OBJECTIVE -To examine the effect of a 12-month pharmaceutical care (PC) program on vascular risk in type 2 diabetes.RESEARCH DESIGN AND METHODS -We recruited 198 community-based patients randomized to PC or usual care. PC patients had face-to-face goal-directed medication and lifestyle counseling at baseline and at 6 and 12 months plus 6-weekly telephone assessments and provision of other educational material. Clinical, biochemical, and medication-related data were sent regularly to each patient's physician(s). The main outcome measure was change in HbA 1c . A diabetes-specific risk engine was used to estimate changes in 10-year coronary heart disease (CHD) and stroke risk in patients without a history of cardiovascular disease.RESULTS -At total of 180 patients (91%) completed the study. Mean (95% CI) reductions were greater in PC case subjects (n ϭ 92) than control subjects (n ϭ 88) P atients with type 2 diabetes are more likely to die from cardiovascular disease than people without diabetes, and modifiable risk factors such as hyperglycemia, dyslipidemia, and hypertension can be targeted to reduce this risk (1-4). In addition to hospital-based care, there is a need for simple, cost-effective programs implemented in the community that allow the benefits of improved metabolic and blood pressure control to be realized more widely (5). Pharmacists could contribute to such programs through pharmaceutical care (PC). PC comprises the detection, prevention, and solution of drug-related problems (6) and has proved beneficial in diseases such as asthma and cancer (7).Previous PC studies in type 2 diabetes have involved small samples (8 -11), were nonrandomized (9 -13), did not report clinically important outcomes such as HbA 1c (10 -12), had a high attrition rate (13), or did not recruit patients representative of type 2 diabetes in the general population (8 -14). Two studies demonstrated some benefits of pharmacist involvement in the diabetes health care team (15,16), but they did not consider vascular risk factors other than glycemia, and in one (16), clinical pharmacist input was only part of the intervention. It has been suggested that rigorously designed PC studies addressing all aspects of diabetes care are of paramount importance (17). Consistent with this aim, we determined the impact of a PC program in a community-based sample of diabetic patients randomized to PC or usual care. We hypothesized that PC would improve glycemic and blood pressure control and dyslipidemia, with a consequent reduction in vascular risk.RESEARCH DESIGN AND METHODS -Adults with type 2 diabetes from the Fremantle Diabetes Study (FDS) were eligible for the present study, which was carried out between February 2001 and November 2002. The FDS was a prospective observational study of diabetes in a postcode-defined Australian population of 120,097 (18,19). From April 1993 to July 1996, 2,258 eligible subjects were identified and 1,426 (63%) were recruited, including 1,294 type 2 diabetic patients (91% of the sample). There were no difference...

Aims To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria. Methods Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT 50 ) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokineticpharmacodynamic relationships. Results Following i.v. bolus, ARTS had a peak concentration of 29.5 mm (11 mg l −1 ), elimination t 1/2 =2.7 min, CL=2.33 l h −1 kg −1 and V=0.14 l kg −1 .The C max for DHA was 9.3 mm (2.64 mg l . Following oral ARTS, relative bioavailability of DHA was 82%, C max was 2.6 mm (0.74 mg l −1 ), t 1/2 =39 min, and MAT=67 min. Overall, the PCT 50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT 50 or FCT and AUC, C max or MRT for DHA. Conclusions Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.

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ABSTRACT:The aim of this study was to elucidate the metabolic pathways for dihydroartemisinin (DHA), the active metabolite of the artemisinin derivative artesunate (ARTS). Urine was collected from 17 Vietnamese adults with falciparum malaria who had received 120 mg of ARTS i.v., and metabolites were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS). ) but not with UGT1A1 or UGT1A6. There was no significant metabolism of DHA by cytochrome-P450 oxidation or by cytosolic sulfotransferases. We conclude that ␣-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.

To provide novel data relating to the dispositions, effects, and toxicities of the artemisinin derivatives in severe malaria, we studied 30 Vietnamese adults with slide-positive falciparum malaria treated with intravenous artesunate. Twelve patients with complications (severe; group 1) and 8 patients without complications but requiring parenteral therapy (moderately severe; group 2) received 120 mg of artesunate by injection, and 10 patients with moderately severe complications (group 3) were given 240 mg by infusion. Serial concentrations of artesunate and its active metabolite dihydroartemisinin in plasma were measured by high-performance liquid chromatography. The time to 50% parasite clearance (PCT 50 ) was determined from serial parasite densities. Full clinical (including neurological) assessments were performed at least daily. In noncompartmental pharmacokinetic analyses, group mean artesunate half-lives (t 1/2 ) were short (range, 2.3 to 4.3 min). The dihydroartemisinin t 1/2 (range, 40 to 64 min), clearance (range, 0.73 to 1.01 liters/h/kg), and volume of distribution (range, 0.77 to 1.01 liters/kg) were also similar both across the three patient groups (P > 0.1) and to previously reported values for patients with uncomplicated malaria. Parasite clearance was prompt (group median PCT 50 range 6 to 9 h) and clinical recovery was complete under all three regimens. These data indicate that the pharmacokinetics of artesunate and dihydroartemisinin are not influenced by the severity of malaria. Since the pharmacokinetic parameters for both artesunate and dihydroartemisinin were similar regardless of whether injection or infusion was used, artesunate can be considered a prodrug that is converted stoichiometrically to dhydroartemisinin. Conventional doses of artesunate are safe and effective when given to patients with complications of falciparum malaria.

