Arterolane Maleate Plus Piperaquine Phosphate for Treatment of Uncomplicated Plasmodium falciparum Malaria: A Comparative, Multicenter, Randomized Clinical Trial

Valecha, Neena; Krudsood, Srivicha; Tangpukdee, Noppadon; Mohanty, Sanjib; Sharma, SK; Tyagi, P. K.; Anvikar, Anupkumar R.; Mohanty, R. K.; Rao, Ballamudi Srinivas; Jha, Abhay K.; Shahi, B.; Singh, Jai; Roy, Arjun; Kaur, Pawandeep; Kothari, Monica T.; Mehta, Shantanu; Gautam, Anirudh; Paliwal, Jyoti; Arora, Sadhna; Saha, Nilanjan

doi:10.1093/cid/cis475

Cited by 48 publications

(57 citation statements)

References 13 publications

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“…Of all the evaluated endoperoxides, including AS and DHA, the most potent compound against isolates (GM IC 50 of 2.4 nM) was artemisone, a semisynthetic endoperoxide with encouraging phase IIa clinical trial results indicative of safety and pharmacological profiles attractive as a component of a new ACT to treat P. falciparum malaria (18). Also included in the test panel was the fully synthetic 1,2,4-trioxolane OZ277, a drug known as arterolane maleate (RBx 11160) (19,(36)(37)(38), that is currently employed in India as an ACT in combination with piperaquine (39). A next-generation ozonide, OZ439, has a more desirable pharmacokinetic profile with slower elimination (20) and is undergoing clinical development as a candidate component of a new ACT for use in malarious areas, including the Greater Mekong subregion.…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

Lanteri

Chaorattanakawee

Lon

et al. 2014

Antimicrob Agents Chemother

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. Ex vivo activities of test endoperoxides positively correlated with dihydroartemisinin and artesunate. The isolates were over 2-fold less susceptible to dihydroartemisinin than the artemisinin-sensitive P. falciparum W2 clone and showed sensitivity comparable to those with test endoperoxides and artesunate, with isolate/W2 IC 50 susceptibility ratios of <2.0. All isolates had P. falciparum chloroquine resistance transporter mutations, with negative correlations in sensitivity to endoperoxides and chloroquine. The activities of endoperoxides (artesunate, dihydroartemisinin, OZ277, and artemisone) significantly correlated with that of the ACT partner drug, mefloquine. Isolates had mutations associated with clinical resistance to mefloquine, with 35% prevalence of P. falciparum multidrug resistance gene 1 (pfmdr1) amplification and 84.5% occurrence of the pfmdr1 Y184F mutation. GM IC 50 s for mefloquine, lumefantrine, and endoperoxides (artesunate, dihydroartemisinin, OZ277, OZ78, and artemisone) correlated with pfmdr1 copy number. Given that current ACTs are failing potentially from reduced sensitivity to artemisinins and partner drugs, newly identified mutations associated with artemisinin resistance reported in the literature and pfmdr1 mutations should be examined for their combined contributions to emerging ACT resistance.

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Section: Discussionmentioning

confidence: 99%

Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

Lanteri

Chaorattanakawee

Lon

et al. 2014

Antimicrob Agents Chemother

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“…[15] The molecular formula is C 26 H 40 N 2 O 8 and molecular weight is 508.61. The Structural formula as shown in Figure 1.…”

Section: Mode Of Actionmentioning

confidence: 99%

“…[15] This action of arterolane is attributed to inhibition of heme detoxification and Pf-encoded sarcoplasmic endoplasmic reticulum calcium ATPase (PfATP6). Arterolane is an active moiety, which gets accumulated either in cytosol or food vacuole of the parasite.…”

Section: Mode Of Actionmentioning

confidence: 99%

“…The reactive radicals are proposed to subsequently cause prevention of heme detoxification by reacting with iron-bound ferriprotoporphyrin IX itself and also inhibit a multitude of intracellular enzymes. [151719]…”

Section: Mode Of Actionmentioning

confidence: 99%

“…[15] For the age group <12 and >65 years the antimalarial treatment can be administered as recommended by WHO. [6] It has been found to be effective in geographical regions with reported chloroquine resistance.…”

Section: Indicationsmentioning

confidence: 99%

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Fixed dose combination of arterolane and piperaquine: A newer prospect in antimalarial therapy

Patil¹,

Katare²,

Baig³

et al. 2014

Ann Med Health Sci Res

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Malaria has been very prevalent vector-borne disease in India and until date bears enormous implications on health care services of the country. Over the period of time, the development of resistance to traditional antimalarials like chloroquine has been posed as major deterrent in efforts of malaria control. As the drug resistance is today universally prevalent, especially in Plasmodium falciparum species, major burden of malarial control resides with the new artemisinin drug class. However, arterolane is one of the first fully synthetic non-artemisinin antimalarial compound with rapid schizontocidal activity, hence offering an alternative to artemisinin drugs in malaria control. Piperaquine is a synthetic bisquinoline (4-amioquinoline Antimalarial) with slow and longer schizontocidal activity. Therefore their combination has been shown to provide rapid parasitemic clearance and quick relief of most malaria-related symptoms along with prevention of recrudescences. This combination was approved by Drugs Controller General of India in 2011 for treatment of uncomplicated P. falciparum malaria. The article is aimed at to review this newer prospect in antimalarial therapy for which comprehensive database search was done in Google, Google Scholar, PubMed using the terms “Malaria,” “Arterolane,” “OZ277,” “Piperaquine,” and “Artemisinin combination therapy.” A total of 323 articles were screened and 28 articles were considered for this review along with the World Health Organization and National malarial program guidelines.

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2010 to 2020: Ten Years of Malaria Drug Discovery

Yeung

Calderón

2021

Burger's Medicinal Chemistry and Drug Discovery

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The seventh edition of Burger's Medicinal Chemistry, Drug Discovery and Development included an extensive review of antimalarial drugs and drug targets. Since it was published nearly 10 years ago, the annual number of deaths due to malaria in endemic countries have steadily declined. However, over the past two years, a stabilization in number of malaria deaths hints to a reversal of this trend. This may be in part due to parasite evolution to overcome efficacy of antimalarial therapies, including the now well‐established spread of resistance to artemisinin‐combination therapies in Southeast Asia. Fortunately, the last decade also witnessed a renewed effort by academic researchers, product development partnerships, and pharmaceutical companies to restart malaria drug discovery. Innovations in high‐throughput screening, assay development, access to large chemical libraries, advancements in parasite biology, and whole‐genome sequencing have resulted in the discovery of new antimalarial drugs as well as novel targets. These new drug candidates, which kill the parasite through new mechanisms of action have bolstered the malaria drug development pipeline since the last edition. This article summarizes the new drug discovery approaches and achievements over the past decade.

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Arterolane Maleate Plus Piperaquine Phosphate for Treatment of Uncomplicated Plasmodium falciparum Malaria: A Comparative, Multicenter, Randomized Clinical Trial

Abstract: The available data support the evaluation of a drug combination in a larger population as a fixed-dose combination. Clinical Trials Registration. CTRI/2007/091/000031.

Cited by 48 publications

References 13 publications

Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

Fixed dose combination of arterolane and piperaquine: A newer prospect in antimalarial therapy

2010 to 2020: Ten Years of Malaria Drug Discovery

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