High-fat Breakfast Research Articles

Exposure measures applied to the bioequivalence of two sustained release formulations of bupropion

To examine the effect of the exposure measures C(max) (peak exposure), AUC(E) (early exposure) and AUC (total exposure) on the bioequivalence of two sustained release formulations of bupropion (i) in the fasted state and (ii), after a high fat meal. The ratio C(max)/AUC (sensitive to rate of absorption) was also evaluated. A two-formulation, two-sequence, four-period replicate design study was performed in 29 healthy men and women after an overnight fast. Similarly, a two-period study was performed in 20 healthy men and women after ingestion of a high fat breakfast. Plasma concentrations of bupropion were measured by HPLC/MS/MS and the data were analyzed (SAS PROC MIXED) by the Schuirmann-Sattersthwaite procedure (four-period study) and by the two one-sided test procedure (SAS PROC GLM) (two-period study). Standard bioequivalence limits of 80 - 125% were applied to all measures including AUC(E) and C(max)/AUC. In the fasting study, the mean plasma concentration vs. time curves from (including over the first 24 hours) following the two administrations of each formulation were similar although there was a significant difference in median t(max) between formulations. This may have contributed to a low estimate of geometric mean ratio (GMR) for AUC(E) (69%) which was judged to have failed bioequivalence. There was also rather low GMRs for Cmax (88%) and C(max)/AUC (89%) but these measure passed because the within-subject variabilities (WSV) were relatively low (19.6% and 11.2%, respectively). Total exposure (AUC(last)) met standard bioequivalence limits of 80 - 125% easily. The raw data from the two-period fed also showed differences in the shapes of the plasma concentration vs. time curves around C(max) although there was no difference in median t(max). The WSV at median t(max) was high (34%) as was the GMR (117%) for AUCE which failed, as did C(max) (GMR 112%). The WSV was very high at early time points before settling into a "plateau" at about 11%. There was no "spike" in the plasma concentration vs. time profiles up to median t(max) or beyond and therefore there was no evidence of dose dumping of the test formulation in either fasted or fed states. No bioequivalence limits have been set for AUC(E) but the application of standard BE limits of 80 to 125% meant that the fed study was clearly underpowered given the high WSV at early time points. More research is needed on the interesting concept of early exposure. The WSV is often high at median t(max) which means that standard bioequivalence limits of 80 - 125% may be inappropriate. Despite the lack of dose dumping, application of AUC(E) to the fasting study, would have resulted in failure to declare bioequivalence since the GMR for this measure was only 69.5%. Application of a 90% confidence interval to AUC(E) to the fed study would have required powering to cope with the fact that this measure was highly variable.

A randomised, double blind, placebo controlled single ascending dose study of PYM50018, with an open label cross-over stage to assess food effect

Background and Aims PYM50018 has neuroprotective properties and an emerging safety profile that make it a promising candidate for the treatment of neurodegenerative disorders, such as amyotrophic lateral sclerosis. This study evaluated the pharmacokinetics, safety and tolerability of the compound, together with the effect of food on its bioavailability. Methods Forty healthy males 18 to 45 years who met the entry criteria were included. Four groups of ten subjects were randomly allocated to receive placebo (n=2) or PYM50018 (n=8; 80 mg, 240 mg, 480 mg or 960 mg). One group also received PYM50018 (240 mg) on two further occasions either after breakfast or fasted. Results Exposure to PYM50018 increased proportionately with dose. At higher exposures a second, slower elimination phase became apparent. Exposure to PYM50018 was increased after a high fat breakfast, as compared with the fasted state. There were no clinically significant changes in the safety parameters or adverse events. Conclusions PYM50018 is well tolerated by healthy male subjects as a single oral dose of up to 960 mg. Systemic exposure to oral PYM50018 is dose proportional. Food has a significant effect on the absorption kinetics of PYM50018. Clinical Pharmacology & Therapeutics (2005) 77, P67–P67; doi: 10.1016/j.clpt.2004.12.146

