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Evidence-based Complementary and... 2020Malaria is one of the major health problems in developing countries. The disease kills a large number of people every year and also affects financial status of many... (Review)
Review
Malaria is one of the major health problems in developing countries. The disease kills a large number of people every year and also affects financial status of many countries. Resistance of the plasmodium parasite, the causative agent, to the existing drugs, including chloroquine, mefloquine, and artemisinin based combination therapy (ACT), is a serious global issue in malaria treatment and control. This warrants an urgent quest for novel compounds, particularly from natural sources such as medicinal plants. Alkaloids have over the years been recognized as important phytoconstituents with interesting biological properties. In fact, the first successful antimalarial drug was quinine, an alkaloid, which was extracted from Cinchona tree. In the present review work, the alkaloids isolated and reported recently (2013 till 2019) to possess antimalarial activity are presented. Several classes of alkaloids, including terpenoidal, indole, bisindole, quinolone, and isoquinoline alkaloids, were identified with a promising antimalarial activity. It is hoped that the reports of the review work will spur further research into the structural modification and/or development of the interesting compounds as novel antimalarial drugs.
PubMed: 32104196
DOI: 10.1155/2020/8749083 -
Proceedings of the National Academy of... Aug 2023multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is...
multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is associated with the resistance to antimalarial drugs. To understand the mechanisms of PfMDR1, we determined the cryo-electron microscopy structures of this transporter in different states. The transporter in the apo state shows an inward-facing conformation with a large cavity opening to the cytoplasm. Upon ATP binding and dimerization of the nucleotide-binding domains (NBDs), PfMDR1 displays an outward-facing conformation with a cavity toward the DV lumen. Drug resistance-associated mutations were investigated in both structures for their effects, and Y184F was identified as an allosteric activity-enhancing mutation. The amphiphilic substrate-binding site of PfMDR1 was revealed by the complex structure with the antimalarial drug mefloquine and confirmed by mutagenesis studies. Remarkably, a helical structure was found to hinder NBD dimerization and inhibit PfMDR1 activity. The location of this regulatory domain in the N terminus is different from the well-studied R domain in the internal linker region of other ABC transporter family members. The lack of the phosphorylation site of this domain also suggests a different regulation mechanism.
Topics: Humans; Plasmodium falciparum; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cryoelectron Microscopy; Antimalarials; Membrane Transport Proteins; ATP-Binding Cassette Transporters; Adenosine Triphosphate; Multidrug Resistance-Associated Proteins; Drug Resistance; Malaria, Falciparum
PubMed: 37527341
DOI: 10.1073/pnas.2219905120 -
Frontiers in Epidemiology 2022Treatment of symptomatic malaria became a routine component of the clinical and public health response to malaria after the second world war. However, all antimalarial...
Treatment of symptomatic malaria became a routine component of the clinical and public health response to malaria after the second world war. However, all antimalarial drugs deployed against malaria eventually generated enough drug resistance that they had to be removed from use. Chloroquine, sulfadoxine-pyrimethamine, and mefloquine are well known examples of antimalarial drugs to which resistance did and still does ready evolve. Artemisinin-based combination therapies (ACTs) are currently facing the same challenge as artemisinin resistance is widespread in Southeast Asia and emerging in Africa. Here, I review some aspects of drug-resistance management in malaria that influence the strength of selective pressure on drug-resistant malaria parasites, as well as an approach we can take in the future to avoid repeating the common mistake of deploying a new drug and waiting for drug resistance and treatment failure to arrive. A desirable goal of drug-resistance management is to reduce selection pressure without reducing the overall percentage of patients that are treated. This can be achieved by distributing multiple first-line therapies (MFT) simultaneously in the population for the treatment of uncomplicated falciparum malaria, thereby keeping treatment levels high but the overall selection pressure exerted by each individual therapy low. I review the primary reasons that make MFT a preferred resistance management option in many malaria-endemic settings, and I describe two exceptions where caution and additional analyses may be warranted before deploying MFT. MFT has shown to be feasible in practice in many endemic settings. The continual improvement and increased coverage of genomic surveillance in malaria may allow countries to implement custom MFT strategies based on their current drug-resistance profiles.
