Moderate-fat Meal Research Articles

Pharmacokinetics of the Antimalarial Drug Piperaquine in Healthy Vietnamese Subjects

We compared plasma maximum concentration (Cmax) and area under the concentration-time curve (AUC) of the antimalarial drug piperaquine in 26 healthy Vietnamese subjects after treatment with either a single oral dose of 500 mg (n = 6) or 1,000 mg (n = 6) of piperaquine phosphate and a three-day course of 500 mg of piperaquine/ day in the fasting state (n = 7) or with food (approximately 17 g fat) (n = 7). The geometric mean plasma Cmax and AUC((0-28)) was 2.8-fold (200 ng/mL versus 70 ng/mL) and 1.9-fold (5,736 ng x h/mL versus 2,999 ng x h/mL), respectively, and higher in subjects receiving the 1,000-mg dose than in those receiving the 500-mg dose. The geometric mean Cmax and AUC((0-28)) was 1.7-fold (198 ng/mL versus 119 ng/mL) and 1.4-fold (11,187 ng x h/mL versus 7,954 ng x h/mL) higher in the fed state than in the fasting state. Piperaquine AUC was proportional to the two doses tested and a moderate-fat meal enhanced the bioavailability of piperaquine by 41%, which should improve the therapeutic efficacy of this drug.

Effects of Acid‐Reducing Agents on the Pharmacokinetics of Lopinavir/Ritonavir and Ritonavir‐Boosted Atazanavir

A total of 71 HIV-negative healthy adults were randomized to 1 of 6 regimens to receive lopinavir/ritonavir tablets 400/100 mg twice daily (bid) or 800/200 mg once daily (qd) or atazanavir 300 mg + ritonavir 100 mg qd from study days 1 to 15 with a moderate-fat meal. One hour before breakfast, either omeprazole 40 mg qd was administered on study days 11 through 15, or a single dose of ranitidine 150 mg was administered on study day 11. Lopinavir, atazanavir, and ritonavir pharmacokinetics were determined on study days 10, 11, and 15 and compared using point estimates and 90% confidence intervals (CIs). The point estimates for lopinavir Cmax and AUCtau were in the range of 0.92 to 1.08, with 90% CI contained within the range of 0.80 to 1.25 after coadministration of omeprazole or ranitidine. The point estimates for atazanavir Cmax and AUCtau were decreased by 48% to 62% with the upper bound of the 90% CI <or=0.55 after coadministration of omeprazole or ranitidine. The results indicated that lopinavir bioavailability was not affected by the coadministration of omeprazole or ranitidine. In contrast, atazanavir bioavailability was decreased by 48% to 62% when coadministered with ritonavir and either omeprazole or ranitidine.

Moderate exercise reduces serum triacylglycerol concentrations but does not affect pre-heparin lipoprotein lipase concentrations after a moderate-fat meal in young men

Aerobic exercise has been shown to lower postprandial TAG concentrations after a meal(s) of high-fat content. This study examined the effects of moderate-intensity cycling on postprandial TAG concentrations and pre-heparin lipoprotein lipase concentrations after subjects consumed a meal of moderate-fat content (45 % of total energy). Twelve male subjects, aged 24 (sem 1) years, completed two 2 d trials (exercise and control) at least 1 week apart in a randomised, repeated measures design. On day 1, subjects either cycled for 30 min at 65 % of maximum heart rate in the afternoon or rested (no exercise). On day 2 of both trials, after an overnight stay with an 11 h fast, subjects consumed a test meal of moderate-fat content (0.61 g fat, 1.34 g carbohydrate, 0.37 g protein and 51 kJ energy/kg body mass) for breakfast. Blood samples were collected at baseline (before the exercise or at an equivalent time-point during the control trial on day 1), in the fasted state (0 h) and at 2, 4 and 6 h postprandially on day 2. The total and incremental areas under the serum TAG concentration v. time curve were 30 % (P = 0.039) and 33 % (P = 0.012) lower on the exercise trial compared with the control trial, respectively. Serum pre-heparin lipoprotein lipase concentrations did not differ between the exercise and control trials. These findings demonstrate that 30 min of moderate-intensity cycling performed the day before a meal of moderate-fat content is effective at lowering postprandial serum TAG concentrations but does not affect serum pre-heparin lipoprotein lipase concentrations in young men.