Effect of food on the pharmacokinetics of rifalazil, a novel antibacterial, in healthy male volunteers

Background This study investigated the safety and pharmacokinetics of a single 25 mg dose of rifalazil, a new antibiotic related to rifampin, administered under three dietary regimens to healthy male volunteers. Methods In a Phase I, randomized, three-way crossover, single oral dose study of rifalazil, healthy male volunteers (N=11) received three single 25 mg oral doses of rifalazil under three conditions (standard breakfast, high-fat breakfast, or overnight fast of 10 hours) with a 21–28 day washout between each dose. Plasma samples were assayed by LC/MS/MS. PK analysis was determined by nonlinear regression methods employing a two-compartmental open model. Results Systemic exposure to rifalazil based on Cmax and AUC were increased progressively and results were statistically significant as the fat content of the test breakfast was increased from 30 to 60% of calories compared with fasting. This positive food effect may be a result of increased fractional absorption with increasing dietary fat content. Conclusions Rifalazil was well tolerated. Food significantly increased rifalazil's systemic exposure and was further enhanced by the percentage of dietary fat content. Clinical Pharmacology & Therapeutics (2005) 77, P44–P44; doi: 10.1016/j.clpt.2004.12.061

Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects With Varying Degrees of Chronic Renal Disease

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C(max), CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.

Bioequivalence of a New Sustained-Release Formulation of Sodium Valproate, Valproate Modified-Release Granules, Compared with Existing Sustained-Release Formulations After Once- or Twice-Daily Administration

To compare the pharmacokinetic properties of valproate modified-release (MR) granules with those of two existing valproate sustained-release (SR) formulations to confirm their bioequivalence. Two randomized, open-label, two-period crossover studies under fasting conditions, and one open-label, randomized, single-dose, three-period crossover study under fasting and nonfasting conditions. Each study had a 7-day washout interval between periods. Three hospitals in France. Healthy male Caucasian volunteers aged 18-35 years (27 subjects in study 1, 24 in study 2, and 24 in study 3). In studies 1 and 2, during two 15-day periods, subjects received either valproate MR granules or an existing valproate SR formulation. In study 3, subjects received only valproate MR granules 500 mg, once with water after a 10-hour fast, once with yogurt after a 10-hour fast, and once 30 minutes after a high-fat morning meal. Blood samples were collected, and pharmacokinetic parameters of valproic acid were determined for single-dose (studies 1-3) and repeated-dose (studies 1 and 2) administration. The 90% confidence intervals (CIs) for area under the concentration-time curve and maximum concentration (C max ) were in the acceptance limits for bioequivalence (i.e., 90% CI 0.80-1.25) after single and repeated doses of valproate MR granules administered once/day or twice/day. Although time to C max was slightly decreased with valproate MR granules, this difference did not induce a significant difference in terms of C max . Valproate MR granule formulation was bioequivalent with existing SR formulations. High-fat breakfast or yogurt did not modify either the bioavailability or pharmacokinetic profile of valproate MR granules. This formulation was well tolerated. The adverse event profile did not differ among the various regimens. Valproate MR granules, administered once/day or twice/day, may be an attractive alternative to existing SR formulations for patients who have difficulties with swallowing tablets or who favor granules over tablets.

Pharmacokinetic properties of combination oxycodone plus racemic ibuprofen: Two randomized, open-label, crossover studies in healthy adult volunteers

