Pharmacokinetic properties of the antimalarial combination therapy artemether-lumefantrine in normal-weight, overweight and obese healthy male adults.

The component drugs in the widely used antimalarial artemisinin combination therapy artemether-lumefantrine are lipophilic, with the possibility that recommended fixed doses in adults may lead to subtherapeutic concentrations and consequent treatment failure in overweight/obese individuals with malaria. The aim of this study was to investigate the pharmacokinetic properties of artemether, lumefantrine and their active metabolites dihydroartemisinin and desbutyl-lumefantrine in 16 normal-weight, overweight and obese healthy male volunteers [body mass index (BMI) categories ≤25 kg/m², >25-≤30 kg/m² and >30 kg/m², respectively; absolute range 19.3-37.2 kg/m²]. Participants received the conventional six doses of artemether-lumefantrine over 3 days, each dose comprising 80 mg artemether plus 480 mg lumefantrine administered with 6.7 g fat, and blood samples were collected at pre-specified time-points over 14 days. Plasma drug/metabolite concentrations were measured using liquid chromatography-mass spectrometry and included in multi-compartmental population pharmacokinetic models. There was a non-significant trend to a lower area under the plasma concentration-time curve with a higher body weight or BMI for dihydroartemisinin and especially artemether which was attenuated when normalized for mg/kg dose, but this relationship was not evident in the case of the more lipophilic lumefantrine and its metabolite desbutyl-lumefantrine. Simulated Day 7 plasma lumefantrine concentrations were >200 µg/L (the threshold at which Plasmodium falciparum recrudescences are minimized) in all participants. These results indicate that there is no need for artemether-lumefantrine dose modification in overweight and obese patients with malaria.

Outcomes Associated With Standardized Ideal Body Weight Dosing of Intravenous Immune Globulin in Hospitalized Patients: A Multicenter Study.

Background: There are limited outcomes data for ideal body weight (IBW)-based dosing of intravenous immune globulin (human, IVIG) in hospitalized patients. Objective: To investigate clinical outcomes associated with a standardized change from total body weight to IBW-based dosing of IVIG. Methods: This was a retrospective, multicenter, pre-post sequential period analysis. Data from pre-implementation and post-implementation of an IBW-based dosing strategy for IVIG were collected in 2-year periods (October 1, 2012, to August 31, 2014, and October 2, 2014, to October 1, 2016, respectively). The primary outcome was incidence of 30-day hospital readmission. Length of stay (LOS) was analyzed as a secondary outcome. Results: For the 2 study periods, 297 patients were included for analysis. Both groups had similar demographics, IVIG indications, and body weight measurements, but the post-implementation period had a lower median grams per dose as compared with the pre-implementation period (40 vs 30 g, P ≤ 0.01). 30-Day hospital readmission rates were not significantly different (4% vs 9%, P = 0.07). In-hospital all-cause mortality was also not statistically significant (7.7% vs 3.4%, P = 0.11). The 2 study groups had a similar median hospital LOS (8 vs 7.6 days, P = 0.27). Conclusion and Relevance: The implementation of a standardized IBW IVIG dosing strategy was not associated with a statistically significant increase in 30-day hospital readmission or LOS but was associated with significantly fewer grams per dose given. Application of these data may aid in decreasing institutional drug spend without affecting patient outcomes. However, the study was underpowered, and further investigation is necessary to validate these findings.

Oral dehydroepiandrosterone restores ß-endorphin response to OGTT in early and late postmenopause.

