Reference Type: Journal Article
Record Number: 334
Author: White, Nicholas J.; McGready, Rose M.; Nosten, Francois, H.
Year: 2008
Title: New Medicines for Tropical Diseases in Pregnancy: Catch-22
Journal: PLoS Medicine
Volume: 5
Issue: 6
Pages: e133
Date: June 01, 2008

Reference Type: Journal Article
Author: Tarning, J.; Ashley, E. A.; Lindegardh, N.; Stepniewska, K.; Phaiphun, L.; Day, N. P.; McGready, R.; Ashton, M.; Nosten, F.; White, N. J.
Year: 2008
Title: Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand
Journal: Antimicrob Agents Chemother
Volume: 52
Issue: 3
Pages: 1052-61
Abstract: The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUC day 0-63]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUC day 3-20) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.

Reference Type: Journal Article
Author: Sharrock, W. W.; Suwanarusk, R.; Lek-Uthai, U.; Edstein, M. D.; Kosiavasee, V.; Travers, T.; Jaidee, A.; Sriprawat, K.; Price, R. N.; Nosten, F.; Russell, B.
Year: 2008
Title: Plasmodium vivax trophozoites insensitive to chloroquine
Journal: Malar J
Volume: 7
Issue: 1
Pages: 94
Abstract: ABSTRACT: BACKGROUND: Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. Chloroquine inhibits the polymerization of haem to inert haemozoin. Free haem monomers are thought to catalyze oxidative damage to the Plasmodium spp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminary in vitro observations on P. vivax clinical isolates suggest that only ring stages (early trophozoites) are sensitive to chloroquine. In this study, the stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax. METHODS: The in vitro chloroquine sensitivity of paired ring and trophozoite stages from 11 cryopreserved P. vivax clinical isolates from Thailand and two Plasmodium falciparum clones (chloroquine resistant K1 and chloroquine sensitive FC27) was measured using a modified WHO microtest method and fluorometric SYBR Green I Assay. The time each stage was exposed to chloroquine treatment was controlled by washing the chloroquine off at 20 hours after the beginning of treatment. RESULTS: Plasmodium vivax isolates added to the assay at ring stage had significantly lower median IC50s to chloroquine than the same isolates added at trophozoite stage (median IC50 12 nM vs 415nM p<0.01). Although only 36% (4/11) of the SYBR Green I assays for P. vivax were successful, both microscopy and SYBR Green I assays indicated that only P. vivax trophozoites were able to develop to schizonts at chloroquine concentrations above 100nM. CONCLUSIONS: Data from this study confirms the diminished sensitivity of P. vivax trophozoites to chloroquine, the stage thought to be the target of this drug. These results raise important questions about the pharmacodynamic action of chloroquine, and highlight a fundamental difference in the activity of chloroquine between P. vivax and P. falciparum.

Reference Type: Journal Article
Author: Rijken, M. J.; McGready, R.; Boel, M. E.; Barends, M.; Proux, S.; Pimanpanarak, M.; Singhasivanon, P.; Nosten, F.
Year: 2008
Title: Dihydroartemisinin-piperaquine rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report
Journal: Am J Trop Med Hyg
Volume: 78
Issue: 4
Pages: 543-5
Date: Apr
Abstract: Dihydroartemisinin-piperaquine (DHA-PPQ) is a promising new artemisinin combination treatment. There are no published data on the intentional use of the drug in pregnancy. Between June 2006 and January 2007, 50 Karen pregnant women with recurrent P. falciparum infections, despite 7-day treatments with quinine or artesunate (+/-clindamycin) or both, were treated with DHA-PPQ. This rescue treatment was effective and well tolerated and there was no evidence of toxicity for the mothers or the fetus. The PCR adjusted cure rate by Kaplan Meier analysis at day 63 was 92.2% (95% CI: 76.9-97.4).
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18385345
Author Address: Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand.

Reference Type: Journal Article
Author: Lwin, K. M.; Ashley, E. A.; Proux, S.; Silamut, K.; Nosten, F.; McGready, R.
Year: 2008
Title: Clinically uncomplicated Plasmodium falciparum malaria with high schizontaemia: a case report
Journal: Malar J
Volume: 7
Pages: 57
Abstract: BACKGROUND: The treatment options for acute Plasmodium falciparum malaria are based on the clinician classifying the patient as uncomplicated or severe according to the clinical and parasitological findings. This process is not always straightforward. CASE PRESENTATION: An adult male presented to a clinic on the western border of Thailand with a physical examination and P. falciparum trophozoite count (1.2% of infected red blood cells, IRBC) from malaria blood smear, consistent with a diagnosis of uncomplicated P. falciparum infection. However, the physician on duty treated the patient for severe malaria based on the reported P. falciparum schizont count, which was very high (0.3% IRBC), noticeably in relation to the trophozoite count and schizont:trophozoite ratio 0.25:1. On intravenous artesunate, the patient deteriorated clinically in the first 24 hours. The trophozoite count increased from 1.2% IRBC at baseline to 20.5% IRBC 18 hours following the start of treatment. By day three, the patient recovered and was discharged on day seven having completed a seven-day treatment with artesunate and mefloquine. CONCLUSION: The malaria blood smear provides only a guide to the overall parasite biomass in the body, due to the ability of P. falciparum to sequester in the microvasculature. In severe malaria, high schizont counts are associated with worse prognosis. In low transmission areas or in non-immune travelers the presence of schizonts in the peripheral circulation is an indication for close patient supervision. In this case, an unusually high schizont count in a clinically uncomplicated patient was indicative of potential deterioration. Prompt treatment with intravenous artesunate is likely to have been responsible for the good clinical outcome in this case.
Notes: United Kingdom Wellcome Trust
Journal Article
Research Support, Non-U.S. Gov't
England
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18402713
Author Address: Shoklo Malaria Research Unit, Mae Sot, Tak, 63110, Thailand. drkhin_mg_lwin@shoklo-unit.com