Background: As part of ongoing studies to evaluate the analgesic efficacy and pharmacokinetic properties of combination oxycodone plus ibuprofen in the treatment of moderate to severe acute pain, 2 pharmacokinetic studies were conducted. Objectives: The goals of these studies were to compare the pharmacokinetic properties of monotherapy with oxycodone or ibuprofen with those of a tablet formulation of these 2 agents combined (study A), and to determine whether the absorption of the individual agents when given in the combination tablet was affected by the concomitant ingestion of food (study B). Methods: Study A was a single-center, open-label, randomized, single-dose, 3-period, 3-way, crossover study Healthy male subjects received oxycodone 5 mg, ibuprofen 400 mg, or a combination tablet containing both, after an overnight fast of ≥8 hours, on study days 1, 8, and 15. Study B was a single-center, open-label, randomized, single-dose, single-crossover study. Healthy volunteers received a tablet containing a combination of oxycodone 5 mg plus ibuprofen 400 mg after either an overnight fast of ≥8 hours or a standardized high-fat breakfast. Both studies included a washout period of ≥7 days between treatments. In both studies, the pharmacokinetic properties (C max, T max, t 1/2, AUC 0-4, AUC 0-1, and AUC 0-∞) of oxycodone and ibuprofen were derived from plasma drug concentrations. Analysis of variance was used to determine and compare pharmacokinetic properties. Results: Twenty-four healthy, white, male subjects were included in study A (mean age, 26.0 years; mean body weight, 71.3 kg; mean height, 170.0 cm). Study B involved 12 subjects (11 men, 1 woman; mean age, 24.8 years; mean body weight, 77.2 kg; mean height, 181.4 cm). The pharmacokinetic properties of ibuprofen and oxycodone were not statistically different when administered alone or combined. Food intake did not affect the rate of oxycodone absorption (90% Cl of C max of fasted state vs fed state, 103–130), or the rate (90% Cl of C max of fasted state vs fed state, 72–95) or extent (90% Cl of AUC 0-∞ of fasted state vs fed state, 88–102) of ibuprofen absorption. The extent of oxycodone absorption was slightly increased when the combination was given with food (90% Cl of AUC 0-∞ of fasted state vs fed state, 115–127). Conclusions: The single-dose pharmacokinetic profiles of oxycodone and ibuprofen in these healthy volunteers were similar when these 2 drugs were given as monotherapy or in combination, suggesting bioequivalence. Food intake before administration of a single dose of the combination did not affect ibuprofen absorption but marginally increased the extent, but not the rate, of oxycodone absorption.

NIGHTTIME DOSING OF OMEPRAZOLE IMMEDIATE-RELEASE ORAL SUSPENSION RAPIDLY DECREASES NOCTURNAL GASTRIC ACIDITY

Purpose: Proton pump inhibitors (PPIs) suppress gastric acid secretion sufficiently to treat most symptoms of GERD. However, in some patients, PPIs fail to control nighttime gastric acid secretion and also fail to control nighttime GERD symptoms. The PPIs used to treat these symptoms have all been delayed-release formulations with enteric coatings. A new omeprazole immediate-release suspension (OME-IR[SUSP]) has been developed, using sodium bicarbonate to protect the acid-labile PPI, rather than the traditional delayed-release enteric coating. The present trial was conducted to evaluate the effectiveness of OME-IR(SUSP) in controlling nighttime gastric acidity after twice-daily (b.i.d.) dosing. Methods: Seventeen healthy subjects were enrolled in this open-label trial. Single 20-mg doses of OME-IR(SUSP) (Santarus, San Diego) were given 1 hr prior to breakfast (qAM) for 7 days. On Day 8, the 20-mg suspension was given b.i.d.: at 0830 hrs (1 hr prior to a standardized high-fat breakfast) and at 2200 hrs (bedtime). On Days 7 and 8, standardized lunch and dinner were given at 1300 and 1800 hrs. Gastric pH was continuously monitored (Medtronic) for 24 hrs following the morning doses on Days 7 and 8. The percent time pH was >4 was assessed for the 8-hr nighttime period (2200-0600 hrs) and for the 24-hr period following the morning dose. The proportion of subjects with “nocturnal acid breakthrough” (NAB) (> 1 hr of continuous pH <4) was assessed for the 8-hr nighttime period. Results: The figure below displays the 24-hr median gastric pH profile at steady state for b.i.d. dosing of OME-IR 20 mg. After the bedtime dose, OME-IR 20 mg abruptly raised the gastric pH and sustained this effect for approximately 8 hrs. The median % time pH was >4 was greater for b.i.d dosing (87%) than for qAM dosing (39%) (p <0.001). NAB occurred in fewer subjects dosed b.i.d. (5/17 [29%]) than dosed qAM (13/17 [76%]) (p = 0.005).[figure 1]FigureConclusions: Twice-daily dosing (before breakfast and at bedtime) with OME-IR(SUSP) is effective in controlling nighttime acidity. Nighttime administration of OME-IR(SUSP) may be more effective in controlling nighttime GERD symptoms than delayed-release PPIs.

Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects

Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections. Eight healthy male subjects received a single 399-mg (81.7 microCi) oral dose of [(14)C]posaconazole after consuming a high-fat breakfast. Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug. Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose. Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h. The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule. The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively. Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole. The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole. These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics.

The effect of food on and the intra-subject variability of the pharmacokinetics of ZD6474, a novel antiangiogenic agent, in healthy subjects

3167 Background: ZD6474 is an orally available, vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor that also has activity against epidermal growth factor receptor (EGFR) tyrosine kinase, which is currently under Phase II evaluation in a range of tumor types. The effect of food on the absorption characteristics of ZD6474 are not known, therefore these studies have a restriction on dosing with food. The effect of food on the pharmacokinetics of ZD6474 has now been assessed in healthy male volunteers. In the same study intra-subject variability in pharmacokinetics was also determined to ensure correct sizing of future clinical pharmacology studies. Methods: Sixteen volunteers were randomized to receive a single oral dose of ZD6474 (300 mg) on each of three occasions: once 30 minutes after a standard high-fat breakfast and twice under fasted conditions, or once under fasted conditions and twice 30 minutes after a standard high-fat breakfast. Due to the long half-life of approximately 10 days there was a 6-week washout between each treatment period. The effect of food on the absorption of ZD6474 compared with fasted conditions was assessed using the criteria for establishing bio-equivalence based on the end-points of Cmax and AUC. These parameters were also used to assess the intra-subject variability. Results: Statistical analysis of provisional data showed there was no clinically significant effect on either Cmax or AUC of ZD6474 when dosed with food compared with the fasted state. In addition, the overall intra-subject variability of ZD6474 was small (coefficients of variation [CVs] of 8% and 11% for AUC and Cmaxrespectively), and appears to decrease when ZD6474 is taken with food (AUC CVs of 5% and 10% and Cmax 10% and 13% for fed and fasted respectively). Conclusions: These data indicate that the restriction on dosing with food can be removed from patient studies with the assurance that the day to day variability in exposure to ZD6474 will not increase as a result of patients taking their daily ZD6474 dose with or without food. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca

The effect of food on and the intra-subject variability of the pharmacokinetics of ZD6474, a novel antiangiogenic agent, in healthy subjects

3167 Background: ZD6474 is an orally available, vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor that also has activity against epidermal growth factor receptor (EGFR) tyrosine kinase, which is currently under Phase II evaluation in a range of tumor types. The effect of food on the absorption characteristics of ZD6474 are not known, therefore these studies have a restriction on dosing with food. The effect of food on the pharmacokinetics of ZD6474 has now been assessed in healthy male volunteers. In the same study intra-subject variability in pharmacokinetics was also determined to ensure correct sizing of future clinical pharmacology studies. Methods: Sixteen volunteers were randomized to receive a single oral dose of ZD6474 (300 mg) on each of three occasions: once 30 minutes after a standard high-fat breakfast and twice under fasted conditions, or once under fasted conditions and twice 30 minutes after a standard high-fat breakfast. Due to the long half-life of approximate...

Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers

The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC–MS –MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8–1.25 for AUC and C max. The ratios of the mean C max and AUC 0–∞ values of deramciclane were 1.24 (90% CI 1.12–1.38) and 1.31 (90% CI 1.21–1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC 0–∞ and C max of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C max and AUC 0–∞ of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.

