Two-period Crossover Trial Research Articles

Adaptive Crossover Design for Normal Responses

In a response-adaptive design, we review and update the trial on the basis of outcomes in order to achive a specific goal. In clinical trials our goal is to allocate a larger number of patients to the better treatment. In the present paper, we use a response adaptive design in a two-treatment two-period crossover trial where the treatment responses are continuous. We provide probability measures to choose between the possible treatment combinations AA, AB, BA, or BB. The goal is to use the better treatment combination a larger number of times. We calculate the allocation proportions to the possible treatment combinations and their standard errors. We also derive some asymptotic results and provide solutions on related inferential problems. The proposed procedure is compared with a possible competitor. Finally, we use a data set to illustrate the applicability of our proposed design.

The Effects of n-3 Long-Chain Polyunsaturated Fatty Acid Supplementation on Biomarkers of Kidney Injury in Adults With Diabetes

OBJECTIVELong-chain n-3 polyunsaturated fatty acid (n-3 PUFA) supplements may have renoprotective effects in patients with diabetes, but previous trials have been inconsistent. We performed a randomized controlled trial of n-3 PUFA supplementation on urine albumin excretion and markers of kidney injury in adults with type 2 diabetes.RESEARCH DESIGN AND METHODSWe conducted a randomized, placebo-controlled, two-period crossover trial to test the effects of 4 g/day of n-3 PUFA supplementation on markers of glomerular filtration and kidney injury in adults with adult-onset diabetes and greater than or equal to trace amounts of proteinuria. Each period lasted 6 weeks and was separated by a 2-week washout. The main outcome was urine albumin excretion and, secondarily, markers of kidney injury (kidney injury molecule-1, N-acetyl β-d-glucosaminidase [NAG], neutrophil gelatinase-associated lipocalin [NGAL], and liver fatty acid–binding protein [LFABP]), serum markers of kidney function (cystatin C, β2-microglobulin, and creatinine), and estimated glomerular filtration rate (eGFR).RESULTSOf the 31 participants, 29 finished both periods. A total of 55% were male, and 61% were African American; mean age was 67 years. At baseline, mean BMI was 31.6 kg/m2, median eGFR was 76.9 mL/min/1.73 m2, and median 24-h urine albumin excretion was 161 mg/day. Compared with placebo, n-3 PUFA had nonsignificant effects on urine albumin excretion (−7.2%; 95% CI −20.6 to 8.5; P = 0.35) and significant effects on urine NGAL excretion (−16% [−29.1 to −0.5%]; P = 0.04). There was no effect on serum markers of kidney function or eGFR. In subgroup analyses, there were significant decreases in 24-h urinary excretion of albumin, NGAL, LFABP, and NAG among participants taking medications that block the renin-angiotensin-aldosterone system (RAAS).CONCLUSIONSThese results suggest a potential effect of n-3 PUFA supplementation on markers of kidney injury in patients with diabetes and early evidence of kidney disease. In the context of prior studies, these results provide a strong rationale for long-term trials of n-3 PUFA on chronic kidney disease progression.

Effect of quercetin on P-glycoprotein transport ability in Chinese healthy subjects

The aim of this study was to investigate the effect of quercetin on P-glycoprotein (P-gp) transport ability in vivo. Genotype data were available from a total of 165 health volunteers. An open, randomized, two-period crossover clinical trial was performed in eighteen subjects with different MDR1 3435 C/T genotypes. All subjects took 500 mg quercetin or placebo daily from 1st to 13th day or from 43 st to 55th day, and 100 mg talinolol was given at the 14th or 56th day. The washout period is 28 days. In this study, we found the values of area under the curve (AUC)0-48 h, AUC0-∞ and Cmax of talinolol in all subjects significantly decreased (6496.6 ± 2389.9 vs 7809.5 ± 2386.8 ng.h/ml, P=0.04), (8414.7 ± 344.8 vs 10478.2 ± 4195.4 ng.h/ml, P=0.03), (412.9 ± 132.6 vs 543.3 ± 97.9 ng.h/ml, P=0.01) after administration of quercetin, respectively. There were no significant differences in tmax and t1/2 of talinolol. The results also showed AUC0-48 h (5598.6 ± 2202.1 vs 8229.4 ± 1491.7 ng.h/ml, P=0.02) and AUC0-∞ (7110.0 ± 3437.0 vs 12681.2 ± 4828.2 ng.h/ml, P=0.01) of talinolol to be significantly decreased in MDR1 3435 TT individuals administered of quercetin. The Cmax of talinolol in MDR1 3435 TT (382.4 ± 149.1 vs 584.9 ± 115.2 ng/ml, P=0.04) and MDR1 3435 CT (383.5 ± 104.9 vs 554.6 ± 80.6 ng/ml, P=0.01) individuals significantly decreased after the administration of quercetin. Quercetin significantly induced the activity of P-gp and this induced effect was more obvious in MDR1 3435 TT individuals.

Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: a multicentre, cluster-randomised, crossover trial

Bacteraemia is an important cause of morbidity and mortality in critically ill children. Our objective was to assess whether daily bathing in chlorhexidine gluconate (CHG) compared with standard bathing practices would reduce bacteraemia in critically ill children.In an unmasked, cluster-randomised, two-period crossover trial, ten paediatric intensive-care units at five hospitals in the USA were randomly assigned a daily bathing routine for admitted patients older than 2 months, either standard bathing practices or using a cloth impregnated with 2% CHG, for a 6-month period. Units switched to the alternative bathing method for a second 6-month period. 6482 admissions were screened for eligibility. The primary outcome was an episode of bacteraemia. We did intention-to-treat (ITT) and per-protocol (PP) analyses. This study is registered with ClinicalTrials.gov (identifier NCT00549393).1521 admitted patients were excluded because their length of stay was less than 2 days, and 14 refused to participate. 4947 admissions were eligible for analysis. In the ITT population, a non-significant reduction in incidence of bacteraemia was noted with CHG bathing (3·52 per 1000 days, 95% CI 2·64-4·61) compared with standard practices (4·93 per 1000 days, 3·91-6·15; adjusted incidence rate ratio [aIRR] 0·71, 95% CI 0·42-1·20). In the PP population, incidence of bacteraemia was lower in patients receiving CHG bathing (3·28 per 1000 days, 2·27-4·58) compared with standard practices (4·93 per 1000 days, 3·91-6·15; aIRR 0·64, 0·42-0·98). No serious study-related adverse events were recorded, and the incidence of CHG-associated skin reactions was 1·2 per 1000 days (95% CI 0·60-2·02).Critically ill children receiving daily CHG bathing had a lower incidence of bacteraemia compared with those receiving a standard bathing routine. Furthermore, the treatment was well tolerated.Sage Products, US National Institutes of Health.

Double-blind, placebo-controlled, two-period, crossover trial to examine the pharmacokinetics of lisdexamfetamine dimesylate in healthy older adults

BackgroundPharmacokinetic and safety data on stimulants in older adults are limited. The objective of this study was to characterize the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, in older adults.MethodsIn this two-period crossover trial, healthy adults (n = 47) stratified by age (55–64, 65–74, and ≥ 75 years) and gender received randomized, double-blind, single doses of LDX 50 mg or placebo. Baseline creatinine clearance, d-amphetamine and intact LDX pharmacokinetics, and safety were assessed.ResultsMean (±standard deviation) baseline creatinine clearance in participants aged 55–64, 65–74, and ≥ 75 years was 102.5 ± 26.1, 105.3 ± 23.1, and 94.9 ± 27.3 mL per minute, respectively. In the groups aged 55–64, 65–74, and ≥ 75 years, the mean maximum plasma d-amphetamine concentration in men was 44.2 ± 11.1, 47.7 ± 7.0, and 53.4 ± 19.4 ng/mL, respectively; area under the concentration time curve from time 0 extrapolated to infinity (AUC0–inf) was 915.0 ± 164.9, 1123.0 ± 227.0, and 1325.0 ± 464.4 nghour/mL; median time to reach peak plasma concentration was 4.5, 3.5, and 5.5 hours; in women, mean maximum plasma d-amphetamine concentration was 51.0 ± 6.7, 50.2 ± 6.8, and 64.3 ± 12.1 ng/mL, AUC0–inf was 1034.5 ± 154.6, 988.4 ± 80.5, and 1347.8 ± 198.9 ng hour/mL, and median time to reach peak plasma concentration was 3.5, 4.1, and 5.5 hours, respectively. d-Amphetamine clearance was unrelated to baseline creatinine clearance. Five participants aged 55–64 years reported treatment-emergent adverse events (versus one each aged 65–74 and ≥ 75 years), and as did six women (versus one man). No trends in blood pressure or pulse changes were seen with LDX according to age. In participants aged 55–64, 65–74, and ≥ 75 years, the mean change from time-matched baseline pulse ranged from –5.0 to 14.7, –4.3 to 9.5, and –3.0 to 14.7 beats per minute; for systolic blood pressure, from –3.9 to 18.5 mmHg, –2.1 to 14.5 mmHg, and –5.9 to 16.0 mmHg; for diastolic blood pressure from –2.5 to 8.3 mmHg, from –0.8 to 9.4 mmHg, and –0.6 to 9.5 mmHg. Vital sign changes were similar between men and women.ConclusionClearance of d-amphetamine decreased with age and was unrelated to creatinine clearance. No trends in pulse or blood pressure changes with LDX were seen according to age. The safety profile of LDX was consistent with prior observations in younger adult study participants.