The Tablet Formulation of Lopinavir/Ritonavir Provides Similar Bioavailability to the Soft-Gelatin Capsule Formulation With Less Pharmacokinetic Variability and Diminished Food Effect

Lopinavir, an HIV protease inhibitor, is coformulated with ritonavir to enhance the bioavailability and pharmacokinetics of lopinavir. The original solid oral formulation of lopinavir/ritonavir, a soft-gelatin capsule (SGC), requires refrigerated storage, is taken as 6 capsules daily at the recommended adult dose, and is administered with food to maximize the bioavailability of lopinavir. Melt extrusion technology was used to produce a tablet formulation reducing the number of dosage units administered per day and simplifying storage requirements. Three studies assessed the bioavailability of tablet doses of lopinavir/ritonavir at 800/200 mg or 400/100 mg under different meal conditions compared with equal doses of the SGC after a moderate-fat meal. The tablet was bioequivalent to the SGC after a moderate-fat meal with respect to lopinavir and ritonavir areas under the concentration-time curve. Compared with the SGC formulation, the tablet formulation resulted in more consistent lopinavir and ritonavir exposures within and across studies and across meal conditions. The diminished food effect and decreased variability of the tablet are likely to result in more consistent lopinavir and ritonavir exposures, minimizing the likelihood of extreme high or low values compared with the SGC.

The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects

This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg + LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. In Part 1, a single RTV dose increased the APL AUC(0-infinity) by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, C(max), and C(min), respectively. No change in LPV AUC or C(max) and a small increase in RTV AUC and C(max) (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported. Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations.

Effects of antioxidant supplementation on postprandial oxidative stress and endothelial dysfunction: A single-blind, 15-day clinical trial in patients with untreated type 2 diabetes, subjects with impaired glucose tolerance, and healthy controls

Background: Increased generation of reactive oxygenspecies (ROS) and oxidative stress may be of crucial importance in the pathogenesis of endothelial damage. Furthermore, there is understood to be a relationship between endothelial damage, glycemic control, disorders of lipid metabolism, and coagulative hemostatic disorders. Objective: This study investigated within- and between-group changes in various circulating markers of oxidation-reduction balance and endothelial function after a balanced moderate-fat meal with and without antioxidant supplementation in patients with early-stage, untreated type 2 diabetes mellitus; subjects with impaired glucose tolerance (IGT); and healthy controls. Methods: In this single-blind, controlled clinical study, groups of patients with type 2 diabetes and subjects with IGT were identified and compared with a group of healthy controls. All groups followed a controlled, well-balanced diet for 10 days before and throughout the study. Before and after consumption of a standardized moderate-fat meal, plasma levels of oxidants (malondialdehyde, 4-hydroxynonenal, oxidized low-density lipoprotein), the antioxidant glutathione peroxidase, and markers of endothelial function (NO, endothelin-1, von Willebrand factor [vWF], vascular cell adhesion molecule-1 [VCAM-1]) were determined. These measures were then reassessed after 15 days of standard antioxidant treatment consisting of a thiol-containing antioxidant (N-acetylcysteine 600 g/d), a bound antioxidant (vitamin E 300 g/d), and an aqueousphase antioxidant (vitamin C 250 mg/d). The efficacy of antioxidant treatment in reversing abnormalities in oxidation-reduction balance after a moderate-fat meal was assessed by evaluating changes in plasma levels of ROS on the morning of the 16th day following an overnight fast. Safety was monitored in terms of adverse events, vital signs, physical findings, and laboratory values. Results: The study included 46 patients with type 2diabetes (23 men, 23 women; mean [SD] age, 41 [3] years; mean body mass index [BMI], 24 [2] kg/m 2), 46 with IGT (23 men, 23 women; mean age, 39 [3] years; mean BMI, 23 [3] kg/m 2), and 46 control subjects (23 men, 23 women; mean age, 40 [1] years; mean BMI, 22 [1] kg/m 2). Before supplementation, all 3 groups had significantly increased levels of oxidants, vWF, and VCAM-1 (all, P < 0.001) and significantly decreased levels of antioxidants and NO (both, P < 0.001) after consumption of a moderate-fat meal. After 15 days of antioxidant treatment, significant improvements in these measures were seen in all groups ( P < 0.05). Conclusions: This study showed changes in oxidation-reductionbalance, NO bioavailability, and nonthrombogenic endothelial factors after a moderate-fat meal in patients with type 2 diabetes and those with IGT, but these postprandial changes were reverse in all subjects after 15 days of standard antioxidant supplementation. These findings suggest that the use of anti-oxidants may have decreased oxidative stress in these subjects.

