5,681 results on '"Mefloquine"'
Search Results
2. A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combinations of 2 Anti-malarial Drugs (Asia) (DeTACT-ASIA)
- Author
-
Mahidol Oxford Tropical Medicine Research Unit
- Published
- 2024
3. Temozolomide, Memantine Hydrochloride, Mefloquine, and Metformin Hydrochloride in Treating Patients With Glioblastoma Multiforme After Radiation Therapy
- Author
-
National Cancer Institute (NCI)
- Published
- 2024
4. Combining Mefloquine with an Mcl-1 Inhibitor as a Novel Therapeutic Strategy for the Treatment of Nasopharyngeal Carcinoma.
- Author
-
Dong, Jiaqi, Zhang, Jianbin, Xiang, Gaojin, and Yang, Ling
- Subjects
- *
BIOLOGICAL models , *FLOW cytometry , *IN vitro studies , *T-test (Statistics) , *DATA analysis , *RESEARCH funding , *MEFLOQUINE , *ANTINEOPLASTIC agents , *APOPTOSIS , *CELL proliferation , *TREATMENT effectiveness , *OXIDATIVE stress , *XENOGRAFTS , *DESCRIPTIVE statistics , *IN vivo studies , *MICE , *CELL lines , *REACTIVE oxygen species , *DRUG repositioning , *ANIMAL experimentation , *WESTERN immunoblotting , *ONE-way analysis of variance , *STATISTICS , *NASOPHARYNX cancer , *COMPARATIVE studies , *SIGNAL peptides , *DRUG synergism , *MALONDIALDEHYDE , *PHARMACODYNAMICS , *CHEMICAL inhibitors - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Solid-State NMR Characterization of Mefloquine Resinate Complexes Designed for Taste-Masking Pediatric Formulations.
- Author
-
Borré, Leandro B., Sousa, Eduardo G. R., San Gil, Rosane A. S., Baptista, Mateus M., Leitão, Alexandre A., De Almeida, João M. A. R., Carr, Olívia, Oliveira Jr., Osvaldo N., Shimizu, Flávio M., and Guimarães, Thiago F.
- Subjects
- *
MAGIC angle spinning , *ELECTRONIC tongues , *CHEMICAL relaxation , *MALARIA prevention , *ION exchange resins , *BITTERNESS (Taste) - Abstract
Mefloquine (MQ) is an antimalarial medication prescribed to treat or malaria prevention.. When taken by children, vomiting usually occurs, and new doses of medication frequently need to be taken. So, developing pediatric medicines using taste-masked antimalarial drug complexes is mandatory for the success of mefloquine administration. The hypothesis that binding mefloquine to an ion-exchange resin (R) could circumvent the drug's bitter taste problem was proposed, and solid-state 13C cross-polarization magic angle spinning (CPMAS) NMR was able to follow MQ–R mixtures through chemical shift and relaxation measurements. The nature of MQ–R complex formation could then be determined. Impedimetric electronic tongue equipment also verified the resinate taste-masking efficiency in vitro. Variations in chemical shifts and structure dynamics measured by proton relaxation properties (e.g., T1ρH) were used as probes to follow the extension of mixing and specific interactions that would be present in MQ–R. A significant decrease in T1ρH values was observed for MQ carbons in MQ–R complexes, compared to the ones in MQ (from 100–200 ms in MQ to 20–50 ms in an MQ–R complex). The results evidenced that the cationic resin interacts strongly with mefloquine molecules in the formulation of a 1:1 ratio complex. Thus, 13C CPMAS NMR allowed the confirmation of the presence of a binding between mefloquine and polacrilin in the MQ–R formulation studied. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
6. Novel Chemotherapeutical Approaches Against Echinococcosis: A Swiss Perspective
- Author
-
Lundström-Stadelmann, Britta, Preza, Matías, Kaethner, Marc, Hemphill, Andrew, Mehlhorn, Heinz, Series Editor, Li, Jian, editor, and Wang, Wei, editor
- Published
- 2024
- Full Text
- View/download PDF
7. Researchers at Federal University Rio de Janeiro Zero in on Malaria (Solid-State NMR Characterization of Mefloquine Resinate Complexes Designed for Taste-Masking Pediatric Formulations)
- Subjects
Pediatrics ,Nuclear magnetic resonance ,Mefloquine ,Malaria ,Physical fitness ,Health - Abstract
2024 AUG 17 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- A new study on malaria is now available. According to news reporting [...]
- Published
- 2024
8. Safety and Efficacy of NF135 CPS Immunization (CPS135)
- Author
-
The PATH Malaria Vaccine Initiative (MVI) and Matthew McCall, dr. MBB McCall
- Published
- 2023
9. Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination.
- Author
-
Capatti Cassiano, Gustavo, Martinelli, Axel, Mottin, Melina, Junior Neves, Bruno, Horta Andrade, Carolina, Eduardo Ferreira, Pedro, and Cravo, Pedro
- Subjects
PLASMODIUM ,WHOLE genome sequencing ,UBIQUITINATION ,MEFLOQUINE ,MOLECULAR structure ,GENETIC variation ,SINGLE nucleotide polymorphisms - Abstract
Introduction: The global evolution of resistance to Artemisinin-based Combination Therapies (ACTs) by malaria parasites, will severely undermine our ability to control this devastating disease. Methods: Here, we have used whole genome sequencing to characterize the genetic variation in the experimentally evolved Plasmodium chabaudi parasite clone AS-ATNMF1, which is resistant to artesunate + mefloquine. Results and discussion: Five novel single nucleotide polymorphisms (SNPs) were identified, one of which was a previously undescribed E738K mutation in a 26S proteasome subunit thatwas selected for under artesunate pressure (in AS-ATN) and retained in AS-ATNMF1. Thewild type and mutated three-dimensional (3D) structure models and molecular dynamics simulations of the P. falciparum 26S proteasome subunit Rpn2 suggested that the E738K mutation could change the toroidal proteasome/cyclosome domain organization and change the recognition of ubiquitinated proteins. The mutation in the 26S proteasome subunit may therefore contribute to altering oxidation-dependent ubiquitination of the MDR-1 and/or K13 proteins and/or other targets, resulting in changes in protein turnover. In light of the alarming increase in resistance to artemisin derivatives and ACT partner drugs in natural parasite populations, our results shed new light on the biology of resistance and provide information on novel molecular markers of resistance that may be tested (and potentially validated) in the field. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
