BackgroundIntra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria.Methods and FindingsAdults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36–1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0–6h were observed.ConclusionsThe pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.

Purpose – The purpose of this paper is to introduce the special issue on improving equitable access to health care through increased public and patient involvement (PPI) in prioritization decisions by discussing the conceptualization, scope and rationales of PPI in priority setting that inform the special issue. Design/methodology/approach – The paper employs a mixed-methods approach in that it provides a literature review and a conceptual discussion of the common themes emerging in the field of PPI and health priority setting. Findings – The special issue focuses on public participation that is collective in character, in the sense that the participation relates to a social, not personal, decision and is relevant to whole groups of people and not single individuals. It is aimed at influencing a decision on public policy or legal rules. The rationales for public participation can be found in democratic theory, especially as they relate to the social and political values of legitimacy and representation. Originality/value – The paper builds on previous definitions of public participation by underlining its collective character. In doing so, it develops the work by Parry, Moyser and Day by arguing that, in light of the empirical evidence presented in this issue, public participatory activities such as protests and demonstrations should no longer be labelled unconventional, but should instead be labelled as “contestatory participation”. This is to better reflect a situation in which these modes of participation have become more conventional in many parts of the world.

Except for propranolol, no other Beta-blocker has been studied thoroughly in the prophylaxis of migraine. Of those studied, propranolol, atenolol and timolol were shown to be useful in double-blind clinical trials. The mode, or even the site of action of these drugs in unknown. Possible mechanisms of action are peripheral vascular effects, a central action, 5-HT antagonism, an anxiolytic effect and a multifactorial action. The only common property of the successful drugs is lack of partial agonist activity and their profiles do not fully support any of the above hypotheses. Trials of drugs in the prophylaxis of migraine have in general been unsatisfactory due to the difficulty in controlling many variables. Beta-blockers with differing properties offer an opportunity to define the properties necessary for anti-migraine activity and perhaps shed light on the pathogenesis of migraine.

No abstract