ß-endorphin is a neuropeptide involved in several brain functions: its plasma levels are higher in obese women and its release increases after oral glucose tolerance test (OGTT) in normal or obese women. The study included 46 healthy women and evaluated the effect of oral dehydroepiandrosterone [DHEA] (50 mg/day) in early postmenopausal women (50-55 years) both of normal weight (group A, n = 12, BMI = 22.1 ± 0.5) and overweight (group B, n = 12, BMI = 28.2 ± 0.5), and late postmenopausal women (60-65 years) both normal weight (group C, n = 11, BMI = 22.5 ± 0.6) and overweight (group D, n = 11, BMI = 27.9 ± 0.4) undergone OGTT, in order to investigate if DHEA could restore/modify the control of insulin and glucose secretion and ß-endorphin release in response to glucose load. The area under the curve (AUC) of OGTT evaluated plasma levels of different molecules. DHEA, DHEAS, and ß-endorphin plasma levels were lower in baseline conditions in older women than younger women. Considering the AUC of ß-endorphin response to OGTT, all groups showed a progressive significant increase after 3 and also after 6 months of treatment in comparison to baseline and 3 months of treatment.

Optimising emergency weight estimation in underweight and obese children: the accuracy of estimations of total body weight and ideal body weight.

OBJECTIVE: During medical emergencies, underweight and obese children are at a higher risk of weight-estimation errors than 'average' children, which may lead to poorer outcomes. In obese children, optimum drug dosing requires a measure of both total body weight (TBW) and ideal body weight (IBW) for appropriate scaling. We evaluated the ability of the Broselow tape, the Mercy method and the PAWPER XL tape to estimate TBW and IBW in obese and underweight children. PARTICIPANTS AND METHODS: Data for children aged 0-18 years were extracted and pooled from three previous weight-estimation studies. The accuracy of estimation of TBW and IBW by each method was evaluated using percentage of estimations within 10% of target weight (PW10) as the primary outcome measure. RESULTS: The Broselow tape estimated TBW poorly in obese and underweight children (PW10: 3.9 and 41.4%), but estimated IBW extremely accurately (PW10: 90.6%). The Mercy method estimated TBW accurately in both obese and underweight children (PW10: 74.3 and 76.3%) but did not predict IBW accurately (PW10: 14.3%). The PAWPER XL tape predicted TBW well (PW10: 73.0% in obese children and 74.9% in underweight children) and predicted IBW extremely accurately (PW10: 100%). CONCLUSION: The Broselow tape predicted IBW, but not TBW, accurately. The Mercy method estimated TBW very accurately, but not IBW. The PAWPER XL tape estimated both TBW and IBW accurately. The PAWPER XL tape should be considered when choosing a weight-estimation strategy for obese and underweight children.

The "Ideal" Body Weight for Pediatric Gentamicin Dosing in the Era of Obesity: A Population Pharmacokinetic Analysis.

BACKGROUND: Obese pediatric patients often require dose reductions when initiating gentamicin therapy. An appropriate method for calculating ideal body weight for dosing gentamicin in pediatric patients has not been validated. METHODS: A retrospective population pharmacokinetic study was designed and included non-intensive care pediatric patients who received gentamicin and had serum gentamicin concentrations sampled. Actual body weight (ABW), adjusted body weight, and fat-free mass (FFM) were used to describe the pharmacokinetic variables. Descriptive statistical methods were used for the population, and pharmacokinetic analysis occurred with NONMEM (ICON Plc, Dublin, Ireland). Simulation was performed to estimate dosing based on adjustments in body weight. RESULTS: A total of 520 patients met inclusion criteria (male 57.3%, mean age 9.6 ± 4.9 years, ABW 38.0 ± 24.3 kg). Obesity was present in 21.3% of the patients and overweight in 15.8%. Gentamicin was administered at 2.17 ± 0.86 mg/kg per dose. A median of 2 (interquartile range, 1-3) gentamicin serum concentrations were sampled at a median 1.8 (interquartile range, 1.1-7.8) hours after a dose. Population pharmacokinetic analysis demonstrated a 2-compartment model with allometrically scaled FFM providing the best fit. Other significant covariates included serum creatinine and age. Simulation demonstrated increased doses per body weight for traditional and once-daily dosing when using FFM for gentamicin dosing. CONCLUSIONS: FFM should be used to adjust ABW for empirically dosing gentamicin in pediatric patients aged 2-18 years.

Pharmacokinetics of human chorionic gonadotropin injection in obese and normal-weight women.

