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Parasites & Vectors Oct 2023In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical... (Review)
Review
In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.
Topics: Humans; Ivermectin; Rifampin; Doxycycline; Fluconazole; Off-Label Use; Anti-Infective Agents; Drug Combinations; Neglected Diseases
PubMed: 37907954
DOI: 10.1186/s13071-023-05909-8 -
Nutrition and Cancer May 2024Considering the established pharmacokinetics and toxicity profiles, drug repurposing has emerged as an alternative therapeutic approach for treating cancer. Mefloquine...
Considering the established pharmacokinetics and toxicity profiles, drug repurposing has emerged as an alternative therapeutic approach for treating cancer. Mefloquine has previously demonstrated inhibitory effects on multiple cancer types. This study aims to explore the impact of mefloquine on nasopharyngeal carcinoma (NPC). We found that mefloquine, at pharmacologically achievable concentrations, displayed anti-NPC activity while sparing normal counterparts. Mefloquine inhibits proliferation and induces death by reducing the levels of Cyclin A2, Bcl-2, and Bcl-xL. Intriguingly, we observed an increase in the levels of the anti-apoptotic protein Mcl-1. Mefloquine exerts its effects on NPC cells by inducing lysosomal-mediated ROS production, and the heightened expression of Mcl-1 is a consequence of ROS generation in mefloquine-treated NPC cells. The combination of an Mcl-1 inhibitor with mefloquine synergistically inhibits NPC growth in mice without causing substantial toxicity. These findings demonstrate the effectiveness and limited toxicity of mefloquine as a monotherapy and in combination with an Mcl-1 inhibitor. Our research underscores the promise of the mefloquine and Mcl-1 inhibitor combination as a potential treatment for NPC. Additionally, the elevation of Mcl-1 is a compensatory response in cells exposed to oxidative stress, offering a potential target to overcome resistance induced by pro-oxidant therapies.
PubMed: 38795070
DOI: 10.1080/01635581.2024.2358561 -
ACS Medicinal Chemistry Letters Jun 2024and are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal...
and are among the most prevalent causes of life-threatening fungal infections globally. The high mortality associated with these infections despite current antifungal therapy highlights the need for new drugs. In our previous work, we demonstrated that an analogue of the clinically used antimalarial mefloquine, (8-chloro-2-(4-chlorophenyl)quinolin-4-yl)(piperidin-2-yl)methanol (), has both antifungal activity and the ability to penetrate the central nervous system. Herein we describe the synthesis and antifungal assay of all four stereoisomers of . All four stereoisomers retain potent antifungal activity with the enantiomers having MIC values of 1 and 4 μg/mL against and respectively, and enantiomers, MIC values of 2 and 8 μg/mL, respectively. These results indicate that the stereochemistry of the piperidine methanol group is not critical for the antifungal properties of and gives guidance to future medicinal chemistry optimization efforts.
PubMed: 38894917
DOI: 10.1021/acsmedchemlett.4c00031 -
The Journal of Infectious Diseases Aug 2023Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects...
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.
Topics: Humans; Atovaquone; Mefloquine; Monkeypox virus
PubMed: 36892247
DOI: 10.1093/infdis/jiad058 -
Epilepsy Research Dec 2023Acquired temporal lobe epilepsy (TLE) characterized by spontaneous recurrent seizures (SRS) and hippocampal inhibitory neuron dysfunction is often refractory to current...
Acquired temporal lobe epilepsy (TLE) characterized by spontaneous recurrent seizures (SRS) and hippocampal inhibitory neuron dysfunction is often refractory to current therapies. Gap junctional or electrical coupling between inhibitory neurons has been proposed to facilitate network synchrony and intercellular molecular exchange suggesting a role in both seizures and neurodegeneration. While gap junction blockers can limit acute seizures, whether blocking neuronal gap junctions can modify development of chronic epilepsy has not been examined. This study examined whether mefloquine, a selective blocker of Connexin 36 gap junctions which are well characterized in inhibitory neurons, can limit epileptogenesis and related cellular and behavioral pathology in a model of acquired TLE. A single, systemic dose of mefloquine administered early after pilocarpine-induced status epilepticus (SE) in rat reduced both development of SRS and behavioral co-morbidities. Immunostaining for interneuron subtypes identified that mefloquine treatment likely reduced delayed inhibitory neuronal loss after SE. Uniquely, parvalbumin expressing neurons in the hippocampal dentate gyrus appeared relatively resistant to early cell loss after SE. Functionally, whole cell patch clamp recordings revealed that mefloquine treatment preserved inhibitory synaptic drive to projection neurons one week and one month after SE. These results demonstrate that mefloquine, a drug already approved for malaria prophylaxis, is potentially antiepileptogenic and can protect against progressive interneuron loss and behavioral co-morbidities of epilepsy.
Topics: Rats; Animals; Neuroprotective Agents; Mefloquine; Status Epilepticus; Seizures; Epilepsy, Temporal Lobe; Hippocampus; Epilepsy; Pilocarpine; Disease Models, Animal
PubMed: 37989006
DOI: 10.1016/j.eplepsyres.2023.107257 -
Pharmaceutics Dec 2023This study investigates the complexation of mefloquine hydrochloride by cyclodextrins to improve its solubility in order to design an oral solution. This approach may...
Rapid Study on Mefloquine Hydrochloride Complexation with Hydroxypropyl-β-Cyclodextrin and Randomly Methylated β-Cyclodextrin: Phase Diagrams, Nuclear Magnetic Resonance Analysis, and Stability Assessment.