The Effect of Acute Exercise upon Postprandial Lipemia Following Correction for Plasma Volume Shifts

1489 PURPOSE: To examine the influence of plasma volume (PV) adjustments on our previously reported finding that isocaloric bouts of acute strength (ST) and aerobic training (AT) had no effect on fasting and postprandial plasma lipoprotein concentrations in 13 healthy normolipidemic males (age, 20.9 ± 0.6 years). METHODS: Subjects participated in three postprandial lipemia tests, one control (CON) and the other two 14-hours following isocaloric bouts of ST and AT. During all 3 tests, venous samples were obtained in a 12-hr fasted state and after the consumption of a high fat breakfast (55 g fat, 149 g carbohydrate, 22 g protein). Blood samples were analyzed for plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and glucose. Changes in PV were determined using the fasting CON trial hematocrit (Hct) and hemoglobin (Hb) values as the reference point from which all blood samples from the CON trial and exercise trials were compared. TG was monitored hourly for 6 hours from which the incremental (INCAUC) and total (TOTAUC) areas under the 6-hour TG curve were calculated. Differences between CON, ST and AT trials, with and without PV corrections. RESULTS: Hb was significantly higher in the fasting AT blood sample compared to the fasting CON sample (CON, 11.48 ± 0.78; AT, 14.13 ± 0.65; ST, 13.46 ± 0.53 mg/dl). The AT and ST fasting blood samples displayed 18 and 14 % reductions in PV, respectively. After PV correction there was no effect on fasting plasma TG or HDL-C concentrations. However, fasting plasma TC (CON, 172.5 ± 7.3; AT 138.1 ± 7.5; ST 149.2 ± 8.2 mg/dl) and glucose (CON, 85.9 ± 1.7 AT 70.8 ± 1.5; ST 69.6 ± 1.6 mg/dl) were significantly lower (P<0.05) following both exercise bouts. The 6-hour plasma TG INCAUC (CON, 355.0 ± 60.4; ST 183.5 ± 36.6; AT, 130.3 ± 30.1 mg/dl × 6h) and glucose TOTAUC (CON, 531.6 ± 19.8; ST 432.4 ± 20.1; AT, 419.8 ± 23.2 mg/dl × 6h) were significantly reduced during both exercise trials. CONCLUSION: These data suggest that PV corrections over multiple tests may provide a clearer picture of the effect of exercise treatments upon PPL. Given uncertainty over the exact cause of post exercise PV shifts and the large PV variation between trials in this study it is suggested that fluid and salt intakes be controlled during the 24-hours preceding fat tolerance tests.

The Effect of Acute Exercise upon Postprandial Lipemia Following Correction for Plasma Volume Shifts

1489 PURPOSE: To examine the influence of plasma volume (PV) adjustments on our previously reported finding that isocaloric bouts of acute strength (ST) and aerobic training (AT) had no effect on fasting and postprandial plasma lipoprotein concentrations in 13 healthy normolipidemic males (age, 20.9 ± 0.6 years). METHODS: Subjects participated in three postprandial lipemia tests, one control (CON) and the other two 14-hours following isocaloric bouts of ST and AT. During all 3 tests, venous samples were obtained in a 12-hr fasted state and after the consumption of a high fat breakfast (55 g fat, 149 g carbohydrate, 22 g protein). Blood samples were analyzed for plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and glucose. Changes in PV were determined using the fasting CON trial hematocrit (Hct) and hemoglobin (Hb) values as the reference point from which all blood samples from the CON trial and exercise trials were compared. TG was monitored hourly for 6 hours from which the incremental (INCAUC) and total (TOTAUC) areas under the 6-hour TG curve were calculated. Differences between CON, ST and AT trials, with and without PV corrections. RESULTS: Hb was significantly higher in the fasting AT blood sample compared to the fasting CON sample (CON, 11.48 ± 0.78; AT, 14.13 ± 0.65; ST, 13.46 ± 0.53 mg/dl). The AT and ST fasting blood samples displayed 18 and 14 % reductions in PV, respectively. After PV correction there was no effect on fasting plasma TG or HDL-C concentrations. However, fasting plasma TC (CON, 172.5 ± 7.3; AT 138.1 ± 7.5; ST 149.2 ± 8.2 mg/dl) and glucose (CON, 85.9 ± 1.7 AT 70.8 ± 1.5; ST 69.6 ± 1.6 mg/dl) were significantly lower (P<0.05) following both exercise bouts. The 6-hour plasma TG INCAUC (CON, 355.0 ± 60.4; ST 183.5 ± 36.6; AT, 130.3 ± 30.1 mg/dl × 6h) and glucose TOTAUC (CON, 531.6 ± 19.8; ST 432.4 ± 20.1; AT, 419.8 ± 23.2 mg/dl × 6h) were significantly reduced during both exercise trials. CONCLUSION: These data suggest that PV corrections over multiple tests may provide a clearer picture of the effect of exercise treatments upon PPL. Given uncertainty over the exact cause of post exercise PV shifts and the large PV variation between trials in this study it is suggested that fluid and salt intakes be controlled during the 24-hours preceding fat tolerance tests.

