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Current Opinion in Microbiology Oct 2022Multidrug-resistant Plasmodium falciparum parasites are a major threat to public health in intertropical regions. Understanding the mechanistic basis, origins, and... (Review)
Review
Multidrug-resistant Plasmodium falciparum parasites are a major threat to public health in intertropical regions. Understanding the mechanistic basis, origins, and spread of resistance can inform strategies to mitigate its impact and reduce the global burden of malaria. The recent emergence in Africa of partial resistance to artemisinins, the core component of first-line combination therapies, is particularly concerning. Here, we review recent advances in elucidating the mechanistic basis of artemisinin resistance, driven primarily by point mutations in P. falciparum Kelch13, a key regulator of hemoglobin endocytosis and parasite response to artemisinin-induced stress. We also review resistance to partner drugs, including piperaquine and mefloquine, highlighting a key role for plasmepsins 2/3 and the drug and solute transporters P. falciparum chloroquine-resistance transporter and P. falciparum multidrug-resistance protein-1.
Topics: Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins
PubMed: 36007459
DOI: 10.1016/j.mib.2022.102193 -
Cold Spring Harbor Perspectives in... Jun 2017One hundred and twenty-five million women in malaria-endemic areas become pregnant each year (see Dellicour et al. e1000221 [2010]) and require protection from... (Review)
Review
One hundred and twenty-five million women in malaria-endemic areas become pregnant each year (see Dellicour et al. e1000221 [2010]) and require protection from infection to avoid disease and death for themselves and their offspring. Chloroquine prophylaxis was once a safe approach to prevention but has been abandoned because of drug-resistant parasites, and intermittent presumptive treatment with sulfadoxine-pyrimethamine, which is currently used to protect pregnant women throughout Africa, is rapidly losing its benefits for the same reason. No other drugs have yet been shown to be safe, tolerable, and effective as prevention for pregnant women, although monthly dihydroartemisinin-piperaquine has shown promise for reducing poor pregnancy outcomes. Insecticide-treated nets provide some benefits, such as reducing placental malaria and low birth weight. However, this leaves a heavy burden of maternal, fetal, and infant morbidity and mortality that could be avoided. Women naturally acquire resistance to over successive pregnancies as they acquire antibodies against parasitized red cells that bind chondroitin sulfate A in the placenta, suggesting that a vaccine is feasible. Pregnant women are an important reservoir of parasites in the community, and women of reproductive age must be included in any elimination effort, but several features of malaria during pregnancy will require special consideration during the implementation of elimination programs.
Topics: Africa; Antimalarials; Artemisinins; Drug Combinations; Drug Resistance; Female; Humans; Malaria; Malaria Vaccines; Mefloquine; Placenta; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Pyrimethamine; Sulfadoxine
PubMed: 28213434
DOI: 10.1101/cshperspect.a025551 -
Neurology India 2023Neuropsychiatric disorders, ranging from mild cognitive impairment to frank psychosis, have been associated with certain parasitic infections. The parasite may cause... (Review)
Review
Neuropsychiatric disorders, ranging from mild cognitive impairment to frank psychosis, have been associated with certain parasitic infections. The parasite may cause damage to the central nervous system in several ways: as a space-occupying lesion (neuro-cysticercosis), alteration of neurotransmitters (toxoplasmosis), generation of the inflammatory response (trypanosomiasis, schistosomiasis), hypovolemic neuronal injury (cerebral malaria), or a combination of these. Certain drugs like quinacrine (mepacrine), mefloquine, quinolone, and interferon alpha which are used to treat these parasitic infections can further cause neuropsychiatric adverse effects. This review summarizes the major parasitic infections that are associated with neuropsychiatric disorders and the pathogenesis involved in their processes. A high index of suspicion for parasitic diseases, especially in endemic areas, should be kept in patients presenting with neuropsychiatric symptoms. A multidimensional approach to identification of the offending parasite using serological, radiological, and molecular tests is required not only to ensure proper and prompt treatment of the primary parasitic infection but also to improve the prognosis of patients by complete resolution of neuropsychiatric symptoms.
