. The matrix effect expressed as the matrix factor (MF) ranged from 0.77 to 0.97. The developed method was used to identify and quantify conventional antimalarials in herbal product samples from Tanzania. Ten out of 50 herbal products were found to contain amodiaquine, sulfadoxine, pyrimethamine, mefloquine, dihydroartemisinin, artemether and lumefantrine. The developed method is considered a valuable tool for getting a better understanding of the adulteration of conventional antimalarials in herbal products.
Assuntos
Antimaláricos , Antimaláricos/análise , Antimaláricos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem/métodos , Mefloquina/uso terapêutico , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Amodiaquina/uso terapêutico , Metanol , Artemeter/análise , LumefantrinaRESUMO
Alveolar echinococcosis is an emerging zoonotic disease caused by the parasite Echinococcus multilocularis. Most patients are diagnosed at a late stage, when lifelong treatment with benzimidazoles is required to stop disease progression. However, for patients who do not tolerate benzimidazole therapy, there are no alternatives. Here, we present a patient with advanced alveolar echinococcosis who was successfully treated with amphotericin B deoxycholate and mefloquine as a rescue therapy after he developed albendazole intolerance.
Assuntos
Anti-Helmínticos , Equinococose , Echinococcus multilocularis , Masculino , Animais , Humanos , Mefloquina/uso terapêutico , Anfotericina B/uso terapêutico , Terapia de Salvação , Equinococose/tratamento farmacológico , Albendazol/uso terapêutico , Anti-Helmínticos/uso terapêuticoRESUMO
OBJECTIVES: Military deployments to the tropics are associated with specific infection risks. To add to the available epidemiological information, infectious disease risks in German military personnel returning from predominantly tropical deployments were assessed. METHODS: Since 2006, German soldiers returning from predominantly tropical deployments have been offered the opportunity of returnee screenings at the Department of Tropical Medicine and Infectious Diseases of the Bundeswehr Hospital Hamburg. Case files and diagnostic results recorded between 2006 and 2018 were retrospectively assessed to identify deployment-associated infectious disease risks. RESULTS: Along with high enteric colonisation rates with apathogenic protozoa and resistant Enterobacteriaceae, direct or indirect proof of infections among the 764 assessed cases comprised Plasmodium spp (n=37), Giardia duodenalis (n=21), Schistosoma spp (n=14), Yersinia enterocolitica (n=5), Strongyloides stercoralis (n=3), Campylobacter jejuni (n=1), Leishmania spp (n=1) and Salmonella enterica (n=1), as well as latent infections with Mycobacterium tuberculosis complex (n=8). The infections were mainly imported from the African region and Eastern Mediterranean region and high proportions of cases lacked typical symptoms. Reported side effect rates of antimalarial chemoprophylaxis for mefloquine (n=121), atovaquone/proguanil (n=49) and doxycycline (n=6) were 36.3%, 19.3% and 11.8%, respectively, while non-compliance rates were 12.9%, 13.0% and 5.9%, respectively. CONCLUSIONS: Considerable rates of infections with sometimes atypical or absent symptoms confirm a need for returnee screenings after tropical deployments. High reported side effect rates for mefloquine support its replacement by atovaquone/proguanil or doxycycline for antimalarial chemoprophylaxis.
