Publications

Natural History of Recurrent Urinary Tract Infections in Women Get access Walter E. Stamm, Walter E. Stamm Department of Medicine, University of Washington School of Medicine, Seattle, Washington Please address requests for reprints to Dr. Walter E. Stamm, Department of Medicine, Harborview Medical Center, 325 9th Avenue, Seattle, Washington 98104 Search for other works by this author on: Oxford Academic PubMed Google Scholar Mary McKevitt, Mary McKevitt Department of Medicine, University of Washington School of Medicine, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Pacita L. Roberts, Pacita L. Roberts Department of Medicine, University of Washington School of Medicine, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicholas J. White Nicholas J. White Department of Medicine, University of Washington School of Medicine, Seattle, Washington Search for other works by this author on: Oxford Academic PubMed Google Scholar Reviews of Infectious Diseases, Volume 13, Issue 1, January 1991, Pages 77–84, https://doi.org/10.1093/clinids/13.1.77 Published: 01 January 1990 Article history Published: 01 January 1990 Received: 10 January 1990 Revision received: 03 May 1990

Dear Editors and readers, We thank Dr Verhoef very much for his interesting letter and for raising this important statistical point. We agree that we should have used a method, such as that of Oldham, to examine the relationship. However, using Oldham's method (Tu and Gilthorpe 2007) does not change the conclusion. Patients with higher mean of admission and day 42 α have a greater reduction in alpha in convalescence (Figure 1, y = −67x + 76, R2 = 0.21, P < 0.001). Therefore, in this case statistical analysis using Oldham's method does not change the conclusion and the evidence indicates that the extent of improvement in thiamin status does depend on the degree of admission thiamin deficiency. Relationship between (admission α and convalescent α)/2 and percentage change in α. We are very grateful to Dr Sue Lee for her statistical advice on this response.

A World Antimalarial Resistance Network (WARN) database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any) studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics). By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered) individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject) characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD) studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component of the WARN database can play a pivotal role in monitoring accurately for true antimalarial drug resistance and promptly correcting sub-optimal dosage regimens to prevent these contributing to the emergence and spread of antimalarial resistance.

Japanese encephalitis virus (JEV), the mosquito-borne flavivirus, annually causes an estimated 35,000-50,000 encephalitis cases and 10,000-15,000 deaths in Asia, and there is no antiviral treatment. The role played by the immune response in determining the outcome of human infection with JEV is poorly understood, although, in animal models of flavivirus encephalitis, unregulated proinflammatory cytokine responses can be detrimental.We studied the innate, cellular, and humoral immune responses in 118 patients infected with JEV, of whom 13 (11%) died.Levels of interferon (IFN)- alpha , the proinflammatory cytokine interleukin (IL)-6, and the chemokine IL-8 were all higher in the cerebrospinal fluid (CSF) of the nonsurvivors than of the survivors (P=.04, P=.006, and P=.04, respectively), as were both the IL-6 : IL-4 ratio in CSF (a marker of the balance of pro- and anti-inflammatory cytokines) and the level of the chemokine RANTES (regulated on activation, normally T cell expressed and secreted) in plasma (P=.03). In contrast, levels of immunoglobulin (Ig) M and IgG in CSF and of IgM in plasma were higher in the survivors (P=.035, P=.003, and P=.009, respectively). Levels of IFN- gamma and nitric oxide did not vary with outcome.During JEV infection, elevated levels of proinflammatory cytokines and chemokines are associated with a poor outcome, but whether they are simply a correlate of severe disease or contribute to pathogenesis remains to be determined.

An in vivo concentration-effect relationship for the malaria drug piperaquine can be used for translational simulations of expected therapeutic outcomes in vulnerable populations.

Summary Objective To assess the prevalence of counterfeit antimalarial drugs in Southeast (SE) Asia. Design Cross‐sectional survey. Setting Pharmacies and shops selling antimalarial drugs in Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand. Main outcome measures Proportion of artemisinin derivatives or mefloquine containing drugs of substandard quality. Results Of the 188 tablet packs purchased which were labelled as ‘artesunate’ 53% did not contain any artesunate. All counterfeit artesunate tablets were labelled as manufactured by ‘Guilin Pharma’, and refinements of the fake blisterpacks made them often hard to distinguish from their genuine counterparts. No other artemisinin derivatives were found to be counterfeited. Of the 44 mefloquine samples, 9% contained &lt;10% of the expected amount of active ingredient. Conclusions An alarmingly high proportion of antimalarial drugs bought in pharmacies and shops in mainland SE Asia are counterfeit, and the problem has increased significantly compared with our previous survey in 1999–2000. This is a serious threat to public health in the region.

