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A Pharmacological Appraisal of Antimalarial Plant Species
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Mahwahwatse J. Bapela, Precious B. Ramontja, Mcebisi J. Mabuza
Aryl-amino alcohols include quinine, mefloquine, halofantrine and lumefantrine, and their antimalarial activity seem to require the presence of an aromatic portion and an amino alcohol portion (Figure 18.2). Like the 4-aminoquinolines, aryl-amino alcohols are assumed to act primarily on the erythrocyte stage of the malaria parasite by inhibiting the formation of hemozoin (Anderson et al., 2006). 8-Aminoquinolines are derived quinoline molecules with an amine group at the 8-position of quinoline. Primaquine is the only 8-aminoquinoline used in malaria therapy, and studies have shown that it interferes with the parasite’s DNA structure and disrupts its mitochondrial membranes (Miller et al., 2013). It is also the only available drug that can prevent transmission of mature gametocytes, although it can cause intravascular hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (Sinha et al., 2014). The precise mechanisms of action of the above-mentioned quinoline-based antimalarial drugs are not yet fully understood, and are still under investigation.
Progress in Antimalarial Drug Discovery and Development
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Anna C.C. Aguiar, Wilian A. Cortopassi, Antoniana U. Krettli
PQ (2), a synthetic 8-aminoquinoline resulting from the drug research programs during World War II, is still used to treat relapses caused by P. vivax and P. ovale. In spite of the limited knowledge of the liver stage of Plasmodium infection, malariologists recognized the importance to overcome the observed phenomenon of relapse in P. vivax malaria by using antimalarials with an effect on the dormant stages of the parasite (Elderfield et al. 1955). PQ (2) also played an important role in preventing reintroduction of endemic malaria to North America by targeting the P. vivax liver dormant stages in soldiers returning from World War II (Baird 2015, Ducharme et al. 1996). After decades counting only on this compound, a new 8-aminoquinoline analog of PQ (2) was recently developed: single-dose tafenoquine (13) kills liver stages (Campo et al. 2015, Commons et al. 2017). In July 2018, GSK and Medicines for Malaria Venture (MMV) announced that “the FDA has approved, under Priority Review, single-dose Krintafel (tafenoquine, 13) for the radical cure (prevention of relapse) of P. vivax malaria in patients aged 16 yr and older who are receiving appropriate antimalarial therapy for acute P. vivax infection”. The importance of finding alternatives to PQ (2) is that this compound can cause severe side effects in patients with genetic G6PD variants leading to deficiency of the enzyme G6PD (Baird 2015). Tafenoquine (13) may also cause severe hemolysis in individuals with G6PD deficiency (Dow et al. 2014, Kitchakarn et al. 2017).
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Published in Anton Sebastian, A Dictionary of the History of Medicine, 2018
Antimalarials [Greek: anti, against + mal, bad + aer, air] Cinchona bark was used in treatment of malarial fever or ague prior to the isolation of quinine from it by Joseph Pelletier (1788–1842) in 1820. Mepacrine or atebrine was introduced in 1933 which drastically reduced the mortality of troops from malaria during World War 11. Development of resistance to mepacrine by Plasmodium falciparum was noted by N.H. Fairley in 1947. Chloroquine was tested by Robert Frederick Loeb in 1946. Paludrine or proguanil was synthesized in England in 1944 and tested against avian malaria by F.S.H. Curd and co-workers in 1945. Alfred Adams introduced paludrine as treatment of human malaria later in the same year. The effectiveness of paludrine on a large scale was demonstrated by N.H. Fairley from the Medical Research Unit of the Australian army in 1946. Primaquine, an 8-aminoquinoline derivative, was introduced as treatment by Harold John Edgcomb and coworkers in 1950. R.S. Hockwald, J. Arnold, J. Clayman and A.S. Alving noted that 5–10% of previously healthy African–American troops developed hemolytic anemia after treatment with primaquin in 1952. Subsequent studies by PE. Carson, C.L. Flanagan, C.E. Ickes and A.S. Alving in 1956 showed that the hemolysis was due to genetically linked deficiency of glucose-6–phosphate dehydrogenase in the red blood cells. See cinchona, Baike William Balfour, chloroquin, Peruvian bark.