Effect of amitriptyline on gastrointestinal function and brain-gut peptides: A double-blind trial

To study the effects of low-dose amitriptyline (AMT) on gastrointestinal function and brain-gut peptides in healthy Chinese volunteers. This was a double-blind, randomised, placebo-controlled, two-period cross-over trial. Twenty-eight healthy volunteers were randomised and administered 1-wk treatments of AMT (12.5 mg tid) or placebo. Before and during the final two days of treatment, gastric emptying, proximal gastric accommodation and visceral sensitivity were measured by drinking-ultrasonography test; the orocecal transit time (OCTT) was measured by lactulose hydrogen breath test, and fasting blood was collected. Plasma levels of ghrelin, motilin and neuropeptide Y (NPY) were measured by enzyme-linked immunosorbent assay kits. AMT slowed the OCTT (109.2 ± 29.68 min vs 96.61 ± 23.9 min, P = 0.004) but did not affect liquid gastric emptying and had no effect on proximal gastric accommodation. AMT resulted in decreases in the visual analogue scale (VAS) for difficulty in drinking 600 and 800 mL of water (3.57 ± 0.94 vs 2.98 ± 0.85, 5.57 ± 0.82 vs 4.57 ± 0.98, P < 0.01 for both), although it had no significant effect on the VAS for difficulty in drinking 200 mL and 400 mL of water. AMT significantly increased the plasma ghrelin level (442.87 ± 176.79 pg/mL vs 526.87 ± 158.44 pg/mL, P = 0.04) and the neuropeptide-Y level (890.15 ± 131.46 pg/mL vs 965.64 ± 165.63 pg/mL, P = 0.03), whereas it had no effect on the MTL level. Low-dose AMT could slow OCTT, make the stomach less sensitive and increase the plasma levels of ghrelin and NPY. Thus, we recommend the use of low-dose AMT for functional gastrointestinal disorders.

A new functional data‐based biomarker for monitoring cardiovascular behavior

Cardiac safety assessment in drug development concerns the ventricular repolarization (represented by electrocardiogram (ECG) T-wave) abnormalities of a cardiac cycle, which are widely believed to be linked with torsades de pointes, a potentially life-threatening arrhythmia. The most often used biomarker for such abnormalities is the prolongation of the QT interval, which relies on the correct annotation of onset of QRS complex and offset of T-wave on ECG. A new biomarker generated from a functional data-based methodology is developed to quantify the T-wave morphology changes from placebo to drug interventions. Comparisons of T-wave-form characters through a multivariate linear mixed model are made to assess cardiovascular risk of drugs. Data from a study with 60 subjects participating in a two-period placebo-controlled crossover trial with repeat ECGs obtained at baseline and 12 time points after interventions are used to illustrate this methodology; different types of wave form changes were characterized and motivated further investigation.

A Translational Approach to Evaluate the Efficacy and Safety of the Novel AMPA Receptor Positive Allosteric Modulator Org 26576 in Adult Attention-Deficit/Hyperactivity Disorder

It has been posited that glutamate dysregulation contributes to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Modulation of glutamate neurotransmission may provide alternative therapeutic options. The novel 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor positive allosteric modulator Org 26576 was investigated with a translational approach including preclinical and clinical testing. Neonatal rat 6-hydroxydopamine lesion-induced hyperactivity was used as preclinical model. Seventy-eight ADHD adults entered a multicenter, double-blind, placebo-controlled, two-period crossover trial. After 1 week placebo lead-in, 67 subjects were randomized into one of four treatment sequences: sequence A (n = 15) Org 26576 (100 mg b.i.d.) for 3 weeks, followed by a 2-week placebo crossover and 3 weeks placebo; sequence B (n = 16) 5 weeks placebo followed by 3 weeks Org 26576 (100 mg b.i.d.); sequence C (n = 18) Org 26576 flexible dose (100-300 mg b.i.d.) for 3 weeks, then 5 weeks placebo; sequence D (n = 18) 5 weeks placebo followed by 3 weeks Org 26576 (100-300 mg b.i.d.). The Adult ADHD Investigator Symptom Rating Scale was used to assess changes in ADHD symptomatology. Org 26576 (1, 3, 10 mg/kg intraperitoneal) produced dose-dependent inhibition of locomotor hyperactivity in 6-hydroxydopamine-lesioned rats. Org 26576 (100 mg b.i.d.) was superior to placebo in treating symptoms of adult ADHD subjects. The primary Adult ADHD Investigator Symptom Rating Scale results were supported by some secondary analyses. However, Org 26576 (100-300 mg b.i.d.) did not confirm these results. Most frequently reported adverse events were nausea, dizziness, and headache. These preclinical and clinical findings suggest that Org 25676 may have utility in the treatment of ADHD.