10. Mefloquine-Induced Inner Ear Damage and Preventive Effects of Electrical Stimulation: An Electrophysiological Study.
- Author
-
Ali-Nazari, Mohammad Mahdi, Rahbar, Nariman, Haddadzade Niri, Hassan, and Vasaghi-Gharamaleki, Behnoosh
- Subjects
- *
ELECTRIC stimulation , *INNER ear , *ELECTROPHYSIOLOGY , *MEFLOQUINE , *BRAIN stem - Abstract
Introduction: Mefloquine is an antimalarial medicine used to prevent and treat malaria. This medicine has some side effects, including ototoxicity. This study, which was designed in two phases, aimed to investigate the side effects of mefloquine and evaluate the preventive effects of electrical stimulation on these side effects. Methods: In the first phase, two doses of mefloquine (50 and 200 μM) were injected into male rats, and after 7 days, they were evaluated by an auditory brainstem response (ABR) test. In the second phase, electrical stimulation was applied for 10 days, and then a toxic dose of mefloquine was injected. Similar to the first phase of the study, the animals were evaluated by an ABR test after 7 days. Results: In the first phase, the results showed that a high dose of mefloquine increased the ABR threshold and wave I latency; however, these changes were not observed in the second phase. Conclusion: Application of electrical stimulation could prevent the ototoxic effects of mefloquine. According to the findings of the present study, electrical stimulation can be used as a preconditioner to prevent the ototoxic effects of mefloquine. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
11. (1 R / S ,7a S / R)-1-Benzyl-1-[2,8-bis(trifluoromethyl)quinolin-4-yl]-hexahydro-oxazolo[3,4- a ]pyridin-3-one.
- Author
-
Kucharski, Dawid J. and Boratyński, Przemysław J.
- Subjects
- *
CARBON-carbon bonds , *MEFLOQUINE , *ETHERIFICATION , *PROTON transfer reactions - Abstract
An unexpected diastereoselective C-alkylation of a mefloquine derivative in up to 57% yield was the result of an attempted Williamson etherification of Boc-mefloquine. The domino reaction involved oxazolidinone ring closure, deprotonation, and stereoselective carbon–carbon bond formation. The structure was confirmed with 2D NMR experiments. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. An In Silico and In Vitro Assessment of the Neurotoxicity of Mefloquine.
- Author
-
El Sharazly, Basma M., Ahmed, Abrar, Elsheikha, Hany M., and Carter, Wayne G.
- Subjects
ACETYLCHOLINESTERASE ,MEFLOQUINE ,NEUROTOXICOLOGY ,REACTIVE oxygen species ,LACTATE dehydrogenase ,CHOLINESTERASE inhibitors ,CELL death ,CELL survival - Abstract
Mefloquine (MQ) is a quinoline-based anti-malarial drug used for chemoprophylaxis or as a treatment in combination with artesunate. Although MQ has clear anti-Plasmodium falciparum properties, it can induce neurotoxicity and undesired neuropsychiatric side effects in humans. Hence, this study aimed to characterize the neurotoxicity of MQ using human neuroblastoma SH-SY5Y cells. The effects of MQ on neuronal toxicity and cell viability were investigated over a concentration range of 1–100 µM using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The influence of MQ on cellular bioenergetics was examined by measuring cellular ATP levels and from the induction of reactive oxygen species (ROS). An in silico approach was used to assess the potential neurotoxicity of MQ mediated via binding to the active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and then experimentally validated via in vitro enzymatic assays. MQ was cytotoxic to neuronal cells in a concentration and exposure duration dependent manner and induced a significant reduction in viability at concentrations of ≥25 µM after a 24 h exposure. MQ adversely impacted cellular bioenergetics and significantly depleted ATP production at concentrations of ≥1 µM after 24 h. MQ-induced cellular ROS production, which was correlated with the induction of apoptosis, as revealed by flow cytometry. In silico studies suggested that MQ was a dual cholinesterase inhibitor and one with remarkably potent binding to BuChE. Modelling data were supported by in vitro studies which showed that MQ inhibited both human AChE and BuChE enzymes. In summary, MQ is an antimalarial drug that may induce neurotoxicity by impacting cellular bioenergetics and perturbing the activity of cholinesterases at exposure concentrations relevant to human dosage. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
13. Efficacy of Mefloquine as Prophylaxis Against COVID-19: A Placebo-control, Randomized Clinical Trial
- Author
-
Ain Shams University, Fayoum University, Assiut University, Tanta University, National Institute of Infectious Diseases, Tokyo, Japan, and Mohamed El Kassas, Associate professor and chief of Endemic Medicine Department
- Published
- 2023
14. Compare the Effectiveness Between Existing Treatment and New Treatment (RDM)
- Published
- 2023
15. A case of progressive multifocal leukoencephalopathy in a post-kidney transplant patient with improvement after discontinuation of immunosuppressive drugs and combination therapy with mefloquine and mirtazapine
- Author
-
Neri Sone, Hiroki Nishiwaki, Mayu Shimokawa, Keishu Kawanishi, Tsuyoshi Oshiro, Reiji Takami, Natsuki Taira, Masahito Amagasa, Shinya Omiya, Tadahide Maezumi, Yoko Nabeshima, Kazuo Nakamichi, Yoshiharu Miura, and Fumihiko Koiwa
- Subjects
Progressive multifocal leukoencephalopathy ,Immunosuppression ,Mirtazapine ,Mefloquine ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background Progressive multifocal leukoencephalopathy is a rare disease, but the prognosis is very poor, especially in the immunosuppressed state with a non-HIV background, and there is no established treatment. Case presentations A 49-year-old patient who had undergone a renal transplant and was receiving prednisolone and mycophenolate mofetil treatment was admitted for peritoneal dialysis initiation. While hospitalized, he experienced aphasia and other percutaneous symptoms. Magnetic resonance imaging of the brain revealed a subcortical demyelinating lesion. JC virus DNA was identified in cerebrospinal fluid, and he was diagnosed with progressive multifocal leukoencephalopathy. Immunosuppressant was ceased, and he was treated with mefloquine and mirtazapine. The patient subsequently underwent a head MRI scan, confirming lesion reduction, improved activities of daily life, and survival. Conclusions Progressive multifocal leukoencephalopathy is commonly observed in patients with compromised immune systems, which was the case for this patient due to long-standing immunosuppressive medication usage and end-stage renal failure necessitating dialysis.