PubMed: 38455307
DOI: 10.3389/fepid.2022.1041896 -
Journal of Global Antimicrobial... Dec 2021Plasmodium falciparum, the causative agent of malaria, has been developing resistance to several drugs worldwide for more than five decades. Initially, resistance was... (Review)
Review
Plasmodium falciparum, the causative agent of malaria, has been developing resistance to several drugs worldwide for more than five decades. Initially, resistance was against drugs such as chloroquine, pyrimethamine, sulfadoxine, mefloquine and quinine. Research studies are now reporting parasites with resistance to the most effective and novel drug used against malaria infection worldwide, namely artemisinin. For this reason, the first-line treatment strategy of artemisinin-based combination therapy is becoming unsuccessful in areas where drug resistance is highly prevalent. The increase in artemisinin-resistant P. falciparum strains has threatened international efforts to eliminate malarial infections and to reduce the disease burden. Detection of several phenotypes that display artemisinin resistance, specification of basic genetic factors, the discovery of molecular pathways, and evaluation of its clinical outcome are possible by the current series of research on genomics and transcriptomic levels in Asia and Africa. In artemisinin resistance, slow parasite clearance among malaria-infected patients and enhanced in vitro survival of parasites occurs at the early ring stage. This resistance is due to single nucleotide polymorphisms within the Kelch 13 gene of the parasite and is related to significantly upregulated resistance signalling pathways; thus, the pro-oxidant action of artemisinins can be antagonised. New strategies are required to halt the spread of artemisinin-resistant malarial parasites.
Topics: Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria, Falciparum; Protozoan Proteins
PubMed: 34517141
DOI: 10.1016/j.jgar.2021.09.001 -
Acta Tropica Jan 2021Conventional anthelmintics such as albendazole could not achieve complete cure of trichinellosis till now. The antimalarial mefloquine mediates oxidative stress and...
Conventional anthelmintics such as albendazole could not achieve complete cure of trichinellosis till now. The antimalarial mefloquine mediates oxidative stress and disrupts lysosomal functions leading to cell death. Therefore, the aim of this work was to investigate the effect of mefloquine on experimental acute and chronic trichinellosis and to clarify the possible mechanisms of such effects. Mice were divided into four groups; Group I: Uninfected untreated control (20 mice); Group II: Infected untreated control (40 mice); Group III: infected and treated with albendazole (400 mg/kg) (40 mice); Group IV: infected and treated with mefloquine (300 mg/kg) (40 mice). All infected treated groups were equally subdivided into 2 subgroups; (a) treated on the 2 day post infection (dpi) for 3 days, (b) treated on the 35 dpi for 5 days. Parasitological adults and larvae counting besides immunohistopathological examination of intestines and muscles were done. Biochemical assay of oxidant/antioxidant status, apoptotic, cytoprotective and inflammatory biomarkers in intestinal and muscle homogenates were achieved. Results showed that both albendazole and mefloquine significantly reduced adults and larvae counts with higher efficacy of albendazole in the intestinal phase and superiority of mefloquine in the muscle phase. The superiority of mefloquine was indicated by increased inflammatory immune infiltration and decreased anti-apoptotic immunohistochemical markers expression in both jejunal and muscle tissues. Biochemically, mefloquine treatment showed highly significant oxidative, apoptotic and inflammatory effects. So, our results suggest that mefloquine might be a superior treatment for chronic trichinellosis.
Topics: Albendazole; Animals; Anthelmintics; Apoptosis; Disease Models, Animal; Jejunum; Larva; Male; Mefloquine; Mice; Muscles; Oxidative Stress; Reactive Oxygen Species; Trichinella spiralis; Trichinellosis
PubMed: 33221280
DOI: 10.1016/j.actatropica.2020.105760 -
Biochemical and Biophysical Research... Nov 2021Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment...
Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment development. Given potent anti-cancer efficacy of mefloquine, FDA-approved anti-malarial drug, there is increasing interest in repurposing mefloquine for treatment of cancers, including glioblastoma. In line with these efforts, our work is the first to demonstrate that mefloquine is also an inhibitor of glioblastoma angiogenesis. Using glioblastoma microvascular endothelial cell (GMEC) isolated from glioblastoma patients, we show that mefloquine at clinically achievable concentration inhibits GMEC differentiation, capillary network formation, adhesion to Matrix, growth and survival. Mefloquine also inhibits growth and induces apoptosis in glioblastoma cells regardless of cellular origin and genetic background. We further show that mefloquine significantly inhibits glioblastoma growth but not formation, and this is associated with decreased glioblastoma angiogenesis in mice. Mechanistically, mefloquine disrupted lysosomal integrity and function in GMECs, leading to oxidative stress and lysosomal lipid damage. Rescue studies confirm that mefloquine acts on GMECs in a lysosomal disruption-dependent manner. Our findings demonstrate the anti-angiogenic activity of mefloquine via disrupting lysosomal function. The dual inhibitory role of mefloquine in glioblastoma angiogenesis and glioblastoma displays its advantage over other anti-cancer drugs for glioblastoma treatment. Our work also highlights the essential role of lysosome in both glioblastoma and its angiogenesis.
Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Male; Mefloquine; Mice, SCID; Neovascularization, Pathologic; Mice
PubMed: 34607260
DOI: 10.1016/j.bbrc.2021.09.069 -
Journal of Avian Medicine and Surgery Mar 2023Avian malaria is an important cause of mortality in captive penguins housed in outdoor exhibits. Mefloquine was used as a prophylaxis to treat a colony of 19 Humboldt...