Laparoscopic Repair of Chylous Ascites

A 44-year-old female underwent hand assisted laparoscopic left donor nephrectomy. The procedure was uneventful and the kidney was successfully transplanted into the biological son. The initial postoperative period was unremarkable. The patient was discharged home on postoperative day 2. She complained of nausea and lack of appetite after discharge from the hospital. Two weeks later she complained of mild increase in abdominal girth. On physical examination she had a moderately distended abdomen, with dullness to percussion. Diagnostic paracentesis was performed in the office, and 120 cc milky white, odorless fluid was aspirated. Laboratory analysis of the fluid was consistent with chylous ascites, and cultures were negative. All other laboratory tests were normal. Computerized tomography of the abdomen with oral and intravenous contrast material confirmed the presence of a large volume of ascites (fig. 1). The patient was rehospitalized and put on a low fat diet and medium chain triglyceride supplementation for 1 week. Management was then changed to total parenteral nutrition and subcutaneous somatostatin for 1 week. Both regimens of conservative treatment failed to improving the condition. Hand assisted laparoscopic exploration was elected. The patient was given a high fat breakfast 6 hours before the operation to increase the chyle flow. On entering the abdomen 12 l chyle was aspirated. The colon was mobilized and the left renal bed was explored. A streak of white chyle was immediately visible (fig. 2). Further dissection showed that the leak was coming from a 1 mm hole in one of the lymphatic channels on the lateral wall of the aorta. The tract was sutured laparoscopically and the surrounding lymphatics were cauterized with bipolar electrocautery. Finally, oxidized regenerated cellulose with fibrin glue was applied to the area. The patient was started on a low fat diet, did well and was discharged home on postoperative day 4. At 1-month followup she was following a regular diet and was asymptomatic. Examination revealed no evidence of ascites, and serum electrolytes, creatinine and proteins were within normal limits.

Plasma and buccal mucosal cell response to short-term supplementation with all trans-β-carotene and lycopene in human volunteers