Effect of aerobic exercise on lipaemia and its fatty acid profile after a meal of moderate fat content in eumenorrhoeic women

Exercise prior to eating has repeatedly been shown to reduce postprandial lipaemia. The aim of the present study was to investigate whether this effect was manifest in the presence of two factors that independently mitigate postprandial lipaemia: eumenorrhoea and moderate fat intake. Eight healthy eumenorrhoeic rowers consumed a meal of moderate fat content (35 % total energy, 0.66 g/kg body mass) 14 h after having either rowed at 55 % of maximal aerobic power (81 % of maximal heart rate) for 80 min or rested. Both trials were performed during the luteal phase. Blood samples were drawn before the meal and for 8 h postprandially for the measurement of individual fatty acids in the triacylglycerol and NEFA fractions, as well as of glucose, insulin and oestradiol. Plasma oestradiol concentrations were not significantly different in the two trials. The postprandial lipaemic response, expressed as either plasma triacylglycerol concentration or area under the triacylglycerol-time curve, was 35 % lower (P<0.05) after exercise. The postprandial glycaemic and insulinaemic responses were also lower, indicating increased insulin sensitivity, whereas the NEFA response was higher, suggesting a lower entrapment of dietary fatty acids in adipose tissue after exercise. Finally, exercise increased the proportion of unsaturated:saturated NEFA during the postprandial period. In conclusion, aerobic exercise performed 14 h before a moderate-fat meal reduced postprandial lipaemia in women in the luteal phase. This effect shows the potential of exercise to mitigate even moderate lipaemic responses in eumenorrhoeic women.

Effect of orlistat on postprandial lipemia, NMR lipoprotein subclass profiles and particle size

Evidence suggests that metabolic phenomena during postprandial lipemia may be important in the pathogenesis of atherosclerosis. Both lipid concentrations and lipoprotein subclass patterns may be important cardiovascular risk modifiers. The pancreatic lipase inhibitor orlistat reduces fat absorption by 30% and is used for the treatment of overweight and obesity. We evaluated the effect of orlistat on postprandial lipemia and lipoprotein particle distribution after moderate-and high-fat meals in healthy volunteers. In this double-blind, randomized, cross-over study, 10 healthy young men received orlistat 120 mg plus a high-fat meal (HFO), orlistat plus a moderate-fat meal (MFO) or placebo plus a high-fat meal (HFP). Plasma triacylglycerol, glucose, insulin, and free fatty acids were measured at baseline (fasting) and postprandially for 8 h. Lipoprotein subclass profile was assessed by nuclear magnetic resonance spectroscopy. The 8 h postprandial mean triacylglycerol area under the curve (AUC) was significantly lower with MFO and HFO (0.79 versus 1.33 mmol/l h) versus HFP (4.33 mmol/l h; p = 0.02). Mean change in large VLDL subclass concentration during the 4–8 h and mean VLDL size after 8 h was significantly lower with HFO and MFO versus HFP ( p < 0.001). Small HDL particle concentration decreased significantly with HFP versus MFO or HFO ( p < 0.001). There was no significant difference in postprandial concentrations of glucose, insulin or free fatty acids on the different regimens. The lowering of postprandial triacylglycerol AUC, shorter postprandial lipemia, lower concentration of large triacylglycerol-rich particles and decrease of VLDL particle size supports the hypothesis of a less atherogenic postprandial lipoprotein profile following orlistat ingestion.

Evaluation of the effects of alcohol, a high-fat breakfast, and a moderate-fat evening meal on the pharmacokinetics of the PDE5 inhibitor vardenafil

Evaluation of the effects of alcohol, a high-fat breakfast, and a moderate-fat evening meal on the pharmacokinetics of the PDE5 inhibitor vardenafil

Postprandial lipemia is associated with platelet and monocyte activation and increased monocyte cytokine expression in normolipemic men.

The activation of platelets and monocytes has been implicated in the development of cardiovascular diseases. We asked the question if postprandial lipemia following a fat- containing meal is associated with platelet and monocyte activation and increased platelet-monocyte interaction. Thirteen healthy, normal weight, normolipemic males, 20 to 49 years, consumed a 40% fat meal of whole foods. Blood samples were obtained at fasting and 3 1/2 and 6 hours after ingestion. Triglyceride levels increased to 48% over baseline at 3 1/2 hours postconsumption and returned to fasting levels by 6 hours. Multiparameter flow cytometry using monoclonal antibodies showed that the percentage of platelets expressing surface P-selectin and the activated conformation the GPIIb-IIa receptor was significantly higher at 3 1/2 hours compared to fasting. The percentage of platelet-monocyte aggregates increased by 36% at 3 1/2 hours and 43% at 6 hours postconsumption. The percentage of monocytes expressing intracellular tumor necrosis factor-alpha (TNF-alpha) increased seven and eightfold at 3 1/2 and 6 hours, respectively. The expression of interleukin-1beta (IL-1beta increased in a similar manner. These data suggest activation of platelets and monocytes after a moderate fat meal. Repetitive activation of platelets and monocytes could be an early event in the initiation and development of atherosclerosis.