Topics: Humans; Parasitic Diseases; Central Nervous System; Mental Disorders; Mefloquine; Cysticercosis
PubMed: 37148042
DOI: 10.4103/0028-3886.375424 -
Drugs Jun 2018The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum... (Review)
Review
The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.
Topics: Aminoquinolines; Antimalarials; Artemisinins; Drug Discovery; Drug Resistance, Multiple; Ferrous Compounds; Humans; Imidazoles; Lumefantrine; Malaria; Metallocenes; Piperazines; Signal Transduction; Treatment Outcome
PubMed: 29802605
DOI: 10.1007/s40265-018-0911-9 -
International Journal For Parasitology.... Dec 2021According to WHO, 2019 witnessed 229 million cases of malaria globally, of which Africa accounted for 94% of cases. Early diagnosis and treatment are the basis of... (Review)
Review
According to WHO, 2019 witnessed 229 million cases of malaria globally, of which Africa accounted for 94% of cases. Early diagnosis and treatment are the basis of malaria management, and the need for good chemoprophylaxis especially for people travelling to endemic areas is vital. There are a number of drug options available for the prophylaxis of malaria, mefloquine being one of the drugs used. Mefloquine has been around from the 1970s, and was developed in the United States keeping in mind the soldiers that were being deployed to areas where chloroquine resistant strains of Plasmodium were discovered. Mefloquine was preferred for its once a week dosage. Within a decade of its introduction, reports of the side effects associated with its long-term use surfaced. Mefloquine is now reported to cause a myriad of neuropsychiatric side effects including anxiety, sleep disturbance, depression, dizziness and frank psychosis, especially in patients with pre-existing psychiatric disorders. Many countries like the United States and the United Kingdom have updated their drug boxes to include the warning of these potential neuropsychiatric effects. This paper reviews the side effects of mefloquine and why there is a need to revisit its use in Indian drug policy.
Topics: Antimalarials; Chloroquine; Humans; Malaria; Mefloquine; Military Personnel
PubMed: 34339933
DOI: 10.1016/j.ijpddr.2021.06.003 -
The FEBS Journal Aug 2017Over the past 50 years, Plasmodium falciparum has developed resistance against all antimalarial drugs used against it: chloroquine, sulphadoxine-pyrimethamine, quinine,... (Review)
Review
Over the past 50 years, Plasmodium falciparum has developed resistance against all antimalarial drugs used against it: chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine and mefloquine. More recently, resistance to the artemisinin derivatives and the resulting failure of artemisinin-based combination therapy (ACT) are threatening all major gains made in malaria control. Each time resistance has developed progressively, with delayed clearance of parasites first emerging only in a few regions, increasing in prevalence and geographic range, and then ultimately resulting in the complete failure of that antimalarial. Drawing from this repeated historical chain of events, this article presents context-specific approaches for combating drug-resistant P. falciparum malaria. The approaches begin with a context of drug-sensitive parasites and focus on the prevention of the emergence of drug resistance. Next, the approaches address a scenario in which resistance has emerged and is increasing in prevalence and geographic extent, with interventions focused on disrupting transmission through vector control, early diagnosis and treatment, and the use of new combination therapies. Elimination is also presented as an approach for addressing the imminent failure of all available antimalarials. The final drug resistance context presented is one in which all available antimalarials have failed; leaving only personal protection and the use of new antimalarials (or new combinations of antimalarials) as a viable strategy for dealing with complete resistance. All effective strategies and contexts require a multipronged, holistic approach.
Topics: Antimalarials; Drug Resistance; Malaria, Falciparum; Plasmodium falciparum
PubMed: 28580606
DOI: 10.1111/febs.14127 -
Microbiology Spectrum Jun 2016For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites... (Review)
Review
For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.
Topics: Animals; Anopheles; Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria, Falciparum; Molecular Epidemiology; Plasmodium falciparum
PubMed: 27337450
DOI: 10.1128/microbiolspec.EI10-0013-2016