Despite interest in the health-beneficial role of carotenoids little is known about the specific storage metabolism and mechanisms involved in various target tissues. The aim of the study was to search for a relatively simple non-invasive method to detect and determine the cellular effects of supplemented dosage of beta-carotene and lycopene to peripheral tissues such as the buccal mucosa in relation to the plasma concentrations. Subjects (30) were allocated into five different subgroups of 6 volunteers. The change in concentration of all-trans-beta-carotene and lycopene in plasma and in buccal mucosal cells was measured in groups of volunteers supplemented with either 15 mg, 30 mg or placebo capsules in a randomised double blind study for a period of 7 days. With the exception of supervised high fat (40 g carotenoid free sunflower oil) breakfasts and capsule ingestion the volunteers ate their habitual diets. Plasma lycopene and beta-carotene concentrations were determined at baseline and following one week of capsule ingestion. In all the supplemented groups the plasma carotenoid levels were significantly higher than in the placebo group indicating absorption of the supplement. Carotenoid concentrations, expressed per unit protein, assayed in buccal mucosal cells before (at baseline) and at the end of the study were found to be significantly higher in the groups supplemented at 30 mg/d, of either carotenoid as compared to the 15 mg/d or placebo supplemented groups. We conclude that buccal mucosal cells respond readily to changes in plasma beta-carotene and lycopene concentration. These observations suggest that dietary carotenoids are quickly incorporated into rapidly turning over mucosal tissues. It is not clear if the change in carotenoid content of the plasma is reflected in existing cells or only in those concurrently produced during the elevated plasma concentration. If desquamated buccal mucosal cells reflect habitual plasma carotenoid concentration then it is not an appropriate tissue for the measurement of acute changes.

Effects of breakfast with different calorigenic amounts on blood glucose, insulin and glucagon levels

This study was aimed to investigate the relationship between breakfast and serum glucose, insulin and glucagon concentrations in order to establish a model breakfast appropriate for Chinese. Twenty-four volunteers were randomly assigned to four study groups: high carbohydrate breakfast, high fat and protein breakfast, the typical breakfast and fasting. Each subject had serum and urine samples collected while fasting and at 1,2 and 3.5 hours following the meal. The concentration of serum glucose, insulin and glucagon was measured. The levels of serum glucose in group A, B and C differed significantly at 1 and 2 hour after meal compared to those at fasting (P<0.05). The serum glucose in group A increased insignificantly after meal. The serum insulin levels were in group A,B and C significant different compared with control group (P<0.05). Those peaked at 1 hour after meal, with group C rising the furthest. Compared with the fasting group, the serum glucagons rose and maintained the increase after breakfast in group A,B and C (P<0.05). The data suggested that various diets with different calorigenic amounts increased hormone concentration to various extents. We found that a breakfast rich in carbohydrates could maintain proper blood glucose level.

THE EFFECT OF 9-WEEKS STRENGTH TRAINING ON POSTPRANDIAL LIPEMIA

PURPOSE The effect of 9-weeks strength training upon postprandial lipemia (PPL) was investigated in 19 healthy (VO2max 54.94 ± 2.09 ml kg min−1) males aged 22–28 yrs. METHODS Subjects were assigned to either a control (CON) or strength trained (ST) group (3 days/week). Before and after the training period; weight, fat free mass (FFM), muscle mass (MM), fat mass (FM), % body fat (%BF) and three-repetition maximum for bench press (3RM) were determined in each subject. Pre and post training PPL was determined using venous blood samples obtained in a 12-hr fasted state and after the consumption of a high fat breakfast (55 g fat, 149 g carbohydrate, 22 g protein). Blood samples were analyzed for plasma triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). Postprandial plasma TG was monitored hourly for 6 hours, from which the total area under the TG curve (TOTAUC) was calculated. Pre and post training between and within group difference were examined with analysis of variance. RESULTS No changes were noted in any variable tested in the CON group. The ST program resulted in significant increases (all P < 0.05) in weight (67.13 ± 3.11 vs 68.10 ± 3.06 kg), MM (55.10 ± 2.20 vs 56.40 ± 2.27 kg) and 3RM (58.06 ± 4.29 vs 72.28 ± 5.04 kg). There were no changes in %BF (13.13 ± 1.55 vs 12.47 ± 1.41 %), fasting TG (88.90 ± 18.13 vs 96.90 ± 18.94 mg.dl−1), TOTAUC (932.36 ± 284.25 vs 1034.88 ± 216.98 mg.dl−1 x6), fasting HDL-C (52.00 ± 4.26 vs 62.60 ± 6.58 mg.dl−1) or fasting TC (163.60 ± 8.03 vs 179.80 ± 9.14 mg.dl−1) with training. CONCLUSIONS These results indicate that 9-weeks of moderate ST does not improve fasting plasma lipoprotein profiles or the total postprandial lipid response, and therefore suggests that ST alone has little effect on reducing coronary heart disease risk.