- Published
- 2023
- Full Text
- View/download PDF
16. Synthesis, antiproliferative and antiplasmodial evaluation of new chloroquine and mefloquine-based harmiquins
- Author
-
Pavić Kristina, Poje Goran, Carvalho Lais Pessanha De, Held Jana, and Rajić Zrinka
- Subjects
chloroquine ,mefloquine ,β-carboline ,harmine ,anti-plasmodial activity ,antiproliferative activity ,Pharmaceutical industry ,HD9665-9675 - Abstract
Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and β-carboline alkaloid harmine against cancer cell lines and Plasmodium falciparum. The hybrids were prepared from the corresponding amines by 1,1′-carbonyldiimidazole (CDI)-mediated synthesis. In vitro evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine 16 as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 (IC50 = 5.48 ± 3.35 μmol L−1). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the Plasmodium life cycle identified CQ-based UT harmiquine 12 as a novel antiplasmodial hit because it displayed low IC50 values in the submicromolar range against CQ-sensitive and resistant strains (IC50 0.06 ± 0.01, and 0.19 ± 0.02 μmol L−1, respectively), and exhibited high selectivity against Plasmodium, compared to mammalian cells (SI = 92).
- Published
- 2023
- Full Text
- View/download PDF
17. Combination of AS101 and Mefloquine Inhibits Carbapenem-Resistant Pseudomonas aeruginosa in vitro and in vivo
- Author
-
Li R, Shen X, Li Z, Shen J, Tang H, Xu H, and Xu Y
- Subjects
as101 ,mefloquine ,carbapenem resistance ,pseudomonas aeruginosa ,synergy ,biofilm ,Infectious and parasitic diseases ,RC109-216 - Abstract
Rongrong Li,1,2 Xuhang Shen,3 Zhengyuan Li,4 Jilong Shen,2 Hao Tang,5 Huaming Xu,6 Jilu Shen,1,7 Yuanhong Xu1 1Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 4Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 5Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 6Department of Clinical Laboratory, the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, People’s Republic of China; 7Anhui Public Health Clinical Center, Hefei, People’s Republic of ChinaCorrespondence: Yuanhong Xu, Tel +86 13505694447, Email xyhong1964@163.comBackground: In recent years, carbapenem-resistant Pseudomonas aeruginosa (CRPA) has spread around the world, leading to a high mortality and close attention of medical community. In this study, we aim to find a new strategy of treatment for CRPA infections.Methods: Eight strains of CRPA were collected, and PCR detected the multi-locus sequence typing (MLST). The antimicrobial susceptibility test was conducted using the VITEK@2 compact system. The minimum inhibitory concentration (MIC) for AS101 and mefloquine was determined using the broth dilution method. Antibacterial activity was tested in vitro and in vivo through the chessboard assay, time killing assay, and a mouse model. The mechanism of AS101 combined with mefloquine against CRPA was assessed through the biofilm formation inhibition assay, electron microscopy, and detection of reactive oxygen species (ROS).Results: The results demonstrated that all tested CRPA strains exhibited multidrug resistance. Moreover, our investigation revealed a substantial synergistic antibacterial effect of AS101-mefloquine in vitro. The assay for inhibiting biofilm formation indicated that AS101-mefloquine effectively suppressed the biofilm formation of CRPA-5 and CRPA-6. Furthermore, AS101-mefloquine were observed to disrupt the bacterial cell wall and enhance the permeability of the cell membrane. This effect was achieved by stimulating the production of ROS, which in turn hindered the growth of CRPA-3. To evaluate the therapeutic potential, a murine model of CRPA-3 peritoneal infection was established. Notably, AS101-mefloquine administration resulted in a significant reduction in bacterial load within the liver, kidney, and spleen of mice after 72 hours of treatment.Conclusion: The present study showed that the combination of AS101 and mefloquine yielded a notable synergistic bacteriostatic effect both in vitro and in vivo, suggesting a potential clinical application of this combination in the treatment of CRPA.Keywords: AS101, mefloquine, carbapenem resistance, Pseudomonas aeruginosa, synergy, biofilm
- Published
- 2023
18. Solid-State NMR Characterization of Mefloquine Resinate Complexes Designed for Taste-Masking Pediatric Formulations
- Author
-
Leandro B. Borré, Eduardo G. R. Sousa, Rosane A. S. San Gil, Mateus M. Baptista, Alexandre A. Leitão, João M. A. R. De Almeida, Olívia Carr, Osvaldo N. Oliveira, Flávio M. Shimizu, and Thiago F. Guimarães
- Subjects
mefloquine ,CPMAS NMR ,ion-exchange resin ,13C NMR ,T1ρH relaxation time ,taste masking ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Mefloquine (MQ) is an antimalarial medication prescribed to treat or malaria prevention.. When taken by children, vomiting usually occurs, and new doses of medication frequently need to be taken. So, developing pediatric medicines using taste-masked antimalarial drug complexes is mandatory for the success of mefloquine administration. The hypothesis that binding mefloquine to an ion-exchange resin (R) could circumvent the drug’s bitter taste problem was proposed, and solid-state 13C cross-polarization magic angle spinning (CPMAS) NMR was able to follow MQ–R mixtures through chemical shift and relaxation measurements. The nature of MQ–R complex formation could then be determined. Impedimetric electronic tongue equipment also verified the resinate taste-masking efficiency in vitro. Variations in chemical shifts and structure dynamics measured by proton relaxation properties (e.g., T1ρH) were used as probes to follow the extension of mixing and specific interactions that would be present in MQ–R. A significant decrease in T1ρH values was observed for MQ carbons in MQ–R complexes, compared to the ones in MQ (from 100–200 ms in MQ to 20–50 ms in an MQ–R complex). The results evidenced that the cationic resin interacts strongly with mefloquine molecules in the formulation of a 1:1 ratio complex. Thus, 13C CPMAS NMR allowed the confirmation of the presence of a binding between mefloquine and polacrilin in the MQ–R formulation studied.
