Phenanthrenes

Publication Title: 
The Journal of Infectious Diseases

The in vivo and in vitro effects of antimalarials on cytoadherence and rosette formation were studied in 17 patients with severe and 46 with uncomplicated falciparum malaria. Cytoadherence was increased in severe malaria (P<.001). Artesunate and artemether were more potent than quinine in inhibiting both adherence properties. Artesunate was the most rapidly acting drug tested, producing >50% inhibition of both cytoadherence and rosetting in vivo and in vitro within 2 hr of drug exposure.

Author(s): 
Udomsangpetch, R.
Pipitaporn, B.
Krishna, S.
Angus, B.
Pukrittayakamee, S.
Bates, I.
Suputtamongkol, Y.
Kyle, D. E.
White, N. J.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The in vitro activity of artemether against 56 African isolates of Plasmodium falciparum from Senegal was evaluated using an isotope-based drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95% confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95% CI = 2.08-4.84 nM versus mean IC50 = 2.80 nM, 95% CI = 2.00-3.60 nM).

Author(s): 
Pradines, B.
Rogier, C.
Fusai, T.
Tall, A.
Trape, J. F.
Doury, J. C.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The sensitivity of Plasmodium falciparum to chloroquine, mefloquine, quinine, quinidine, halofantrine, artemisinin, and sulfadoxine/pyrimethamine was investigated in Lambarene, Gabon in 1994. The development of in vitro susceptibility has been traced from 1983 or 1992 to 1994 for chloroquine, mefloquine, halofantrine, and quinine. Standard in vitro microtests according to World Health Organization methodology were performed.

Author(s): 
Philipps, J.
Radloff, P. D.
Wernsdorfer, W.
Kremsner, P. G.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The factors affecting the development of patent Plasmodium falciparum gametocytemia were assessed in 5,682 patients entered prospectively into a series of antimalarial drug trials conducted in an area of low and seasonal transmission on the western border of Thailand. Of the 4,565 patients with admission thick smear assessments, 110 (2.4%) had gametocytemia. During the follow-up period 170 (3%) of all patients developed patent gametocytemia, which in 89% had developed by day 14 following treatment.

Author(s): 
Price, R.
Nosten, F.
Simpson, J. A.
Luxemburger, C.
Phaipun, L.
ter Kuile, F.
van Vugt, M.
Chongsuphajaisiddhi, T.
White, N. J.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

Co-artemether (Coartem, Riamet) is a tablet containing 20 mg artemether and 120 mg lumefantrine for treatment of falciparum malaria. Lumefantrine has some chemical similarities to halofantrine (Halfan), an antimalarial known for QTc prolongation. Effects on the QTc interval of fed single oral doses of 500 mg halofantrine and 80/480 mg co-artemether were compared in 13 healthy males in a randomized double-blind crossover study. Electrocardiograms (ECGs) were recorded from 48 hours before dosing until 48 hours thereafter.

Author(s): 
Bindschedler, Margaretha
Lefèvre, Gilbert
Degen, Peter
Sioufi, Antoine
Publication Title: 
The Journal of Infectious Diseases

The global dissemination of drug-resistant Plasmodium falciparum is spurring intense efforts to implement artemisinin (ART)-based combination therapies for malaria, including mefloquine (MFQ)-artesunate and lumefantrine (LUM)-artemether. Clinical studies have identified an association between an increased risk of MFQ, MFQ-artesunate, and LUM-artemether treatment failures and pfmdr1 gene amplification.

Author(s): 
Sidhu, Amar Bir Singh
Uhlemann, Anne-Catrin
Valderramos, Stephanie G.
Valderramos, Juan-Carlos
Krishna, Sanjeev
Fidock, David A.
Publication Title: 
Malaria Journal

Conventional methods of assessing in-vitro antimalarial drug-concentration effect relationships in field testing of fresh isolates assess each parasite isolate individually. This leads to systematic overestimation of EC50 values for the most resistant isolates, and thus overestimation of the degree of resistance. In antimalarial drug-susceptibility studies conducted on the north-western border of Thailand the overestimation of EC50 for the most resistant isolate ranged from 15% for artesunate to 43% for mefloquine.

Author(s): 
Stepniewska, Kasia
Chotivanich, Kesinee
Brockman, Alan
Day, Nicholas P. J.
White, Nicholas J.
Publication Title: 
Cell

Traditional medicines provide fertile ground for modern drug development, but first they must pass along a pathway of discovery, isolation, and mechanistic studies before eventual deployment in the clinic. Here, we highlight the challenges along this route, focusing on the compounds artemisinin, triptolide, celastrol, capsaicin, and curcumin.

Author(s): 
Corson, Timothy W.
Crews, Craig M.
Publication Title: 
Current Drug Discovery Technologies

Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures.

Author(s): 
Graziose, Rocky
Lila, Mary Ann
Raskin, Ilya
Publication Title: 
Antimicrobial Agents and Chemotherapy

Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype.

Author(s): 
Legrand, Eric
Yrinesi, Joséphine
Ekala, Marie-Thérèse
Péneau, Julie
Volney, Béatrice
Berger, Franck
Bouchier, Christiane
Bertani, Stéphane
Musset, Lise
Meynard, Jean-Baptiste
Mercereau-Puijalon, Odile

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