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

Effects of food on the pharmacokinetics of levodopa in a dual-release formulation

The objective was to assess the effect of food on the pharmacokinetics of levodopa and 3- O-methyldopa after administration of a new levodopa/benserazide formulation with a dual-release drug delivery profile (Madopar ® DR). In an open-label, two-way cross-over study, 19 healthy volunteers who had fasted overnight were randomized to receive a single oral dose of levodopa/benserazide (200/50 mg) in the absence or presence of a standardized, high-fat breakfast, administered 30 min before drug administration. The treatment periods (fasting, non-fasting) were preceded by a baseline regimen of levodopa/benserazide (100/25 mg t.i.d. for 6 or 7 days). Blood samples were taken at specific times over a 12-hour period. Plasma concentrations of levodopa and 3- O-methyldopa were determined by high-performance liquid chromatography for pharmacokinetic evaluation. The parameter C max of levodopa was significantly lower and t max longer under postprandial conditions than under fasting conditions (mean C max 1.41 vs. 2.09 mg l −1; mean t max 3.1 vs. 1.0 h). With food, the area under the curve (AUC) of levodopa was equivalent to that following an overnight fast. Compared with volunteers who had fasted, food did not alter t 1/2. Estimates of C max, t max and AUC of 3- O-methyldopa under non-fasting conditions were not significantly different from those under fasting conditions. In conclusion, food decreases the rate of levodopa absorption, but had no effect on the systemic exposure to levodopa and the degree of 3- O-methyldopa formation. Standardization of levodopa/benserazide administration with respect to meal times is recommended.

High-Fat Diet May Affect Absorption Of Once-Daily ADHD Medications

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessHigh-Fat Diet May Affect Absorption Of Once-Daily ADHD MedicationsJim RosackJim RosackSearch for more papers by this authorPublished Online:2 Aug 2002https://doi.org/10.1176/pn.37.15.0019aThe absorption of the two long-acting medications used to treat symptoms of attention-deficit/hyperactivity disorder (ADHD) is differentially affected by the presence of food in the stomach, especially if that food is high in fat, according to a new study.The data, reported in the July issue of Current Medical Research and Opinion, indicate that serum levels of methylphenidate in individuals taking the long-acting medication Concerta are not substantially different when the medication is taken with food or on an empty stomach.In contrast, individuals in the study who took Adderall XR, an extended-release formulation of mixed amphetamine salts, displayed drastically lower early blood levels when taking the medication with food compared with taking it on an empty stomach.The study was conducted by researchers at McNeil Consumer and Specialty Pharmaceuticals, which markets Concerta. Adderall is marketed by Shire Pharmaceuticals Group.The study compared the effect of eating a high-fat breakfast on the absorption and distribution of a typical morning dose of each medication (36 mg of Concerta or 20 mg of Adderall) in 36 healthy adults. Breakfast consisted of eggs, buttered bread, bacon, hash-brown potatoes, and eight ounces of whole milk. Blood samples were taken 18 times over the ensuing 28-hour period. Subjects received either Concerta or Adderall following either an overnight fast or 15 minutes after eating the high-fat breakfast.Blood levels of methylphenidate in subjects who received Concerta varied only about 3 percent between the fasting and post high-fat-meal dosings. Subjects who took Adderall after the high-fat meal, however, had on average a 55 percent decrease in their blood levels of amphetamine during the first four hours following dosing, compared with those who took Adderall after fasting.When a drug’s absorption is significantly affected by food intake, its label usually says it is best taken either one hour before or two hours after a meal. The current approved labeling for Adderall does not address any need to take the medication on an empty stomach.Requests by Psychiatric News for comment about the data from Shire Pharmaceuticals Group were not answered by press time. ▪ ISSUES NewArchived