CONTEXT: Obese women have poorer in vitro fertilization outcomes, but underlying mechanisms remain unclear. OBJECTIVE: The objectives of the study were to compare the pharmacokinetics of human chorionic gonadotropin (hCG) and ovarian steroid hormone production, after subcutaneous (s.c.) and intramuscular (i.m.) injection of hCG in obese and normal-weight women. DESIGN AND SETTING: This was a randomized, experimental study. PATIENTS OR OTHER PARTICIPANTS: Twenty-two women aged 18-42 years with body mass index of 18.5-24.9 (normal) or 30-40 kg/m(2) (obese). INTERVENTIONS: Participants received im urinary hCG or s.c. recombinant hCG and returned for a second injection type after a 4-week washout. Intramuscular injections were performed under ultrasound guidance. Blood was taken 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and 36 hours after injection. MAIN OUTCOME MEASURES: hCG was measured at each time point; estradiol, progesterone, 17-hydroxyprogesterone (17-OHP), testosterone (T), dehydroepiandrosterone, and SHBG were measured at 0 and 36 hours. RESULTS: Twenty-two women completed the study. In both normal-weight and obese women, peak serum concentration (Cmax), area under the curve (AUC), and average hCG concentration were higher after i.m. injection as compared with s.c. injection (all P < .003). Obese women had markedly lower Cmax, AUC, and average hCG concentration after s.c. injection as compared with normal-weight women (P = .02, P = .009, and P = .008, respectively). After i.m. injection, Cmax, AUC, and average concentration were similar for normal-weight and obese women (P = .31, P = .25, and P = .18, respectively). Thirty-six percent of obese women had muscular layers beyond the reach of a standard 1.5 inch needle. hCG caused a significant rise in 17-OHP in both obese and normal-weight women and an increase in T in obese but not normal-weight women (all P < .04). CONCLUSIONS: Subcutaneous injection yields lower hCG levels in obese women. Standard-length needles are insufficient to administer i.m. injections in many obese women.

Daptomycin dosing based on ideal body weight versus actual body weight: comparison of clinical outcomes.

Daptomycin use at our institution changed to ideal body weight dosing based on a published analysis of pharmacokinetic-pharmacodynamic efficacy target attainment, bacterial ecology, and a desire to reduce drug toxicity. The current study compared outcomes between actual body weight and ideal body weight dosing of daptomycin before and after this intervention. In the evaluable group, 69 patients received doses based on actual body weight and 48 patients received doses based on ideal body weight. Patients were treated for documented Enterococcus species, Staphylococcus aureus, or coagulase-negative Staphylococcus infections, including bloodstream, intraabdominal, skin and soft tissue, urinary, and bone. There was no statistically significant difference in clinical success between the groups (88.9% for actual body weight compared to 89.1% for ideal body weight, P = 0.97). After we adjusted for gender, age, body mass index, concomitant 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, infection type, and organism type, clinical success rates remained similar between groups (adjusted odds ratio of 0.68 in favor of actual body weight, 95% confidence interval [CI] of 0.13 to 3.55). Microbiological outcomes, length of stay, mortality, and adverse effects were also similar between groups. Further studies are warranted to confirm that ideal body weight dosing provides similar outcomes to actual body weight dosing for all patients and types of infections and organisms.

Flaxseed oil does not affect inflammatory markers and lipid profile compared to olive oil, in young, healthy, normal weight adults.