- Published
- 2024
- Full Text
- View/download PDF
19. Study Results from NOVA University Lisbon Broaden Understanding of Malaria [Whole Genome Sequencing Identifies Novel Mutations In Malaria Parasites Resistant To Artesunate (Atn) and To Atn Plus Mefloquine Combination]
- Subjects
Nucleotide sequencing -- Genetic aspects ,Genomics -- Genetic aspects ,DNA sequencing -- Genetic aspects ,Mefloquine ,Plasmodium falciparum -- Genetic aspects ,Physical fitness ,Health ,Nova Southeastern University - Abstract
2024 APR 13 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- New research on Mosquito-Borne Diseases - Malaria is the subject of a [...]
- Published
- 2024
20. Rapid Study on Mefloquine Hydrochloride Complexation with Hydroxypropyl-β-Cyclodextrin and Randomly Methylated β-Cyclodextrin: Phase Diagrams, Nuclear Magnetic Resonance Analysis, and Stability Assessment.
- Author
-
Durand, Amaury, Mathiron, David, Rigaud, Sébastien, Djedaini-Pilard, Florence, and Marçon, Frédéric
- Subjects
- *
NUCLEAR magnetic resonance , *CYCLODEXTRINS , *MEFLOQUINE , *PHASE diagrams , *DRUG solubility , *HIGH performance liquid chromatography , *LIQUID chromatography-mass spectrometry - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
21. Design, synthesis, and in silico-in vitro antimalarial evaluation of 1,2,3-triazole-linked dihydropyrimidinone quinoline hybrids.
- Author
-
Adigun, Rasheed A., Malan, Frederick P., Balogun, Mohammed O., and October, Natasha
- Subjects
- *
CHEMICAL synthesis , *CLICK chemistry , *GLUTATHIONE reductase , *MEFLOQUINE , *MOLECULAR dynamics , *QUINOLINE - Abstract
In response to the malaria parasite's resistance towards quinoline-based antimalarial drugs, we have employed quinoline-containing compounds in combination with dihydropyrimidinone (DHPM) analogues as resistance reversal agents (RAs) and investigated their antimalarial activities based on DHPM's resistance reversal abilities. The present study employed click chemistry to link DHPM and quinoline compounds which offered several synthetic advantages over the previously used amide coupling for the same hybrids. Among the synthesised compounds, 4 hybrids with the 7-chloroquinoline moiety showed antimalarial activity below 1 µM while compounds with the mefloquine moiety showed lower antimalarial activity than chloroquine (CQ) and the 7-chloroquinoline hybrids. Among the tested hybrids for the IC50 determination, four compounds displayed good antimalarial activity with increased sensitivity against the CQ-resistant K1 strain between 421 and 567 nM and showed higher activity between 138 and 245 nM against the NF54 CQ-sensitive strain, while three compounds have IC50 values greater than 5 µM. Additionally, in silico molecular docking and molecular dynamics studies were conducted to investigate the binding affinities of all the synthesised compounds as glutathione reductase protein competitive inhibitors. Further optimisation of the compound with the highest binding affinity generated 16 compounds with higher binding affinities than the flavine adenine dinucleotide (FAD) cofactor. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
22. The pipeline for drugs for control and elimination of neglected tropical diseases: 2. Oral anti-infective drugs and drug combinations for off-label use.
- Author
-
Pfarr, Kenneth M., Krome, Anna K., Al-Obaidi, Issraa, Batchelor, Hannah, Vaillant, Michel, Hoerauf, Achim, Opoku, Nicholas O., and Kuesel, Annette C.
- Subjects
- *
NEGLECTED diseases , *ORAL medication , *OFF-label use (Drugs) , *AFRICAN trypanosomiasis , *THERAPEUTICS , *ITRACONAZOLE - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