Reference Type: Journal Article
Author: Lek-Uthai, U.; Suwanarusk, R.; Ruengweerayut, R.; Skinner-Adams, T. S.; Nosten, F.; Gardiner, D. L.; Boonma, P.; Piera, K. A.; Andrews, K. T.; MacHunter, B.; McCarthy, J. S.; Anstey, N. M.; Price, R. N.; Russell, B.
Year: 2008
Title: HIV-1 protease inhibitors and clinical isolates of Plasmodium: Greater activity against P. vivax than P. falciparum
Journal: Antimicrob. Agents Chemother.
Date: April 28, 2008
Abstract: Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during HIV-1 and malaria co-infection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic protease inhibitors (PIs); saquinavir (SQV) and ritonavir (RTV) against P. vivax (n=30) and P. falciparum (n=20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thai-Burmese border. The median IC50 values of P. vivax to RTV and SQV were 2233nM (range; 732-7738nM) and 4230nM (range; 1326-8452nM) respectively, both within the therapeutic concentration range commonly found in patients treated with these PIs. RTV was four fold more effective at inhibiting P. vivax than P. falciparum compared to a two fold difference in SQV sensitivity. Increased Pfmdr1 copy number was present in 33% (3/9) of isolates and that of Pvmdr1 in 9% (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium spp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum. PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients resident in areas where multi-drug resistant P. vivax or P. falciparum is found.
URL: http://aac.asm.org/cgi/content/abstract/AAC.00169-08v1

Reference Type: Journal Article
Author: Guthmann, J. P.; Pittet, A.; Lesage, A.; Imwong, M.; Lindegardh, N.; Min Lwin, M.; Zaw, T.; Annerberg, A.; de Radigues, X.; Nosten, F.
Year: 2008
Title: Plasmodium vivax resistance to chloroquine in Dawei, southern Myanmar
Journal: Trop Med Int Health
Volume: 13
Issue: 1
Pages: 91-8
Date: Jan
Abstract: OBJECTIVE: To assess the efficacy of chloroquine in the treatment of Plasmodium vivax malaria in in Dawei District, southern Myanmar. METHODS: Enrolled patients at Sonsinphya clinic >6 months of age were assessed clinically and parasitologically every week for 28 days. To differentiate new infections from recrudescence, we genotyped pre- and post-treatment parasitaemia. Blood chloroquine was measured to confirm resistant strains. RESULTS: Between December 2002 and April 2003, 2661 patients were screened, of whom 252 were included and 235 analysed. Thirty-four per cent (95% CI: 28.1-40.6) of patients had recurrent parasitaemia and were considered treatment failures. 59.4% of these recurrences were with a different parasite strain. Two (0.8%) patients with recurrences on day 14 had chloroquine concentrations above the threshold of 100 ng/ml and were considered infected with chloroquine resistant parasites. 21% of failures occurred during the first 3 weeks of follow-up: early recurrence and median levels of blood chloroquine comparable to those of controls suggested P. vivax resistance. CONCLUSIONS: Plasmodium vivax resistance to chloroquine seems to be emerging in Dawei, near the Thai-Burmese border. While chloroquine remains the first-line drug for P. vivax infections in this area of Myanmar, regular monitoring is needed to detect further development of parasite resistance.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18291007
Author Address: Epicentre, Paris, France.