OBJECTIVE: Olive oil (OO) is a rich source of monounsaturated fat and bioactive components that exert strong anti-oxidant and anti-inflammatory properties. Flaxseed oil (FO) is rich in α-linolenic n-3 fatty acid (ALA), which also exhibits anti-inflammatory effects. This randomized, cross-over study aimed at exploring whether diet's enrichment with FO could beneficially alter inflammatory markers and lipid profile, compared to OO, in a sample of normal weight, apparently healthy young adults. MATERIALS AND METHODS: Participants were supplied with 15 mL/day of either FO or OO. Each intervention and the wash-out period lasted 6 weeks. Dietary, anthropometric and physical activity variables were recorded at the beginning and the end of each intervention. Serum biochemical and inflammatory markers were measured. Compliance to the intervention was evaluated by fatty acid analysis in erythrocytes. Repeated Measures ANOVA was used to assess the effect of the treatment. RESULTS: Thirty seven participants completed the study. No difference between the two interventions was observed in adiponectin, TNF-α, high sensitivity-CRP or glucose levels and lipid profile. At the end of the FO period, participants exhibited significant reductions in total (-5.0%) and LDL-cholesterol (-6.7%) levels (all P<0.01). During the FO and the OO period serum adiponectin changes were significantly correlated with changes in erythrocyte %ALA (rs=0.34, P=0.007) and in erythrocyte %EPA (r(s)=0.47, P=0.01), respectively. CONCLUSIONS: Daily consumption of FO did not confer any benefit in inflammatory or biochemical markers in normal weight young adults, who traditionally use olive oil as the main edible oil.

Comparison of bivalirudin dosing strategies using total, adjusted, and ideal body weights in obese patients with heparin-induced thrombocytopenia.

STUDY OBJECTIVES: To compare dosing strategies using total body weight (actual measured body weight), adjusted body weight, and ideal body weight when starting bivalirudin for the treatment for heparin-induced thrombocytopenia (HIT) in obese patients, and to compare differences in dosing requirements and clinical outcomes between obese and nonobese patients. DESIGN: Retrospective medical record review. SETTING: Academic tertiary care medical center. PATIENTS: One hundred thirty-five medical and surgical patients who were treated with bivalirudin for HIT between June 1, 2004, and October 1, 2009. MEASUREMENTS AND MAIN RESULTS: The 135 patients were separated into two groups based on body mass index (BMI): 46 patients had a BMI greater than 30 kg/m(2) and were classified in the obese group; the nonobese group consisted of 89 patients with a BMI less than 30 kg/m(2) . The mean BMI in the obese group was 37.7 kg/m(2) (range: 30.1-56.2 kg/m(2) ). Weight-standardized doses that achieved activated partial thromboplastin time (aPTT) goal were compared in the obese group. The mean ± SD doses that achieved aPTT goal with total (actual), adjusted, and ideal body weights in this group were 0.1 ± 0.07, 0.11 ± 0.08, and 0.14 ± 0.09 mg/kg/hour, respectively. Of the three weight-based dosing approaches, total body weight followed by adjusted body weight provided the closest correlation to rates observed at the target aPTT goal. The secondary analysis compared initial doses of bivalirudin, doses required to reach goal aPTT, time to achieve goal aPTT, and clinical outcomes (number of patients not achieving goal, new thrombosis, major bleeding, and 30-day all-cause mortality) between the obese and nonobese groups. A significant difference in initial dose was noted between groups; however, no significant differences in dose required to achieve goal aPTT, time to achieve goal aPTT, and clinical outcomes were noted between the obese and nonobese groups. CONCLUSION: This study provides evidence that the dosing strategy for bivalirudin based on total body weight is the most accurate predictor of achieving aPTT goal in obese patients with HIT. The study also suggests that there are no clinical differences that warrant different dosing strategies between obese and nonobese patients. Further prospective studies are needed to confirm these findings.

Effect of second and third generation oral contraceptives on C-reactive protein, lipids and apolipoproteins in young, non-obese, non-smoking apparently healthy women.

OBJECTIVE: Third generation oral contraceptives (OC) may increase the risk of cardiovascular events in healthy young women. DESIGN AND METHODS: We assessed the effect of second and third generation OC on CRP, lipids and apolipoproteins in 128 women. RESULTS: CRP was significantly higher in third generation contraceptive users. The main determinant of CRP in OC users was triglycerides. CONCLUSIONS: Young women using oral contraceptives, especially third generation formulas, might not be free of cardiovascular risk having increased CRP concentration.