23. Mefloquine targets NLRP3 to reduce lipopolysaccharide‐induced systemic inflammation and neural injury.
- Author
-
Jiang, Si‐Yuan, Tian, Tian, Li, Wen‐Jie, Liu, Ting, Wang, Cong, Hu, Gang, Du, Ren‐Hong, Liu, Yang, and Lu, Ming
- Abstract
The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well‐known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA‐approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide‐induced systemic inflammation and Parkinson's disease‐like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3‐driven diseases and migth expand its clinical use considerably. Synopsis: Mefloquine is a highly selective and potent NLRP3 inhibitor. Mefloquine directly binds to the NACHT and LRR domains of NLRP3, impairs inflammasome assembly and reduces NLRP3‐dependent systemic inflammation and neural injury in mice. By screening a panel of FDA‐approved drugs, mefloquine is identified as a potent and specific NLRP3 inhibitor.Mefloquine directly binds to NLRP3 and inhibits inflammasome activation.Mefloquine suppresses LPS‐induced NLRP3‐driven systemic inflammation and neural injury in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
24. Mefloquine-curcumin combinations improve host mitochondrial respiration and decrease mitotoxic effects of mefloquine in Plasmodium berghei-infected mice
- Author
-
John Oludele Olanlokun, Oshireku Wisdom Abiodun, Adekunle Theophilus Adegbuyi, Neil Anthony Koorbanally, and Olufunso Olabode Olorunsogo
- Subjects
Curcumin ,Electron transport protein ,Malaria ,Mefloquine ,Plasmodium berghei ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Plasmodium infection is a health challenge. Although, antiplasmodial drugs kill the parasites, information on the effects of infection and drugs on the expression of some genes is limited.Malaria was induced in two different studies using NK65 (chloroquine-susceptible, study 1), and ANKA (chloroquine-resistant, study 2) strains of Plasmodium berghei in 30 male Swiss mice (n = 5) in each study. Mice orally received 10 mL/kg distilled water, (infected control), Mefloquine (MF) (10 mg/kg), MF and Curcumin (CM) (25 mg/kg), MF and CM (50 mg/kg), CM (25 mg/kg) and CM (50 mg/kg). Five mice (un-infected) were used as the control. After treatment, total Ribonucleic acid (RNA) was isolated from liver and erythrocytes while Deoxyribonucleic acid (DNA)-free RNA were converted to cDNA. Polymerase Chain Reaction (PCR) amplification was performed and relative expressions of FIKK12, AQP3, P38 MAPK, NADH oxidoreductase, and cytochrome oxidase expressions were determined. Markers of glycolysis, toxicity and antioxidants were determined using ELISA assays. While the expression of FIKK12 was blunted by MF in the susceptible study, co-treatment with curcumin (25 mg/kg) yielded the same results in the chloroquine-resistant study. Similar results were obtained on AQP3 in both studies. Curcumin decreased P38 MAPK in both studies. Plasmodium infection decreased NADH oxidoreductase and cytochrome oxidase but mefloquine-curcumin restored the expression of these genes. While glycolysis and toxicity were inhibited, antioxidant systems improved in the treated groups. Curcumin is needed for effective therapeutic efficacy and prevention of toxicity. Plasmodium infection and treatment modulate the expressions of some genes in the host. Curcumin combination with mefloquine modulates the expression of some genes in the host.
- Published
- 2024
- Full Text
- View/download PDF
25. Mefloquine
- Author
-
Pant, AB
- Published
- 2024
- Full Text
- View/download PDF
26. Malaria PK/PD and the Role Pharmacometrics Can Play in the Global Health Arena: Malaria Treatment Regimens for Vulnerable Populations
- Author
-
Hughes, Emma, Wallender, Erika, Ali, Ali Mohamed, Jagannathan, Prasanna, and Savic, Radojka M
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Clinical Sciences ,HIV/AIDS ,Pediatric ,Rare Diseases ,Infectious Diseases ,Clinical Research ,Malaria ,Orphan Drug ,Vector-Borne Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Amodiaquine ,Anti-HIV Agents ,Antimalarials ,Artemether ,Lumefantrine Drug Combination ,Artemisinins ,Artesunate ,Child ,Preschool ,Dose-Response Relationship ,Drug ,Drug Combinations ,Drug Interactions ,Drug Therapy ,Combination ,Female ,Global Health ,HIV Infections ,Humans ,Malnutrition ,Mefloquine ,Models ,Biological ,Pregnancy ,Pregnancy Complications ,Parasitic ,Pyrimethamine ,Quinolines ,Sulfadoxine ,Vulnerable Populations ,Pharmacology and Pharmaceutical Sciences ,Pharmacology & Pharmacy ,Pharmacology and pharmaceutical sciences - Abstract
Malaria is an infectious disease which disproportionately effects children and pregnant women. These vulnerable populations are often excluded from clinical trials resulting in one-size-fits-all treatment regimens based on those established for a nonpregnant adult population. Pharmacokinetic/pharmacodynamic (PK/PD) models can be used to optimize dose selection as they define the drug exposure-response relationship. Additionally, these models are able to identify patient characteristics that cause alterations in the expected PK/PD profiles and through simulations can recommend changes to dosing which compensate for the differences. In this review, we examine how PK/PD models have been applied to optimize antimalarial dosing recommendations for young children, including those who are malnourished, pregnant women, and individuals receiving concomitant therapies such as those for HIV treatment. The malaria field has had great success in utilizing PK/PD models as a foundation to update treatment guidelines and propose the next generation of dosing regimens to investigate in clinical trials. We propose how the malaria field can continue to use modeling to improve therapies by further integrating PK data into clinical studies and including data on drug resistance and host immunity in PK/PD models. Finally, we suggest that other disease areas can achieve similar success in applying pharmacometrics to improve outcomes by implementing three key principals.
- Published
- 2021
27. Antimalarial prophylaxis failure: Malaria in a returning traveler despite mefloquine prophylaxis.
- Author
-
Utpat, Sandeepa, Hussain, Fahad, Dikengil, Cem, Utpat, Nishka, and Nookala, Vinod
- Subjects
- *
MEFLOQUINE , *MALARIA , *BREAKTHROUGH infections , *PREVENTIVE medicine , *ANTIMALARIALS - Abstract
This case report presents a perplexing case of Plasmodium malariae breakthrough infection despite prophylaxis with appropriate antimalarial prophylactic regimen of mefloquine in a compliant patient. A 78-year-old missionary who travels each year to the African subcontinent for multiple weeks to months, over 25 years, adheres to stringent antimalarial prophylaxis with Mefloquine as prescribed, starting prior to the trip and continuing after the return to the U.S.A. She gave no prior history of malaria during her 25 years of travel to Africa and back. Since she had no prior history of malaria and due to her excellent compliance with antimalarial regiment, despite her presentation which were suggestive of malaria, neither the patient nor her providers recognized the onset of malaria in this case. Infectious diseases physicians approached this case with an open mind, investigated appropriately, requested appropriate tests, found the presence of malarial parasite, identified as P. malariae species thereafter. She was started on antimalarial treatment in a timely fashion and showed an excellent response. This intriguing recovery of malarial parasite and response to treatment despite the patient being on antimalarial prophylaxis raised the possibility of mefloquine failure as an antimalarial prophylactic agent against P. malariae species. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
28. Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis
- Author
-
Roman Memedovski, Matías Preza, Joachim Müller, Tobias Kämpfer, Reto Rufener, Marcus Vinicius Nora de Souza, Emerson Teixeira da Silva, Gabriel Fernandes de Andrade, Sophie Braga, Anne-Christine Uldry, Natasha Buchs, Manfred Heller, and Britta Lundström-Stadelmann
- Subjects
Echinococcus multilocularis ,Alveolar echinococcosis ,Mefloquine ,Structure-activity relationship (SAR) ,Mode of action ,nLC-MS/MS ,Infectious and parasitic diseases ,RC109-216 - Abstract
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.