Tafenoquine for the treatment of Plasmodium vivax malaria
Published in Expert Opinion on Pharmacotherapy, 2022
Alejandro Llanos-Cuentas, Paulo Manrrique, Angel Rosas-Aguirre, Sonia Herrera, Michelle S. Hsiang
There are two major challenges associated with PQ administration. First, the total dose is administered over a long 7 to 14 day, or even 8 week period, resulting in poor adherence. Non-adherence to PQ treatment varies from 2 to 40% [20,23]. Other factors contributing to non-adherence include: lack of immediate benefit, limited understanding of long-term benefits for the individual and community, and mis-perception of vivax malaria as a benign disease. Providers and patients are concerned about potential adverse effects, and especially the risk of severe hemolysis in people with underlying glucose 6-phosphate dehydrogenase (G6PD) deficiency. To address the challenge of adherence to PQ, the 8-aminoquinoline, tafenoquine (TFQ), was co-developed by GlaxoSmithKline and Medicines for Malaria Venture as a single-dose therapy for radical cure of P. vivax malaria. At a dose of 300 mg, the drug was approved for radical cure for adults 16 years of age and older by the United States Food and Drug Administration (FDA) [24] and the Australian Therapeutic Goods Administration (TGA) in 2018 [25]. These approvals came after TFQ was shown to have similar efficacy to PQ in preventing recurrences [26–28]. Although there are concerns regarding the safety of TFQ in people with G6PD deficiency, the recent availability of point-of-care tests to quantitatively measure the activity of the G6PD enzyme [29,30] provides an opportunity national malaria programs to incorporate these tools into their control and elimination strategies.
Leishmaniasis: treatment, drug resistance and emerging therapies
Published in Expert Opinion on Orphan Drugs, 2019
Shyam Sundar, Jaya Chakravarty, Lalit P Meena
8-aminoquinoline (sitamaquine) had shown to have antileishmanial activity against L. donovani in the hamster model. It was shown to be 708 times more active than MA against L. donovani in hamsters. Development of this drug has been stopped for VL due to nephrotoxicity at higher doses, and tolerated lower doses had unacceptably low efficacy [48]. Better bioavailability and efficacy of antileishmanial drug in polymeric nanoparticles such as poly-lactic-coglycolic acid (PLGA) have been observed by nanoencapsulation. These nanocarriers have advanced properties which improve bioavailability and control targetability in drug delivery. In a study conducted by Kumara et al., sitamaquine was encapsulated in PLGA-PEG nanoparticle attached with antibody to CD14 to target macrophages infected with Leishmania parasite [86]. It was found that the PLGA-PEG encapsulated sitamaquine nanoparticles were more effective than the free form of sitamaquine.
Tafenoquine: a toxicity overview
Published in Expert Opinion on Drug Safety, 2021
The 8-aminoquinoline group of drugs is known to have several toxicities that limit their use. The most serious adverse effect is a dose-dependent drug-induced hemolysis in G6PD deficient populations [12–14]; this includes tafenoquine [7]. The prevalence of G6PD deficiency is approximately 8% in malaria-endemic countries reaching 30% in some localities [15]. Mild to moderate elevations in methemoglobin levels are nearly universal after primaquine treatment, while severe, life-threatening methemoglobinemia is rare [16] only occurring in individuals with nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase deficiency [17]. Abdominal pain is a dose-related adverse effect which is improved if the drug is taken after food [18]. Elevations in liver function test results are uncommon, and hepatotoxicity is rare. Early synthetic 8-aminoquinoline analogs such as pamaquine and pentaquine had significant adverse effects as noted above [19]. The subsequent development of primaquine resulted in a drug that was better tolerated and more efficacious [20]; however, low access to reliable G6PD testing and risk of drug-induced hemolysis in G6PD deficient individuals have limited the widespread use of primaquine in many P. vivax endemic areas. In addition, the prolonged treatment course (7 to 14 days) required for the radical cure of P. vivax has limited adherence [21]. Nevertheless, over 150 million doses of primaquine have been prescribed during mass drug administration programs for P. vivax elimination without significant numbers of passively reported severe adverse events, including hemolysis [22–26].