Information regarding the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug provides the basis for optimizing dosing. PK-PD information should be obtained from patients representative of the overall target population, but in many tropical hospitals or health care facilities it may be medically hazardous or logistically difficult for an ill patient or a young child to be sampled repeatedly. Traditional methods used to determine the pharmacokinetic properties of a drug require analysis of a large number of blood samples per subject. However, using modern statistical methods, sparse datasets (i.e. with assay results from only a few, or as little as one blood sample per subject) can now be analysed by a method termed 'the population approach'. Modern assay techniques can often be adapted to small blood volumes allowing finger prick blood samples to be taken. One of the major aims of the population approach is to distinguish and characterize patient and disease contributors to inter-individual variance in drug pharmacokinetics. The purpose of this paper is to explain the basis of the population approach, to highlight its advantages compared to traditional methods of analysis, and to review the application of the population approach to data from field studies of antimalarial drugs. The design of population pharmacokinetic studies is also discussed briefly. The principles discussed in the paper are also applicable to pharmacodynamic data.
No abstract is provided for this article.
Inter‐sexual segregation between habitats or between sites within a habitat is very widespread in sexually dimorphic ungulates. As an explanation, it has been suggested that males, because of their larger forage requirements, are driven from preferred, high quality forage habitats into marginal habitats of lower forage quality but higher forage biomass by female competition (‘indirect competition hypothesis’). However, this hypothesis has hardly been tested. In the present study, we tested the indirect competition hypothesis for site segregation of red deer on the Isle of Rum, Scotland, within two vegetation communities: short Agrostis/Festuca grassland and Calluna heath. We predicted that: (1) males should choose sites within each vegetation community that are of higher forage biomass but lower forage quality, than sites selected by females; (2) the degree of inter‐sexual site segregation should be highest within the vegetation community in which indirect competition was most intense. We found that the sexes were significantly segregated between sites within both vegetation communities, but males did not use sites of lower forage quality or of higher forage biomass than did females. Moreover, degree of site segregation was not significantly higher in the vegetation community in which competition was more intense (i.e. short Agrostis/Festuca grassland). We conclude that the indirect competition hypothesis cannot explain site segregation in red deer on the Isle of Rum.
Although recent models for the evolution of personality, using game theory and life‐history theory, predict that individuals should differ consistently in their cooperative behaviour, consistent individual differences in cooperative behaviour have rarely been documented. In this study, we used a long‐term data set on wild meerkats to quantify the repeatability of two types of cooperative care (babysitting and provisioning) within individuals and examined how repeatability varied across age, sex and status categories. Contributions to babysitting and provisioning were significantly repeatable and positively correlated within individuals, with provisioning more repeatable than babysitting. While repeatability of provisioning was relatively invariant across categories of individuals, repeatability of babysitting increased with age and was higher for subordinates than dominants. These results provide support for theoretical predictions that life‐history trade‐offs favour the evolution of consistent individual differences in cooperative behaviour and raise questions about why some individuals consistently help more than others across a suite of cooperative behaviours.
It has been suggested recently, based on pharmacokinetic-pharmacodynamic modelling exercises, that twice daily dosing of artemisinins increases malaria parasite killing and so could "dramatically enhance and restore drug effectiveness" in artemisinin resistant P. falciparum malaria infections. It was recommended that split dosing should be incorporated into all artemisinin combination regimen designs. To explain why parasite clearance rates were not faster with split dose regimens it was concluded that splenic malaria parasite clearance capacity was readily exceeded, resulting in the accumulation of dead parasites in the circulation, that parasite clearance was therefore an unreliable measure of drug efficacy, and instead that human immunity is the primary determinant of clearance rates. To test these various hypotheses we performed a logistic meta-regression analysis of cure rates from all falciparum malaria treatment trials (n = 40) with monotherapy arms containing artemisinin or a derivative (76 arms). There was no evidence that split dosing enhanced cure rates.
Strains of Salmonella typhi which are resistant to the three first-line antibiotics, chloramphenicol, trimethoprim-sulphamethoxazole and amoxycillin, are increasingly prevalent in tropical countries. These strains retain sensitivity both to the fluoroquinolones and to the third-generation cephalosporins in vitro, although therapeutic responses following fluoroquinolone treatment are superior. In studies involving over 300 adults and children in Viet Nam with uncomplicated multidrug-resistant typhoid fever treatment, 3–5 day courses of oral ofloxacin or fleroxacin gave cure rates of between 96 and 100% and were well tolerated. A short course of fluoroquinolones may become the treatment of choice for enteric fever in areas where multidrug-resistant strains of S. typhi are prevalent.
Journal Article Biochemical Evidence of Muscle Injury in African Children with Severe Malaria Get access Kirk D. Miller, Kirk D. Miller Please address requests for reprints to Dr. Kirk D. Miller, 1725 17th Street NW. (Apartment 303), Washington, D. C. 20009. Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicholas J. White, Nicholas J. White Search for other works by this author on: Oxford Academic PubMed Google Scholar John A. Lorr, John A. Lorr Search for other works by this author on: Oxford Academic PubMed Google Scholar Jacquelin M. Roberts, Jacquelin M. Roberts Search for other works by this author on: Oxford Academic PubMed Google Scholar Brian M. Greenwood Brian M. Greenwood Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 159, Issue 1, January 1989, Pages 139–142, https://doi.org/10.1093/infdis/159.1.139 Published: 01 January 1989 Article history Received: 09 May 1988 Revision received: 21 July 1988 Published: 01 January 1989
Intravenous quinine dihydrochloride (5 mg kg‐1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/‐ 1 s.d.) after the infusion were 5.1 +/‐ 1.3 mg 1(‐1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half‐time (t 1/2, lambda 1) was 1.89 +/‐ 0.54 min (mean +/‐ 1 s.d.), elimination half‐time (t 1/2, z) 11.1 +/‐ 2.1 h, apparent volume of the central compartment (V1) 0.57 +/‐ 0.32 1 kg‐1, total apparent volume of distribution 1.80 +/‐ 0.37 1 kg‐1 and total clearance 1.92 +/‐ 0.45 ml min‐1 kg‐1.
We recorded electrocardiograms from 31 patients receiving quinine and 14 patients receiving quinidine for the treatment of Plasmodium falciparum malaria. Despite plasma quinine concentrations of up to 20 mg/L, there was no evidence of cardiotoxicity. QT prolongation was considerably greater in the quinidine-treated patients. The mean ratio of change in corrected QT interval to change in plasma concentration (ΔQTc%/ΔCo) was 3.2%·mg−1·L1 for quinidine, compared to 0.74%·mg−1·L1 for quinine (p < 0.001). T-wave flattening was observed in both groups. Plasma concentrations of quinine cannot be predicted from the EKG, because concentrations within the therapeutic range produced only minor and unpredictable abnormalities.
What do men who can command, who are born of rulers, who evince power in act and deportment, have to do with contracts? Such beings are unaccountable, they come like destiny, without rhyme or reason, ruthlessly, bare of pretext.At least religious atheists could believe that God was dead, but what can the erotic atheist believe?