- Published
- 2023
- Full Text
- View/download PDF
29. Randomised Trial of 3 Artemisinin Combination Therapy for Malaria in Pregnancy (DMA)
- Published
- 2022
30. (1R/S,7aS/R)-1-Benzyl-1-[2,8-bis(trifluoromethyl)quinolin-4-yl]-hexahydro-oxazolo[3,4-a]pyridin-3-one
- Author
-
Dawid J. Kucharski and Przemysław J. Boratyński
- Subjects
mefloquine ,oxazolidinone ,C-alkylation ,diastereoselectivity ,Inorganic chemistry ,QD146-197 - Abstract
An unexpected diastereoselective C-alkylation of a mefloquine derivative in up to 57% yield was the result of an attempted Williamson etherification of Boc-mefloquine. The domino reaction involved oxazolidinone ring closure, deprotonation, and stereoselective carbon–carbon bond formation. The structure was confirmed with 2D NMR experiments.
- Published
- 2023
- Full Text
- View/download PDF
31. Potential Anti-Mpox Virus Activity of Atovaquone, Mefloquine, and Molnupiravir, and Their Potential Use as Treatments.
- Author
-
Akazawa, Daisuke, Ohashi, Hirofumi, Hishiki, Takayuki, Morita, Takeshi, Iwanami, Shoya, Kim, Kwang Su, Jeong, Yong Dam, Park, Eun-Sil, Kataoka, Michiyo, Shionoya, Kaho, Mifune, Junki, Tsuchimoto, Kana, Ojima, Shinjiro, Azam, Aa Haeruman, Nakajima, Shogo, Park, Hyeongki, Yoshikawa, Tomoki, Shimojima, Masayuki, Kiga, Kotaro, and Iwami, Shingo
- Subjects
- *
MOLNUPIRAVIR , *MEFLOQUINE , *DIHYDROOROTATE dehydrogenase , *MONKEYPOX , *VIRAL DNA - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
32. Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer
- Subjects
Membrane lipids ,Mefloquine ,Physical fitness ,Health - Abstract
2024 JAN 13 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- According to news reporting based on a preprint abstract, our journalists obtained [...]
- Published
- 2024
33. Pyronaridine - Artesunate (3:1) Versus Mefloquine Plus Artesunate in Plasmodium Falciparum Malaria Patients
- Author
-
Shin Poong Pharmaceuticals
- Published
- 2021
34. An In Silico and In Vitro Assessment of the Neurotoxicity of Mefloquine
- Author
-
Basma M. El Sharazly, Abrar Ahmed, Hany M. Elsheikha, and Wayne G. Carter
- Subjects
antimalarial drug ,cholinesterase inhibitor ,mefloquine ,neurotoxicity ,redox stress ,Biology (General) ,QH301-705.5 - Abstract
Mefloquine (MQ) is a quinoline-based anti-malarial drug used for chemoprophylaxis or as a treatment in combination with artesunate. Although MQ has clear anti-Plasmodium falciparum properties, it can induce neurotoxicity and undesired neuropsychiatric side effects in humans. Hence, this study aimed to characterize the neurotoxicity of MQ using human neuroblastoma SH-SY5Y cells. The effects of MQ on neuronal toxicity and cell viability were investigated over a concentration range of 1–100 µM using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The influence of MQ on cellular bioenergetics was examined by measuring cellular ATP levels and from the induction of reactive oxygen species (ROS). An in silico approach was used to assess the potential neurotoxicity of MQ mediated via binding to the active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and then experimentally validated via in vitro enzymatic assays. MQ was cytotoxic to neuronal cells in a concentration and exposure duration dependent manner and induced a significant reduction in viability at concentrations of ≥25 µM after a 24 h exposure. MQ adversely impacted cellular bioenergetics and significantly depleted ATP production at concentrations of ≥1 µM after 24 h. MQ-induced cellular ROS production, which was correlated with the induction of apoptosis, as revealed by flow cytometry. In silico studies suggested that MQ was a dual cholinesterase inhibitor and one with remarkably potent binding to BuChE. Modelling data were supported by in vitro studies which showed that MQ inhibited both human AChE and BuChE enzymes. In summary, MQ is an antimalarial drug that may induce neurotoxicity by impacting cellular bioenergetics and perturbing the activity of cholinesterases at exposure concentrations relevant to human dosage.
- Published
- 2024
- Full Text
- View/download PDF
35. Comparison of Arterolane-piperaquine Versus Arterolane-piperaquine+Mefloquine Versus Artemether-lumefantrine in Kenyan Children (TACTKenya)
- Author
-
Mahidol Oxford Tropical Medicine Research Unit
- Published
- 2021
36. Integrative Genetic Manipulation of Plasmodium cynomolgi Reveals Multidrug Resistance-1 Y976F Associated With Increased In Vitro Susceptibility to Mefloquine.
