Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

Henrich, Philipp P.; Passi, Neha; Fidock, David A.

doi:10.1097/qco.0b013e32834cd3ed

Cited by 115 publications

(92 citation statements)

References 72 publications

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“…Widespread resistance has limited the therapeutic utility of most existing antimalarial drugs, and artemisinin, the highly efficacious cornerstone of artemisinin combination therapies, appears to be at risk for the same fate (2). The need for new antimalarial chemotherapeutic strategies is thus acute.…”

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confidence: 99%

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Hanson

Ressurreição

Buchholz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Residence within a customized vacuole is a highly successful strategy used by diverse intracellular microorganisms. The parasitophorous vacuole membrane (PVM) is the critical interface between Plasmodium parasites and their possibly hostile, yet ultimately sustaining, host cell environment. We show that torins, developed as ATP-competitive mammalian target of rapamycin (mTOR) kinase inhibitors, are fast-acting antiplasmodial compounds that unexpectedly target the parasite directly, blocking the dynamic trafficking of the Plasmodium proteins exported protein 1 (EXP1) and upregulated in sporozoites 4 (UIS4) to the liver stage PVM and leading to efficient parasite elimination by the hepatocyte. Torin2 has single-digit, or lower, nanomolar potency in both liver and blood stages of infection in vitro and is likewise effective against both stages in vivo, with a single oral dose sufficient to clear liver stage infection. Parasite elimination and perturbed trafficking of liver stage PVM-resident proteins are both specific aspects of torin-mediated Plasmodium liver stage inhibition, indicating that torins have a distinct mode of action compared with currently used antimalarials.host-parasite interactions | malaria | protein trafficking | P. falciparum

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mentioning

confidence: 99%

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Hanson

Ressurreição

Buchholz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Proses pemulihan dari dorman ini juga dapat mempertinggi kekambuhan setelah pengobatan monoterapi dengan artemisinin atau artesunat. 16 Data hasil penelitian menggunakan simulasi model pada manusia dengan pemberian terapi artemisinin selama 1, 3, dan 7 hari menunjukkan bahwa paparan obat antimalaria artemisinin mampu menginduksi periode dorman pada P. falciparum, akan tetapi semakin lama pemberian terapi, terjadi penurunan persentase parasit dorman. Parasit tersebut dapat ditemukan lagi setelah 28 hari meskipun terjadi penurunan pada pemberian yang lebih lama.…”

Section: 8unclassified

Profil Fenotipik Plasmodium falciparum Galur Papua 2300 Akibat Paparan Antimalaria Artemisinin in Vitro

Maslachah¹,

Dachlan²,

Nidom³

et al. 2015

mkb

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AbstrakResistensi parasit P. falciparum dan penurunan efikasi terhadap artemisinin mengakibatkan masalah malaria menjadi semakin kompleks. Hal ini menjadi salah satu permasalahan kesehatan di dunia yang belum dapat diselesaikan sampai saat ini karena belum ada obat baru pengganti artemisinin. Penelitian ini untuk membuktikan bahwa paparan obat antimalaria artemisinin berulang in vitro dapat menyebabkan perubahan profil fenotipik P. falciparum galur Papua 2300. Phenotypic Profile of Plasmodium falciparum Papua 2300 Strain Exposed to in Vitro Antimalarial Artemisinin AbstractThe presence of the P. falciparum resistance and decreased of efficacy against artemisinin and its derivatives result in increasingly complex malaria issues. Malaria has become one of the currently unresolved world's health problems due to the lack of new artemisinin replacement drugs. This study aimed to provide evidence that the repeated exposure of in vitro artemisinin may cause a change in P. falciparum Papua 2300 strain phenotypic. This study was conducted during the period of February to November 2013 in Biomedics Brawijaya University and the Faculty of Veterinary Medicine, Airlangga University. A post-test control only experimental design was used.In vitro cultures of P. falciparum Papua 2300 strain were treated by repeated artemisin in IC 50 concentration and were observed for their viability and IC 50 using probit analysis. The control group did not show any changes after IC 50 value and PO1 treatment. An increase in IC 50 value was occurred after PO2. Repeated exposures of artemisinin in PO2, PO3, and PO4 had shorter viability periods than PO1. The viability of was stable after PO3 in this group. In conclusion, repeated exposures of artemisinin influence changes in IC 50 value and viability period of P. falciparum Papua 2300 strain. [MKB. 2015;47(1):1-9]

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“…4) are potent antimalarial drugs. However, a decline of the efficacy of artemisinin and artesunate monotherapy due to the emergence of resistant strains was detected in Western Cambodia [51], in the Thai-Cambodian border [52], and in the Thailand-Myanmar border [53]. Since the spread of artemisinin resistance would be disastrous for global malaria control, the WHO strongly recommends the association of artemisinin with other antimalarials [54,55].…”

Section: Artemisinin and Its Derivatesmentioning

confidence: 99%

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Zucca

Scutera²,

Savoia³

2013

CMC

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Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.Keywords: Antibiotics, antiprotozoal chemotherapy, Leishmania, natural products, Plasmodium, Trypanosoma. 4 INTRODUCTIONInfections caused by parasitic protozoa take an enormous toll on human health. Their prevalence is higher in tropical and equatorial countries, where the major number of deaths is due to malaria, leishmaniasis, and African and American trypanosomiasis. High mortality rates are associated to poor sanitary conditions, high percentages of untreated HIV-infected individuals, and lack of efficient prophylactic measures [1]. In the developed countries the situation is not so tragic, but nonetheless it has its drawbacks. If it is true that in these countries most HIV-infected patients are treated, the number of chronically immuno-deficient carriers of transplanted organs is set to grow. In these patients latent parasitic infections, such as leishmaniasis and toxoplasmosis, can reappear as opportunistic infections. Moreover, the climate changes linked to global warming in temperate countries are extending the insect vector habitats, as is the case of the northward spread of leishmania-transmitting sandflies, assessed by epidemiological surveys of canine leishmaniasis in Italy [2][3][4]. Some additional cases of parasitic infections have also been registered due to "transplant tourism", i.e. travel with the intent of receiving or donating an organ, a practice that is rapidly increasing [5]. A further danger for industrialized countries comes from massive migration of infected subjects from endemic countries: a typical example is the presence of thousands of Trypanosoma cruzi-infected people in North America and Spain [6].In the absence of prophylactic or curative vaccines the only available choice is chemotherapy. However, this relies on drugs which are tens of years old, afflicted with serious disadvantages, such as heavy side-effects, selection of resistant strains, or high production costs. Unfortunately, this situation is not likely to improve in the short t...

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Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

Cited by 115 publications

References 72 publications

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins

Profil Fenotipik Plasmodium falciparum Galur Papua 2300 Akibat Paparan Antimalaria Artemisinin in Vitro

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

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