Journal Article The relationship between capillary and venous concentrations of the antimalarial drug lumefantrine (benflumetol) Get access M. van Vugt, M. van Vugt 1Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand2Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand3Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Ezzet, F. Ezzet 4Novartis Pharma AG, Basel, Switzerland Search for other works by this author on: Oxford Academic PubMed Google Scholar L. Phaipun, L. Phaipun 1Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Nosten, F. Nosten 1Shoklo Malaria Research Unit, Mae Sot, Tak Province, Thailand2Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand5Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar N.J. White N.J. White 2Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand5Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK Address for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand; phone + 66 2 246 0832, fax +66 2 246 7795. Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 92, Issue 5, September-October 1998, Pages 564–565, https://doi.org/10.1016/S0035-9203(98)90917-8 Published: 01 September 1998 Article history Received: 24 March 1998 Revision received: 26 June 1998 Accepted: 30 June 1998 Published: 01 September 1998

Background The artemisinins are potent and widely used antimalarial drugs that are eliminated rapidly. A simple concentration–effect pharmacometric model does not explain why dosing more frequently than once daily fails to augment parasite clearance and improve therapeutic responses in vivo. Artemisinins can induce a temporary non-replicative or ‘dormant’ drug refractory state in Plasmodium falciparum malaria parasites which may explain recrudescences observed in clinical trials despite full drug susceptibility, but whether it explains the dosing–response relationship is uncertain. Objectives To propose a revised model of antimalarial pharmacodynamics that incorporates reversible asexual parasite injury and temporary drug refractoriness in order to explain the failure of frequent dosing to augment therapeutic efficacy in falciparum malaria. Methods The model was fitted using a Bayesian Markov Chain Monte Carlo approach with the parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from western Cambodia and 40 patients from northwestern Thailand reported previously. Results The revised model captured the dynamics of parasite clearance data. Its predictions are consistent with observed therapeutic responses. Conclusions A within-host pharmacometric model is proposed in which it is hypothesized that some malaria parasites enter a temporary drug refractory state after exposure to artemisinin antimalarials, which is followed by delayed parasite death or reactivation. The model fitted the observed sequential parasite density data from patients with acute P. falciparum malaria, and it supported reduced ring stage activity in artemisinin-resistant infections.

Abstract Prolonged association between mothers and their offspring is common in ungulates, with the level of maternal investment likely to play a central role in shaping this trait. Here we examined patterns of association between mothers and offspring over time, the apparent benefits of association to offspring, and costs to mothers. We analyzed 40 years’ worth of census data from an individually-monitored, food-limited population of red deer ( Cervus elaphus ) on the Isle of Rum, Scotland. Starting from birth, female calves associated more frequently with their mothers than male calves in their first year. Calves also associated less with their mothers if the mother did not conceive a new calf. Association frequency decreased with mother’s age and population density, and survival over the first year was not related to mother-calf association. Yearlings, now in their second year, were more often associated with their mothers if they were female, if there was no subsequent calf (or the subsequent calf died as a neonate), and if they were still being suckled. Increased association between mothers and yearlings was associated with increased survival to adulthood at 28 months, but suckling a yearling did not improve its probability of survival. For individuals that reached maturity, increased association in the yearling year was associated with slightly shorter adult life spans. The level of association between a calf and mother was not associated with the mother’s immediate survival or fecundity. Our findings suggest that juveniles born to poor-condition mothers benefit from prolonged association through improved yearling survival.

Journal Article Pulmonary oedema in vivax malaria Get access S. Pukrittayakamee, S. Pukrittayakamee 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Chantra, A. Chantra 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Vanijanonta, S. Vanijanonta 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar N.J. White N.J. White ∗ 1Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand2Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK ∗Address for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand; phone +66 2 246 0832, fax +66 2 246 7795. fnnjw@diamond.mahidol.ac.th Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 92, Issue 4, July-August 1998, Pages 421–422, https://doi.org/10.1016/S0035-9203(98)91075-6 Published: 01 July 1998 Article history Received: 23 March 1998 Accepted: 29 April 1998 Published: 01 July 1998

Conventional 48-h in vitro susceptibility tests have low sensitivity in identifying artemisinin-resistant Plasmodium falciparum, defined phenotypically by low in vivo parasite clearance rates. We hypothesized originally that this discrepancy was explained by a loss of ring-stage susceptibility and so developed a simple field-adapted 24-h trophozoite maturation inhibition (TMI) assay focusing on the ring stage and compared it to the standard 48-h schizont maturation inhibition (WHO) test. In Pailin, western Cambodia, where artemisinin-resistant P. falciparum is prevalent, the TMI test mean (95% confidence interval) 50% inhibitory concentration (IC50) for artesunate was 6.8 (5.2 to 8.3) ng/ml compared with 1.5 (1.2 to 1.8) ng/ml for the standard 48-h WHO test (P = 0.001). TMI IC50s correlated significantly with the in vivo responses to artesunate (parasite clearance time [r = 0.44, P = 0.001] and parasite clearance half-life [r = 0.46, P = 0.001]), whereas the standard 48-h test values did not. On continuous culture of two resistant isolates, the artemisinin-resistant phenotype was lost after 6 weeks (IC50s fell from 10 and 12 ng/ml to 2.7 and 3 ng/ml, respectively). Slow parasite clearance in falciparum malaria in western Cambodia results from reduced ring-stage susceptibility.