ATP-Binding Cassette Transporters

Publication Title: 
Clinical Epigenetics

BACKGROUND: There is growing interest in the hypertriglyceridemic waist (HTGW) phenotype, defined as high waist circumference (?95†cm in males and ?80†cm in females) combined with high serum triglyceride concentration (?2.0†mmol/L in males and ?1.5†mmol/L in females) as a marker of type 2 diabetes (T2D) and cardiovascular disease. However, the prevalence of this phenotype in high-risk populations, its association with T2D, and the genetic or epigenetic influences on HTGW are not well explored.

Author(s): 
Mamtani, Manju
Kulkarni, Hemant
Dyer, Thomas D.
Gˆring, Harald H. H.
Neary, Jennifer L.
Cole, Shelley A.
Kent, Jack W.
Kumar, Satish
Glahn, David C.
Mahaney, Michael C.
Comuzzie, Anthony G.
Almasy, Laura
Curran, Joanne E.
Duggirala, Ravindranath
Blangero, John
Carless, Melanie A.
Publication Title: 
Science (New York, N.Y.)

Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance.

Author(s): 
Sidhu, Amar Bir Singh
Verdier-Pinard, Dominik
Fidock, David A.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

We assessed whether mutations in the Plasmodium falciparum multidrug-resistance gene 1 (pfmdr1) (C1034S, D1042N, and Y1246D) would predict treatment outcome during a 28-day in vivo treatment trial in the Peruvian Amazon. Mefloquine (MQ) was compared with mefloquine-artesunate (MQ-AS) in a randomized, multi-clinic protocol for the first time in the Americas. Of 115 patients enrolled in the in vivo arm, 97 patients were eligible for molecular analysis.

Author(s): 
Pillai, Dylan R.
Hijar, Gisely
Montoya, Ysabel
Marouiño, Wilmer
Ruebush, Trenton K.
Wongsrichanalai, Chansuda
Kain, Kevin C.
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: 
The American Journal of Tropical Medicine and Hygiene

We have analyzed artemisinin sensitivity in Plasmodium falciparum isolates obtained from patients in South Vietnam and show that artemisinin sensitivity does not differ before and after drug treatment. There was an increase in the level of mefloquine resistance in the isolates after drug treatment that was concomitant with a decrease in chloroquine resistance, suggesting that treatment with artemisinin has selected for increased mefloquine resistance. Mutations in the pfmdr1 gene, previously shown to be associated with sensitivity to mefloquine, were selected against.

Author(s): 
Ngo, Thanh
Duraisingh, Manoj
Reed, Michael
Hipgrave, David
Biggs, Beverley
Cowman, Alan F.
Publication Title: 
Nucleic Acids Research. Supplement (2001)

Drug resistance in Plasmodium falciparum is a serious problem in most endemic areas. Recent studies have suggested the potential involvement of genes in the MDR gene family in resistance to quinoline-containing compounds in P. falciparum. In our present studies, a molecular analysis of pfmdr 1 in isolate strain of P. falciparum, 523a R, from Japanese mefloquine-resistant patient was done to determine the reported association of pfmdr 1 intragenic alleles and mefloquine resistance, and to examine the antimalarial activities of several antimalarial agents against the P. falciparum strain.

Author(s): 
Kim, H. S.
Okuda, Y.
Begum, K.
Nagai, Y.
Wataya, Y.
Kimura, M.
Huruta, T.
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: 
Antimicrobial Agents and Chemotherapy

Malaria parasites carrying genes conferring resistance to antimalarials are thought to have a selective advantage which leads to higher rates of transmissibility from the drug-treated host. This is a likely mechanism for the increasing prevalence of parasites with resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine in sub-Saharan Africa. Combination therapy is the key strategy being implemented to reduce the impact of resistance, but its effect on the transmission of genetically resistant parasites from treated patients to mosquito vectors has not been measured directly.

Author(s): 
Hallett, Rachel L.
Sutherland, Colin J.
Alexander, Neal
Ord, Rosalynn
Jawara, Musa
Drakeley, Chris J.
Pinder, Margaret
Walraven, Gijs
Targett, Geoffrey A. T.
Alloueche, Ali
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: 
The Journal of Infectious Diseases

Artemisinin derivative-based combination therapy is expected to suppress the development of Plasmodium falciparum drug resistance in Africa. We have performed an artemether-lumefantrine (Coartem; Novartis) follow-up clinical trial in Zanzibar, in which pfcrt K76T and pfmdr1 N86Y frequencies were determined before drug administration and in all recurrent parasites during a follow-up period of 42 days. A significant increase in pfmdr1 86N was observed after exposure to the drug.

Author(s): 
Sisowath, Christin
Strömberg, Johan
Mårtensson, Andreas
Msellem, Mwinyi
Obondo, Christine
Björkman, Anders
Gil, José P.

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