Second meal effect: modified sham feeding does not provoke the release of stored triacylglycerol from a previous high-fat meal.

The present study was carried out to determine whether cephalic stimulation, associated with eating a meal, was sufficient stimulus to provoke the release of stored triacylglycerol (TAG) from a previous high-fat meal. Ten subjects were studied on three separate occasions. Following a 12 h overnight fast, subjects were given a standard mixed test meal which contained 56 g fat. Blood samples were taken before the meal and for 5 h after the meal when the subjects were randomly allocated to receive either water (control) or were modified sham fed a low-fat (6 g fat) or moderate-fat (38 g fat) meal. Blood samples were collected for a further 3 h. Compared with the control, modified sham feeding a low- or moderate-fat meal did not provoke an early entry of TAG, analysed in either plasma or TAG-rich lipoprotein (TRL) fraction (density <1.006 kg/l). The TRL-retinyl ester data showed similar findings. A cephalic phase secretion of pancreatic polypeptide, without a significant increase in cholecystokinin levels, was observed on modified sham feeding. Although these data indicate that modified sham feeding was carried out successfully, analysis of the fat content of the expectorant showed that our subjects may have accidentally ingested a small amount of fat (0.7 g for the low-fat meal and 2.4 g for the moderate-fat meal). Nevertheless, an early TAG peak following modified sham feeding was not demonstrated in the present study, suggesting that significant ingestion of food, and not just oro-sensory stimulation, is necessary to provoke the release of any TAG stored from a previous meal.

Gastric emptying, pulmonary function, gas exchange, and respiratory quotient after feeding a moderate versus high fat enteral formula meal in chronic obstructive pulmonary disease patients

High fat enteral formulas have been advocated for the nutritional support of chronic obstructive pulmonary disease (COPD) patients because dietary fat utilization under ideal conditions produces less CO 2 per O 2 consumed than carbohydrate. No data exist for these patients comparing the effects of a moderate fat vs. a high fat enteral formula on gastric emptying times (GE) and subsequent CO 2 production (V̇ co 2), oxygen consumption (V̇O 2), respiratory quotient (RQ), and pulmonary function. Our doubleblind crossover study compared these parameters after feeding a 355 mL (530 kcal) meal with either 41% fat calories (Respalor®) or 55% fat calories (Pulmocare®). Thirty-six COPD outpatients with a forced expiratory volume in 1 s (FEV 1) <60% of predicted were studied after an overnight fast. Gastric emptying half-time (GE t 1 2 ) was measured using the 99MTc-radionuclide technique; V̇ co 2, V̇O 2, RQ, and other pulmonary functions were measured at 0, 30, 90, and 150 min postprandial using the Canopy Mode of the Deltatrac Metabolic Monitor and the Renaissance Spirometry System. We observed a significantly ( p = 0.0001) longer GE t 1 2 of the high fat meal when compared to the moderate fat meal (134.1 vs. 108.6 min). At 30 and 90, but not at 150 min postprandial, the V̇ co 2 and V̇O 2 for patients fed the moderate-fat formula were significantly ( p = 0.05) higher than for those fed the high-fat formula; no differences were observed for the other pulmonary functions. Although RQ increased significantly ( p = 0.01) after both meals, no differences between formulas were noted at all postprandial times tested. Compared to the high-fat meal, the moderate-fat meal significantly enhanced gastric emptying. The earlier rise in V̇ co 2 and V̇O 2 after the moderate-fat meal did not impact pulmonary function and reflected the earlier utilization of the moderate-fat meal. The fact that RQ was not different between the two meals at all postprandial times tested suggest that the higher rise in V̇ co 2 and V̇O 2 after the moderate-fat meal was most likely due to earlier gastric emptying of the moderate-fat meal rather than the difference of the fat-to-carbohydrate ratio between the two tested meals. The impact of these findings on long-term management of COPD patients awaits long-term prospective studies.