Reference Type: Journal Article
Author: Dondorp, A. M.; Lee, S. J.; Faiz, M. A.; Mishra, S.; Price, R.; Tjitra, E.; Than, M.; Htut, Y.; Mohanty, S.; Yunus, E. B.; Rahman, R.; Nosten, F.; Anstey, N. M.; Day, N. P.; White, N. J.
Year: 2008
Title: The relationship between age and the manifestations of and mortality associated with severe malaria
Journal: Clin Infect Dis
Volume: 47
Issue: 2
Pages: 151-7
Date: Jul 15
Accession Number: 18533842
Abstract: BACKGROUND: The reported case-fatality rate associated with severe malaria varies widely. Whether age is an independent risk factor is uncertain. METHODS: In a large, multicenter treatment trial conducted in Asia, the presenting manifestations and outcome of severe malaria were analyzed in relation to age. RESULTS: Among 1050 patients with severe malaria, the mortality increased stepwise, from 6.1% in children (age, <10 years) to 36.5% in patients aged >50 years (P<0.001). Compared with adults aged 21-50 years, the decreased risk of death among children (adjusted odds ratio, 0.06; 95% confidence interval, 0.01-0.23; P<0.001) and the increased risk of death among patients aged >50 years (adjusted odds ratio, 1.88; 95% confidence interval, 1.01-3.52; P<0.001) was independent of the variation in presenting manifestations. The incidence of anemia and convulsions decreased with age, whereas the incidence of hyperparasitemia, jaundice, and renal insufficiency increased with age. Coma and metabolic acidosis did not vary with age and were the strongest predictors of a fatal outcome. The number of severity signs at hospital admission also had a strong prognostic value. CONCLUSION: Presenting syndromes in severe malaria depend on age, although the incidence and the strong prognostic significance of coma and acidosis are similar at all ages. Age is an independent risk factor for a fatal outcome of the disease.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18533842
Author Address: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Reference Type: Journal Article
Author: Blacksell, S. D.; Luksameetanasan, R.; Kalambaheti, T.; Aukkanit, N.; Paris, D. H.; McGready, R.; Nosten, F.; Peacock, S. J.; Day, N. P.
Year: 2008
Title: Genetic typing of the 56-kDa type-specific antigen gene of contemporary Orientia tsutsugamushi isolates causing human scrub typhus at two sites in north-eastern and western Thailand
Journal: FEMS Immunol Med Microbiol
Volume: 52
Issue: 3
Pages: 335-42
Date: Apr
Abstract: Orientia tsutsugamushi is the causative agent of scrub typhus, a major cause of febrile illness in the rural areas of Southeast Asia. Twenty-three strains of O. tsutsugamushi were isolated from patients with scrub typhus in north-east (Udorn Thani province) and western Thailand (Tak province) between 2003 and 2005. The isolates were characterized by sequencing the entire ORF of the 56-kDa-type-specific antigen gene, followed by phylogenetic analysis. The majority (15/23) of isolates clustered with the Karp-type strain, six with a Gilliam-type strain and one each with the TA716- and TA763-type strains. Overall, there was considerable diversity in sequence, comparable to that seen in strains from across the rest of the scrub typhus-endemic world. There was no significant difference in the distributions of strains between the two provinces (P=0.08, Fisher's exact) nor a temporal change in distribution with year of isolation (P=0.80, Fisher's exact). Within this diversity there were also examples of isolates with identical 56-kDa genotypes that were cultured from patients from the same geographical areas.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18312580
Author Address: Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand. stuart@tropmedres.ac

Reference Type: Journal Article
Author: Imwong, M.; Pukrittayakamee, S.; Pongtavornpinyo, W.; Nakeesathit, S.; Nair, S.; Newton, P.; Nosten, F.; Anderson, T. J.; Dondorp, A.; Day, N. P.; White, N. J.
Year: 2008
Title: Gene amplification of Plasmodium vivax multidrug resistance 1 gene in Thailand, Laos, and Myanmar
Journal: Antimicrob Agents Chemother
Date: Apr 28
Abstract: Plasmodium vivax mdr1 gene amplification, quantified by real time PCR, was significantly more common on the western Thailand border (6 of 66 samples), where mefloquine pressure has been intense, than elsewhere in Southeast Asia (3 of 149; p=0.02). Five coding mutations in pvmdr1, independent of gene amplification, were found also.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18443118

Reference Type: Journal Article
Record Number: 331
Author: Blacksell, S. D.; Luksameetanasan, R.; Kalambaheti, T.; Aukkanit, N.; Paris, D. H.; McGready, R.; Nosten, F.; Peacock, S. J.; Day, N. P.
Year: 2008
Title: Genetic typing of the 56-kDa type-specific antigen gene of contemporary Orientia tsutsugamushi isolates causing human scrub typhus at two sites in north-eastern and western Thailand
Journal: FEMS Immunol Med Microbiol
Volume: 52
Issue: 3
Pages: 335-42
Date: Apr
Abstract: Orientia tsutsugamushi is the causative agent of scrub typhus, a major cause of febrile illness in the rural areas of Southeast Asia. Twenty-three strains of O. tsutsugamushi were isolated from patients with scrub typhus in north-east (Udorn Thani province) and western Thailand (Tak province) between 2003 and 2005. The isolates were characterized by sequencing the entire ORF of the 56-kDa-type-specific antigen gene, followed by phylogenetic analysis. The majority (15/23) of isolates clustered with the Karp-type strain, six with a Gilliam-type strain and one each with the TA716- and TA763-type strains. Overall, there was considerable diversity in sequence, comparable to that seen in strains from across the rest of the scrub typhus-endemic world. There was no significant difference in the distributions of strains between the two provinces (P=0.08, Fisher's exact) nor a temporal change in distribution with year of isolation (P=0.80, Fisher's exact). Within this diversity there were also examples of isolates with identical 56-kDa genotypes that were cultured from patients from the same geographical areas.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18312580
Author Address: Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand. stuart@tropmedres.ac