The disposition of chloroquine (CQ) and the related 4-aminoquinoline, piperaquine (PQ), were compared in Papua New Guinean children with uncomplicated malaria. Twenty-two children were randomized to 3 days of PQ phosphate at 20 mg/kg/day (12 mg of PQ base/kg/day) coformulated with dihydroartemisinin (DHA-PQ), and twenty children were randomized to 3 days of CQ at 10 mg base/kg/day with a single dose of sulfadoxinepyrimethamine (CQ-SP). After a 42-day intensive sampling protocol, PQ, CQ, and its active metabolite monodesethyl-chloroquine (DECQ) were assayed in plasma by using high-performance liquid chromatography. A two-compartment model with first-order absorption was fitted to the PQ and CQ data. There were no significant differences in age, gender, body weight, or admission parasitemia between the two groups. The PCR-corrected 42-day adequate clinical and parasitological responses were 100% for DHA-PQ and 94% for CQ-SP, but P. falciparum reinfections during follow-up were common (33 and 18%, respectively).

Abstract. To investigate the pharmacokinetic and pharmacodynamic properties of artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) in Plasmodium vivax infections, 12 male Vietnamese adults with slide-positive vivax malaria received either intravenous ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2) with the alternative preparation given 8 hr later in a randomized, open, cross-over study. Following intravenous injection, ARTS had a peak plasma drug concentration (C max ) of 35.6 M (13.7 mg/L), an elimination half-life (t ½ ) of 2.2 min, a clearance (CL) of 3.0 L/hr/kg, and a volume of distribution (V) of 0.16 L/kg. Dihydroartemisinin had a C max of 7.7 M (2.2 mg/L), a t max of 8 min, a t ½ of 37 min, an apparent CL of 1.1 L/hr/kg, and an apparent V of 0.9 L/kg. Following oral ARTS, the mean relative bioavailability of DHA was 85%, the C max was 3.0 M (0.85 mg/L), the t max was 75 min, and t ½ was 40 min. The mean time to 50% reduction in the parasite count (PCT 50 ) and median fever clearance time were 3 hr and 16 hr, respectively. Following intravenous ARTS (group 1), the PCT 50 for total parasites, rings, trophozoites, and gametocytes was 3.3 hr, 3.2 hr, 4.0 hr, and 3.6 hr, respectively. This study confirms that ARTS is effective against P. vivax, with rapid clearance of sexual and asexual forms of the parasite. Artesunate is a suitable initial treatment for vivax malaria, or when the plasmodial species cannot be reliably identified.Artemisinin derivatives are often used first-line in the treatment of slide-positive falciparum malaria. Where microscopy is unavailable in the primary care setting or when there is doubt concerning the plasmodial species present in the blood film, artemisinin drugs can be given empirically. Preliminary evidence suggests that this practice is justifiable. Artemisinin is effective in the treatment of vivax malaria although, as in the case of falciparum malaria, recrudescence may occur. 1 Pharmacokinetic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) have been reported recently in Vietnamese children 2 and adults 3 with uncomplicated falciparum malaria. Studies in healthy volunteers 4,5 have shown that peak plasma concentrations of DHA are significantly lower. There is, therefore, a need to determine the pharmacokinetic properties of ARTS in vivax and other benign human malarias to ensure that relatively low drug concentrations do not result from administration of the recommended dosing regimens used in falciparum malaria, a situation that might contribute to high recrudescence rates.Pharmacodynamic studies of ARTS in falciparum malaria demonstrate rapid parasite clearance, 6 but are limited by the fact that only parasite forms in the first half of the life cycle are present in peripheral blood. All stages of development can be seen in vivax malaria. This provides an opportunity to assess the effects of antimalarial drugs across the 48-hr parasite life cycle.The aims of the present study were to obtain pharmacokinetic data for ARTS ...

Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in Plasmodium berghei-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5-to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (t 1/2 ), clearance (CL), and volume of distribution (V) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL ‫؍‬ 3.86 ؋ W 0.56 , V ‫؍‬ 230 ؋ W 0.94 , and t 1/2 ‫؍‬ 123 ؋ W 0.2 ) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations.Chloroquine (CQ) was introduced 50 years ago as an alternative to quinine (25,70). It became the drug of choice for both prophylaxis and treatment of malaria, but resistance has caused a decline in the contemporary clinical use of chloroquine (25,35,40,70,72). Nevertheless, CQ remains one of the most important antimalarial drugs, especially in the treatment of vivax malaria and special patient groups, such as children and pregnant women (32,37,48,51,73), not least because it is inexpensive and well tolerated and has a rapid onset of action. Recent studies have clarified the mechanism of CQ resistance and shown that clinical efficacy of CQ may return at least a decade after it has been withdrawn from use, prompting suggestions that CQ could reemerge as an important therapeutic option for malaria, most likely in combination with artemisinin compounds or chemosensitizing agents (25,28,36,42,45,70).Notwithstanding its clinical status, CQ has a prominent role as a comparator for in vitro and in vivo preclinical testing of new antimalarial drugs (54,56,68,74). Remarkably, there is a paucity of pharmacokinetic and pharmacodynamic data for CQ in preclinical animal models, particularly in murine malaria models (4,11,29).The pharmacokinetic parameters for CQ exhibit wide interindividual variation, although limitations in study design and analytical procedures have been contributing factors (18,64,65). Recent clinical stud...