Avian malaria is an important cause of mortality in captive penguins housed in outdoor exhibits. Mefloquine was used as a prophylaxis to treat a colony of 19 Humboldt penguins () for avian malaria. A target dose of 30 mg/kg was obtained from anecdotal literature for sphenisciforms that was not based on pharmacokinetic or toxicity studies. For this reason, preliminary plasma concentrations of mefloquine were acquired after the first dose in some penguins to ensure that plasma concentrations reached human malaria prophylactic concentrations. Afterward, each penguin in the entire colony received mefloquine (26-31 mg/kg [125 mg in toto] PO q7d). Regurgitation was frequently observed starting after the fourth weekly administration. Plasma concentrations of mefloquine after the seventh dose showed elevated concentrations, and the treatment was immediately terminated. Eight penguins died during and after the treatment period. The first fatality occurred after the fifth weekly administration, and 7 birds died within 7-52 days after the seventh weekly administration. Three penguins were found dead without previous symptoms. The other five presented with marked lethargy, dyspnea, poor appetite, and vomiting, and all died despite medical care. The remaining 11 penguins of the colony survived without any supportive care; 5 did not exhibit any clinical disease signs, while the other 6 showed a mild apathy and decreased appetite. Mefloquine toxicity was highly suspected on the basis of clinical signs, the elevated mefloquine plasma concentrations, and no other underlying pathologic disease conditions identified through postmortem examinations. Nonspecific lesions, including pulmonary congestion and edema and hepatic perivascular hematopoiesis, were noted in the birds that died. Additionally, 1 case presented with myocarditis, and mycobacteria were observed within granulomas in the respiratory tract of 2 penguins. Caution is advised, and further studies are encouraged before administering mefloquine to penguins.
Topics: Humans; Animals; Spheniscidae; Malaria, Avian; Mefloquine
PubMed: 36935212
DOI: 10.1647/21-00054 -
The Journal of Infectious Diseases May 2023
Topics: Humans; Plasmodium vivax; Mefloquine; Plasmodium cynomolgi; Antimalarials; Malaria, Vivax; Drug Resistance; Drug Resistance, Multiple
PubMed: 36478038
DOI: 10.1093/infdis/jiac470 -
Frontiers in Physiology 2022According to the "hydrodynamic theory," dentinal pain or sensitivity is caused by dentinal fluid movement following the application of various stimuli to the dentin...
According to the "hydrodynamic theory," dentinal pain or sensitivity is caused by dentinal fluid movement following the application of various stimuli to the dentin surface. Recent convergent evidence has shown that plasma membrane deformation, mimicking dentinal fluid movement, activates mechanosensitive transient receptor potential (TRP)/Piezo channels in odontoblasts, with the Ca signal eliciting the release of ATP from pannexin-1 (PANX-1). The released ATP activates the P2X receptor, which generates and propagates action potentials in the intradental Aδ afferent neurons. Thus, odontoblasts act as sensory receptor cells, and odontoblast-neuron signal communication established by the TRP/Piezo channel-PANX-1-P2X receptor complex may describe the mechanism of the sensory transduction sequence for dentinal sensitivity. To determine whether odontoblast-neuron communication and odontoblasts acting as sensory receptors are essential for generating dentinal pain, we evaluated nociceptive scores by analyzing behaviors evoked by dentinal sensitivity in conscious Wistar rats and Cre-mediated transgenic mouse models. In the dentin-exposed group, treatment with a bonding agent on the dentin surface, as well as systemic administration of A-317491 (P2X receptor antagonist), mefloquine and PANX (non-selective and selective PANX-1 antagonists), GsMTx-4 (selective Piezo1 channel antagonist), and HC-030031 (selective TRPA1 channel antagonist), but not HC-070 (selective TRPC5 channel antagonist), significantly reduced nociceptive scores following cold water (0.1 ml) stimulation of the exposed dentin surface of the incisors compared to the scores of rats without local or systemic treatment. When we applied cold water stimulation to the exposed dentin surface of the lower first molar, nociceptive scores in the rats with systemic administration of A-317491, PANX, and GsMTx-4 were significantly reduced compared to those in the rats without systemic treatment. Dentin-exposed mice, with somatic odontoblast-specific depletion, also showed significant reduction in the nociceptive scores compared to those of Cre-mediated transgenic mice, which did not show any type of cell deletion, including odontoblasts. In the odontoblast-eliminated mice, P2X receptor-positive A-neurons were morphologically intact. These results indicate that neurotransmission between odontoblasts and neurons mediated by the Piezo1/TRPA1-pannexin-1-P2X receptor axis is necessary for the development of dentinal pain. In addition, odontoblasts are necessary for sensory transduction to generate dentinal sensitivity as mechanosensory receptor cells.
PubMed: 36589456
DOI: 10.3389/fphys.2022.891759