- Author
-
Ward, Kurt E, Christensen, Peter, Racklyeft, Annie, Dhingra, Satish K, Chua, Adeline C Y, Remmert, Caroline, Suwanarusk, Rossarin, Matheson, Jessica, Blackman, Michael J, Kaneko, Osamu, Kyle, Dennis E, Lee, Marcus C S, Moon, Robert W, Snounou, Georges, Rénia, Laurent, Fidock, David A, Russell, Bruce, and Bifani, Pablo
- Subjects
- *
MEFLOQUINE , *REVERSE genetics , *PLASMODIUM , *PLASMODIUM vivax , *DRUG resistance - Abstract
The lack of a long-term in vitro culture method has severely restricted the study of Plasmodium vivax , in part because it limits genetic manipulation and reverse genetics. We used the recently optimized Plasmodium cynomolgi Berok in vitro culture model to investigate the putative P. vivax drug resistance marker MDR1 Y976F. Introduction of this mutation using clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9 (CRISPR-Cas9) increased sensitivity to mefloquine, but had no significant effect on sensitivity to chloroquine, amodiaquine, piperaquine, and artesunate. To our knowledge, this is the first reported use of CRISPR-Cas9 in P. cynomolgi , and the first reported integrative genetic manipulation of this species. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
37. Whole sporozoite immunization with Plasmodium falciparum strain NF135 in a randomized trial.
- Author
-
van der Boor, Saskia C., Alkema, Manon, van Gemert, Geert-Jan, Teelen, Karina, van de Vegte-Bolmer, Marga, Walk, Jona, van Crevel, Reinout, de Mast, Quirijn, Ockenhouse, Christian F., Sauerwein, Robert W., and McCall, Matthew B. B.
- Subjects
- *
PLASMODIUM falciparum , *IMMUNIZATION , *SPOROZOITES , *MEFLOQUINE - Abstract
Background: Whole sporozoite immunization under chemoprophylaxis (CPS regime) induces long-lasting sterile homologous protection in the controlled human malaria infection model using Plasmodium falciparum strain NF54. The relative proficiency of liver-stage parasite development may be an important factor determining immunization efficacy. Previous studies show that Plasmodium falciparum strain NF135 produces relatively high numbers of large liver-stage schizonts in vitro. Here, we evaluate this strain for use in CPS immunization regimes. Methods: In a partially randomized, open-label study conducted at the Radboudumc, Nijmegen, the Netherlands, healthy, malaria-naïve adults were immunized by three rounds of fifteen or five NF135-infected mosquito bites under mefloquine prophylaxis (cohort A) or fifteen NF135-infected mosquito bites and presumptive treatment with artemether/lumefantrine (cohort B). Cohort A participants were exposed to a homologous challenge 19 weeks after immunization. The primary objective of the study was to evaluate the safety and tolerability of CPS immunizations with NF135. Results: Relatively high liver-to-blood inocula were observed during immunization with NF135 in both cohorts. Eighteen of 30 (60%) high-dose participants and 3/10 (30%) low-dose participants experienced grade 3 adverse events 7 to 21 days following their first immunization. All cohort A participants and two participants in cohort B developed breakthrough blood-stage malaria infections during immunizations requiring rescue treatment. The resulting compromised immunizations induced modest sterile protection against homologous challenge in cohort A (5/17; 29%). Conclusions: These CPS regimes using NF135 were relatively poorly tolerated and frequently required rescue treatment, thereby compromising immunization efficiency and protective efficacy. Consequently, the full potential of NF135 sporozoites for induction of immune protection remains inconclusive. Nonetheless, the high liver-stage burden achieved by this strain highlights it as an interesting potential candidate for novel whole sporozoite immunization approaches. Trial registration: The trial was registered at ClinicalTrials.gov under identifier NCT03813108. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
38. Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis.
- Author
-
Memedovski, Roman, Preza, Matías, Müller, Joachim, Kämpfer, Tobias, Rufener, Reto, de Souza, Marcus Vinicius Nora, da Silva, Emerson Teixeira, de Andrade, Gabriel Fernandes, Braga, Sophie, Uldry, Anne-Christine, Buchs, Natasha, Heller, Manfred, and Lundström-Stadelmann, Britta
- Abstract
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. [Display omitted] • E. multilocularis metacestodes cause alveolar echinococcosis (AE) in humans. • Current AE treatment is based on benzimidazoles with parasitostatic effects. • Mefloquine (MEF) acts in vitro and in mice against metacestodes. • MEF derivatives for analysis of structure activities and modes of action. • Energy metabolism and cellular transport as MEF-binding target pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
39. Assessment of Artesunate/Mefloquine in the Peruvian Amazon (Artesunate)
- Author
-
U.S. Naval Medical Research Unit No.6 (NAMRU-6)
- Published
- 2021
40. Merozoite Surface Protein 1 Antibody Response in Asymptomatic Human Malaria Infection
- Author
-
Walter Reed Army Institute of Research (WRAIR)
- Published
- 2021
41. Evaluation of Artesunate-mefloquine as a Novel Alternative Treatment for Schistosomiasis in African Children (SchistoSAM)
- Author
-
Institut de Recherche en Santé, de Surveillance Épidémiologique et de Formation (IRESSEF)
- Published
- 2021
42. JC virus-induced progressive multifocal leukoencephalopathy in a presumably healthy patient
- Author
-
Xiang Wang, Jinxiu Chen, Jing Gong, Ying Wu, and Xiang-hao Liu
- Subjects
Progressive multifocal leukoencephalopathy ,JC virus ,Immunocompetence ,Mirtazapine ,Mefloquine ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract 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. Graphical Abstract
- Published
- 2022
- Full Text
- View/download PDF
43. Drug Combinations of Atovaquone-Proguanil (AP) With ACT (APACT)
- Author
-
National Center for Parasitology, Entomology, and Malaria Control (CNM) and Naval Medical Research Unit-2 (NAMRU-2)
- Published
- 2021
44. Malaria Elimination Pilot Study in Military Forces in Cambodia
- Author
-
National Center for Parasitology, Entomology, and Malaria Control (CNM) and Ministry of National Defense, Royal Cambodian Armed Forces Department of Health
- Published
- 2021
45. A Study of the Effectiveness of an Off Label Mefloquine Use for the Treatment of Patients With COVID19
- Author
-
Tatyana Astrelina, MD PhD, DSc (medicine), Head of Center for Biomedical Technologies State Research Center Burnasyan Federal Medical Biophysical Center FMBA of Russia
- Published