Assuntos
Antimaláricos , Doenças Transmissíveis , Militares , Humanos , Antimaláricos/uso terapêutico , Proguanil/uso terapêutico , Atovaquona/uso terapêutico , Mefloquina/uso terapêutico , Doxiciclina/uso terapêutico , Estudos RetrospectivosRESUMO
Toxoplasmosis is a disease with a worldwide distribution and significant morbidity and mortality. In search of effective treatment, mefloquine (MQ) was repurposed and loaded with niosomes to treat acute and chronic phases of toxoplasmosis in experimental mice. Mice were orally inoculated with 20 cysts of Toxoplasma gondii (ME 49 strain) for the acute model of infection and 10 cysts for the chronic model of infection. Infected mice were dosed with MQ solution or MQ-niosomes at 50 mg/kg/day, starting from the second day post-infection (PI) (acute model) or the fifth week PI (chronic model), and this was continued for six consecutive days. The effects of MQ solution and MQ-niosomes were compared with a pyrimethamine/sulfadiazine (PYR/SDZ) dosing combination as mortality rates, brain cyst number, inflammatory score, and immunohistochemical studies that included an estimation of apoptotic cells (TUNEL assays). In the acute infection model, MQ solution and MQ-niosomes significantly reduced the mortality rate from 45% to 25 and 10%, respectively, compared with infected untreated controls, and decreased the number of brain cysts by 51.5% and 66.9%, respectively. In the chronic infection model, cyst reduction reached 80.9% and 12.3% for MQ solution and MQ-niosomes treatments, respectively. MQ-niosomes significantly decreased inflammation induced by acute or chronic T. gondii infection. Additionally, immunohistochemical analysis revealed that MQ solution and MQ-niosomes significantly increased the number of TUNEL-positive cells in brain tissue, indicative of induction of apoptosis. Collectively, these results indicate that MQ-niosomes may provide a useful delivery strategy to treat both acute and chronic toxoplasmosis.
Assuntos
Toxoplasma , Toxoplasmose Animal , Toxoplasmose , Animais , Camundongos , Mefloquina/uso terapêutico , Mefloquina/farmacologia , Lipossomos , Toxoplasmose/tratamento farmacológico , Pirimetamina/farmacologia , Sulfadiazina , Toxoplasmose Animal/tratamento farmacológicoRESUMO
BACKGROUND: In early 2016, in Preah Vihear, Northern Cambodia, artesunate/mefloquine was used to cope with dihydroartemisinin/piperaquine-resistant Plasmodium falciparum parasites. Following this policy, P. falciparum strains harbouring molecular markers associated with artemisinin, piperaquine and mefloquine resistance have emerged. However, the lack of a viable alternative led Cambodia to adopt artesunate/mefloquine countrywide, raising concerns about a surge of triple-resistant P. falciparum strains. OBJECTIVES: To assess the prevalence of triple-resistant parasites after artesunate/mefloquine implementation countrywide in Cambodia and to characterize their phenotype. METHODS: For this multicentric study, 846 samples were collected from 2016 to 2019. Genotyping of molecular markers associated with artemisinin, piperaquine and mefloquine resistance was coupled with phenotypic analyses. RESULTS: Only four triple-resistant P. falciparum isolates (0.47%) were identified during the study period. These parasites combined the pfk13 polymorphism with pfmdr1 amplification, pfpm2 amplification and/or pfcrt mutations. They showed significantly higher tolerance to artemisinin, piperaquine and mefloquine and also to the mefloquine and piperaquine combination. CONCLUSIONS: The use of artesunate/mefloquine countrywide in Cambodia has not led to a massive increase of triple-resistant P. falciparum parasites. However, these parasites circulate in the population, and exhibit clear resistance to piperaquine, mefloquine and their combination in vitro. This study demonstrates that P. falciparum can adapt to more complex drug associations, which should be considered in future therapeutic designs.
Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Quinolinas , Humanos , Mefloquina/farmacologia , Mefloquina/uso terapêutico , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artesunato , Camboja/epidemiologia , Prevalência , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Quinolinas/farmacologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Resistência a Medicamentos/genéticaRESUMO
BACKGROUND: JC virus (JCV) is common among healthy individuals and remains latent but may be reactivated under immunosuppressive conditions, resulting in progressive multifocal leukoencephalopathy (PML). Here, we present a rare case of PML caused by JC virus infection in a previously healthy and immunocompetent patient. CASE PRESENTATION: A 67-year-old female without any disease history was admitted after presenting with rapidly progressive dementia. The preoperative diagnosis was progressive multifocal leukoencephalopathy, and corticosteroid treatment did not improve the symptoms. Brain lesions were surgically sampled, and JCV infection was confirmed by high-throughput DNA gene detection. This patient received a combined treatment of mirtazapine, mefloquine, and traditional Chinese herbs, and had stabilization of the disease on followed-up. CONCLUSIONS: Although it is a rare, this case demonstrates that JC virus infection within the brain occurs in apparently healthy people. This case may increase our understanding of virus infection when facing the coronavirus epidemic in recent years, considering that similar medications were used.