Polymorphism, Genetic

Publication Title: 
The Journal of Infectious Diseases

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment.

Author(s): 
von Seidlein, L.
Jaffar, S.
Pinder, M.
Haywood, M.
Snounou, G.
Gemperli, B.
Gathmann, I.
Royce, C.
Greenwood, B.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

Artemisinin derivatives are first-line antimalarial drugs in Thailand. No firm evidence of clinically relevant artemisinin resistance exists. When used as monotherapy, artesunate has been associated with a high treatment failure (recrudescence) rate, which could be due to low-level artemisinin resistance. To understand the causes of recrudescence, we retrospectively studied a cohort of 104 malaria patients treated with artesunate monotherapy, 32 of whom recrudesced.

Author(s): 
Ittarat, Wanida
Pickard, Amy L.
Rattanasinganchan, Panthip
Wilairatana, Polrat
Looareesuwan, Sornchai
Emery, Kathryn
Low, Jonathan
Udomsangpetch, Rachanee
Meshnick, Steven R.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Resistance to antimalarial drugs is a public health problem worldwide. Molecular markers for drug-resistant malaria, such as pfcrt and pfmdr1 polymorphisms, could serve as useful surveillance tools. To evaluate this possibility, sequence polymorphisms in pfcrt (position 76) and pfmdr1 (positions 86, 184, 1034, 1042, and 1246) and in vitro drug sensitivities were measured for 65 Plasmodium falciparum isolates from Thailand, Myanmar, Vietnam, and Bangladesh.

Author(s): 
Pickard, Amy L.
Wongsrichanalai, Chansuda
Purfield, Anne
Kamwendo, Deborah
Emery, Kathryn
Zalewski, Christy
Kawamoto, Fumihiko
Miller, R. Scott
Meshnick, Steven R.
Publication Title: 
Lancet (London, England)

BACKGROUND: The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known.

Author(s): 
Price, Ric N.
Uhlemann, Anne-Catrin
Brockman, Alan
McGready, Rose
Ashley, Elizabeth
Phaipun, Lucy
Patel, Rina
Laing, Kenneth
Looareesuwan, Sornchai
White, Nicholas J.
Nosten, François
Krishna, Sanjeev
Publication Title: 
Journal of Vector Borne Diseases

Ever since the discovery of the first case of chloroquine resistance along the Thai-Combodian border in the late 1950s, Southeast Asia has played an important role as a focus for the development of drug resistance in Plasmodium falciparum.

Author(s): 
Farooq, Umar
Mahajan, R. C.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample.

Author(s): 
Anderson, Timothy J. C.
Nair, Shalini
Qin, Huang
Singlam, Sittaporn
Brockman, Alan
Paiphun, Lucy
Nosten, François
Publication Title: 
Tropical medicine & international health: TM & IH

Recently, Ghana has changed the first-line treatment of uncomplicated malaria from chloroquine to amodiaquine (AQ) plus artesunate. AQ may cause adverse events such as agranulocytosis and hepatoxicity. The pro-drug AQ is transformed by cytochrome P450 CYP2C8 to the active metabolite N-desethylaminodiaquine. Several polymorphic variants of CYP2C8 are known, some with reduced activity. In 200 randomly selected children from Northern Ghana, we determined the allele frequencies of the CYP2C8 variants CYP2C8*1 (wild type), CYP2C8*2, CYP2C8*3, and CYP2C8*4.

Author(s): 
Röwer, Susanne
Bienzle, Ulrich
Weise, Alexander
Lambertz, Ulrike
Forst, Thomas
Otchwemah, Rowland N.
Pfützner, Andreas
Mockenhaupt, Frank P.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Polymorphisms in the Plasmodium falciparum pfmdr1 gene were assayed in pretreatment samples and in samples from patients reinfected following therapy with artemether-lumefantrine. The pfmdr1 alleles 86N, 184F, and 1246D significantly increased in prevalence after treatment. All samples had a single pfmdr1 copy. Treatment with artemether-lumefantrine selects for polymorphisms that may alter antimalarial drug response.

Author(s): 
Dokomajilar, Christian
Nsobya, Samuel L.
Greenhouse, Bryan
Rosenthal, Philip J.
Dorsey, Grant
Publication Title: 
The EMBO journal

The P-glycoprotein homolog of the human malaria parasite Plasmodium falciparum (Pgh-1) has been implicated in decreased susceptibility to several antimalarial drugs, including quinine, mefloquine and artemisinin. Pgh-1 mainly resides within the parasite's food vacuolar membrane. Here, we describe a surrogate assay for Pgh-1 function based on the subcellular distribution of Fluo-4 acetoxymethylester and its free fluorochrome. We identified two distinct Fluo-4 staining phenotypes: preferential staining of the food vacuole versus a more diffuse staining of the entire parasite.

Author(s): 
Rohrbach, Petra
Sanchez, Cecilia P.
Hayton, Karen
Friedrich, Oliver
Patel, Jigar
Sidhu, Amar Bir Singh
Ferdig, Michael T.
Fidock, David A.
Lanzer, Michael
Publication Title: 
The Journal of Antimicrobial Chemotherapy

BACKGROUND AND OBJECTIVES: The immunosuppressant cyclosporin A and a number of other cyclosporins have potent and selective antimalarial activity. Their exact mechanism of antimalarial action is unknown but the structure-activity relationships for malarial parasite inhibition and immunosuppression differ markedly. The 3'-keto derivative of cyclosporin D (valspodar) is particularly potent against the human malarial parasite Plasmodium falciparum in culture but causes negligible immunosuppression.

Author(s): 
Gavigan, C. S.
Shen, M.
Machado, S. G.
Bell, A.

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