This study investigates the complexation of mefloquine hydrochloride by cyclodextrins to improve its solubility in order to design an oral solution. This approach may enhance the effectiveness of mefloquine, a drug which can be used for malaria prophylaxis and treatment in children. Mefloquine hydrochloride's solubility was assessed in different buffer solutions, and its quantification was achieved through high-performance liquid chromatography. The complexation efficiency with cyclodextrins was evaluated, and nuclear magnetic resonance (NMR) methods were employed to determine the interactions between mefloquine and cyclodextrins. Mefloquine's solubility increased when combined with hydroxypropyl-β-cyclodextrin (HP-β-CD) and randomly methylated β-cyclodextrin (RAMEB), with RAMEB being more effective. The drug's solubility varied across different pH buffers, being higher in acidic buffers. Interestingly, mefloquine's solubility decreased with a citrate buffer, possibly due to precipitation. The NMR studies highlighted non-covalent interactions between RAMEB, HP-β-CD, and mefloquine, explaining the solubilizing effect via complexation phenomena. Furthermore, the NMR experiments indicated the complexation of mefloquine by all the studied cyclodextrins, forming diastereoisomeric complexes. Cyclodextrin complexation improved mefloquine's solubility, potentially impacting its bioavailability.
PubMed: 38140134
DOI: 10.3390/pharmaceutics15122794 -
Current Microbiology Jun 2024The antimalarial drug Mefloquine has demonstrated antifungal activity against growth and virulence factors of Candida albicans. The current study focused on the...
The antimalarial drug Mefloquine has demonstrated antifungal activity against growth and virulence factors of Candida albicans. The current study focused on the identification of Mefloquine's mode of action in C. albicans by performing cell susceptibility assay, biofilm assay, live and dead assay, propidium iodide uptake assay, ergosterol quantification assay, cell cycle study, and gene expression studies by RT-PCR. Mefloquine inhibited the virulence factors in C. albicans, such as germ tube formation and biofilm formation at 0.125 and 1 mg/ml, respectively. Mefloquine-treated cells showed a decrease in the quantity of ergosterol content of cell membrane in a concentration-dependent manner. Mefloquine (0.25 mg/ml) arrested C. albicans cells at the G2/M phase and S phase of the cell cycle thereby preventing the progression of the normal yeast cell cycle. ROS level was measured to find out oxidative stress in C. albicans in the presence of mefloquine. The study revealed that, mefloquine was found to enhance the ROS level and subsequently oxidative stress. Gene expression studies revealed that mefloquine treatment upregulates the expressions of SOD1, SOD2, and CAT1 genes in C. albicans. In vivo, the antifungal efficacy of mefloquine was confirmed in mice for systemic candidiasis and it was found that there was a decrease in the pathogenesis of C. albicans after the treatment of mefloquine in mice. In conclusion, mefloquine can be used as a repurposed drug as an alternative drug against Candidiasis.
Topics: Antifungal Agents; Candida albicans; Animals; Mefloquine; Mice; Virulence Factors; Candidiasis; Biofilms; Reactive Oxygen Species; Microbial Sensitivity Tests; Oxidative Stress; Cell Cycle; Superoxide Dismutase-1; Ergosterol; Fungal Proteins
PubMed: 38847863
DOI: 10.1007/s00284-024-03739-0 -
Travel Medicine and Infectious Disease 2023Hair 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...
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.
Topics: Humans; Antimalarials; Proguanil; Atovaquone; Mefloquine; Chromatography, Liquid; Drug Therapy, Combination; Travel; Tandem Mass Spectrometry; Drug Combinations
PubMed: 37209974
DOI: 10.1016/j.tmaid.2023.102590 -
Antimicrobial Agents and Chemotherapy May 2024Capillary samples offer practical benefits compared with venous samples for the measurement of drug concentrations, but the relationship between the two measures varies... (Comparative Study)
Comparative Study
Comparison of lumefantrine, mefloquine, and piperaquine concentrations between capillary plasma and venous plasma samples in pregnant women with uncomplicated falciparum and vivax malaria.
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, = 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, = 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, = 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.
Topics: Humans; Female; Mefloquine; Antimalarials; Pregnancy; Quinolines; Lumefantrine; Malaria, Falciparum; Adult; Malaria, Vivax; Young Adult; Ethanolamines; Fluorenes; Adolescent; Piperazines
PubMed: 38597636
DOI: 10.1128/aac.00093-24 -
BioRxiv : the Preprint Server For... Sep 2023, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which...
, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which couples fast-acting artemisinin derivatives with longer-acting drugs like lumefantrine, mefloquine, and amodiaquine. However, the urgency for new treatments has risen due to the parasite's growing resistance to existing therapies. Our study shows that a common characteristic of the proteome - stretches of poly-lysine residues such as those found in proteins related to adhesion and pathogenicity - can serve as an effective peptide treatment for infected erythrocytes. A single dose of these poly-basic peptides can successfully diminish parasitemia in human erythrocytes with minimal toxicity. The effectiveness of the treatment correlates with the length of the poly-lysine peptide, with 30 lysine peptides supporting the eradication of erythrocytic parasites within 72 hours. PEG-ylation of the poly-lysine peptides or utilizing poly-lysine dendrimers and polymers further increases parasite clearance efficiency and bolsters the stability of these potential new therapeutics. Lastly, our affinity pull-downs and mass-spectrometry identify outer membrane proteins as likely targets for polybasic peptide medications. Since poly-lysine dendrimers are already FDA-approved for drug delivery, their adaptation as antimalarial drugs presents a promising new therapeutic strategy.
PubMed: 37745508
DOI: 10.1101/2023.09.16.558069