- 2021
46. The cardiovascular toxicity of antimalarial drugs
- Author
-
Chan, Xin-Hui Supanee and White, Nicholas John
- Subjects
616.9 ,Malaria--Chemotherapy ,Cardiac arrest ,Malaria ,Long QT syndrome ,Malaria--Prevention ,Antimalarials ,Quinoline ,Quinine ,Quinidine ,Arrhythmia ,Sudden death ,Primaquine ,Chloroquine ,Mefloquine ,Hypotension - Abstract
Malaria is an ancient mosquito-borne parasitic disease from which over a thousand – mostly children in sub-Saharan Africa – still die of needlessly every day. For half a millennium, quinine and quinine-like antimalarial drugs have been the mainstay of malaria treatment and prevention. In the 18th century, the chance observation of their ability to quell palpitations led to their becoming the first anti-arrhythmic agents. Some of these anti-arrhythmic antimalarials later came to define the adverse drug reaction of repolarisation-related cardiotoxicity as sudden deaths, ventricular tachyarrhythmias, and electrocardiographic QT interval prolongation were in turn causally associated with their use. With increasing population-level use of antimalarials for malaria elimination, there has been renewed global interest in defining the cardiovascular toxicity of key members of this drug class to guide antimalarial choice and dosage for development and deployment. In this thesis, I investigate the repolarisation-related cardiotoxicity of the quinoline and structurally-related oral antimalarials mostly widely used in malaria treatment, prevention, and drug development. In Chapter 3, I find that the risk of sudden unexplained death after dihydroartemisinin-piperaquine, a leading candidate for mass drug administration and intermittent preventive therapy for malaria, is no higher than baseline. In Chapter 4, I report how torsade de pointes and other clinically significant arrhythmias have not been documented after front-line antimalarials at standard malaria doses despite extensive use. In Chapter 5, I identify independent effects of malaria severity and fever on the QT interval accounting for the greater post-drug prolongation in malaria patients compared to healthy individuals. In Chapter 6, I present the QT interval prolongation and heart rate reduction from artesunate-amodiaquine compared with other front-line antimalarials and propose bradycardia may underlie amodiaquine-associated asthenia. I conclude that chloroquine, piperaquine, amodiaquine, and lumefantrine remain safe at World Health Organization-recommended doses and combinations for the treatment, prevention, and global eradication of malaria.
- Published
- 2019
47. In silico analysis of novel azetidinone substituted benzotriazole and benzimidazole derivatives as Plasmodium falciparum glutamate dehydrogenase inhibitors
- Author
-
Badeliya, Sandip N., Kapupara, Pankaj P., and Chaudhary, Ankit B.
- Published
- 2022
- Full Text
- View/download PDF
48. A Cross-sectional Cohort Study to Assess Long-term Neurocognitive and Psychiatric Symptoms of Mefloquine Use in Veterans.
- Author
-
Reinhard, Matthew J, Chester, Jeremy E, Breneman, Charity B, Samuel, Immanuel B H, Prisco, Michelle K, Vincent, Terra D, Rumm, Peter D, Smith, Shanna R, and Barrett, John P
- Subjects
- *
MEFLOQUINE , *ANTIMALARIALS , *DRUG side effects , *VETERANS , *QUINOLINE - Abstract
Introduction To evaluate the associations between neurocognitive and psychiatric health outcomes with mefloquine or any antimalarial exposure. Materials and Methods Medical records were systematically reviewed to identify veterans that indicated antimalarial medication use. Linear regression was performed to examine associations between mefloquine/antimalarial exposure and health outcomes. The mefloquine-exposed group was further compared with normative populations for the same health outcomes. Results In the adjusted models, no significant differences were noted between the two exposure groups and the unexposed group for any of the health measures (P -value > 0.05). When compared to normative population samples, the mefloquine-exposed group had poorer health and greater neurobehavioral symptom severity or cognitive complaints. Conclusion This study suggests that mefloquine use by veterans referred for intensive evaluation of their military deployment exposures and health was not associated with increased, long-term, neurocognitive/psychiatric symptoms compared to unexposed veterans. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
49. Pioneer Use of Antimalarial Transdermal Combination Therapy in Rodent Malaria Model.
- Author
-
Aly, Nagwa S. M., Matsumori, Hiroaki, Dinh, Thi Quyen, Sato, Akira, Miyoshi, Shin-Ichi, Chang, Kyung-Soo, Yu, Hak Sun, Cao, Duc Tuan, and Kim, Hye-Sook
- Subjects
MEFLOQUINE ,MALARIA ,RODENTS ,ANTIMALARIALS ,CHLOROQUINE - Abstract
We have previously reported 1,2,6,7-tetraoxaspiro [7.11]nonadecane (N-89) as a promising antimalarial compound. In this study, we evaluated the effect of transdermal therapy (tdt) of N-89 in combination (tdct) with other antimalarials as an application for children. We prepared ointment formulas containing N-89 plus another antimalarial drug, specifically, mefloquine, pyrimethamine, or chloroquine. In a 4-day suppressive test, the ED
50 values for N-89 alone or combined with either mefloquine, pyrimethamine, or chloroquine were 18, 3, 0.1, and 3 mg/kg, respectively. Interaction assays revealed that N-89 combination therapy showed a synergistic effect with mefloquine and pyrimethamine, but chloroquine provoked an antagonistic effect. Antimalarial activity and cure effect were compared for single-drug application and combination therapy. Low doses of tdct N-89 (35 mg/kg) combined with mefloquine (4 mg/kg) or pyrimethamine (1 mg/kg) gave an antimalarial effect but not a cure effect. In contrast, with high doses of N-89 (60 mg/kg) combined with mefloquine (8 mg/kg) or pyrimethamine (1 mg/kg), parasites disappeared on day 4 of treatment, and mice were completely cured without any parasite recurrence. Our results indicated that transdermal N-89 with mefloquine and pyrimethamine provides a promising antimalarial form for application to children. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
50. Prediction of improved antimalarial chemotherapy of artesunate-mefloquine in combination with mefloquine sensitive and resistant Plasmodium falciparum malaria.
- Author
-
Saeheng, Teerachat and Na-Bangchang, Kesara
- Subjects
- *
MEFLOQUINE , *COMBINATION drug therapy , *PLASMODIUM falciparum , *MALARIA , *PATIENT compliance - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.