Bioequivalence Study of Two Different Clopidogrel Bisulfate Film-coated Tablets

The aim of the present study was to evaluate the bioequivalence of two oral clopidogrel (CAS 113665-84-2) formulations. The study was conducted as a monocentric, open, randomized, single-dose, two-period crossover trial in 48 healthy volunteers with a duration of hospitalization of approximately 24 h after dosing on day 1 and with a real wash-out period of 7 days. Blood samples were collected for 24 h post dosing in each period. The plasma was separated and the concentrations of clopidogrel were determined by a LC-MS/MS method. AUC(0-tlast), Cmax, tmax, AUC(0-inf), MRT and t1/2 were calculated for both formulations. The arithmetic means of AUC(0-tlast) and Cmax were 3,656.01 pg x h/ml and 1970.22 pg/ml for the test formulation and 3771.51 pg x h/ml and 1756.52 pg/ml, respectively, for the reference formulation. The mean tmax was 1.16 h for the test and 1.13 h for the reference formulation. The point estimators of the ratios of the test and reference formulations for AUC(0-tlast) and Cmax were 1.042 and 1.115, respectively. Furthermore, the 90% confidence intervals calculated by means of ANOVA-log for the first primary endpoint of the trial, the intra-individual ratio (T/R) of AUC(0-tlast) of clopidogrel was between 0.932 and 1.165. The 90% confidence interval calculated by means of ANOVA-log for Cmax of clopidogrel was between 0.973 and 1.277. The 90% confidence intervals for both parameters were within the predefined acceptance ranges (0.80-1.25 for AUC(0-tlast) and 0.75-1.33 for Cmax). The intraindividual coefficients of variation determined by means of ANOVA-log were 33.51% for AUC(0-tlast) and 41.29% for Cmax. While both products were bioequivalent in terms of the rate and extent of absorption, the present study also confirmed a high variability for clopidogrel suggesting high volunteer numbers in bioequivalence trials.

Influence of casting method on effectiveness of foot orthoses using plantar pressure distribution

Existing techniques of taking foot impressions for producing foot orthoses are static, while walking is a dynamic process. The aim of the study was to evaluate a newly developed dynamic casting method for foot orthoses in comparison with static casts. Double-blind, randomized two-period cross-over trial. Twelve healthy volunteers (six women, six men) were randomly assigned within gender to two groups. The first group wore orthoses made from static casts for two weeks and then orthoses made from dynamic casts for two weeks, and the second group vice versa. The orthoses were worn during work in sports shoes. The outcome measure was coefficient of variation (CV, defined as standard deviation/mean) over seven measurement spots on each foot. Foot orthoses produced by a dynamic casting system redistributed plantar pressure (reduced CV) more effectively in the first period on both feet. In the second period, carry-over effect and/or treatment wearing off was observed. The dynamic casting procedure is simple, low-cost and appears promising, but further research is needed to introduce it into clinical practice.

The effect of the once-daily human glucagon-like peptide 1 analog liraglutide on the pharmacokinetics of acetaminophen

Acetaminophen is a commonly used analgesic and antipyretic drug, and is frequently used to study gastric emptying. Due to its high permeability and high solubility, acetaminophen can be used as a pharmacologic model for medications with similar characteristics. The objective of this study was to assess the effect of liraglutide on the pharmacokinetics (PK) of acetaminophen in patients with type 2 diabetes. This was a randomized, placebo-controlled, two-period crossover trial in which subjects with type 2 diabetes received placebo or liraglutide. After steady state PK of liraglutide 1.8 mg/ placebo were established, a single dose of acetaminophen 1 g was administered at the time of liraglutide C(max) (maximum concentration). The PK profile of acetaminophen was assessed at 18 time points during the 8-hour post-dosing period. Placebo and liraglutide were considered equivalent with respect to area under the curve (AUC)(0-∞) and AUC(0-480) min of acetaminophen if the 90% CI for the ratio was fully contained within the limits of 0.80 to 1.25. All subjects (n=18; mean [SD] age 59 [7] years, body mass index [BMI] 29.7 [4.2] kg/m(2), and glycated hemoglobin [HbA(1c)] 7.8% [0.6%]) completed the study. Equivalence was demonstrated between liraglutide 1.8 mg at steady state and placebo, with respect to acetaminophen AUC(0-∞) (estimated ratio 1.04; 90% CI: 0.97, 1.10) and acetaminophen AUC(0-480) min (estimated ratio 0.95; 90% CI: 0.89, 1.01). During liraglutide, a lower C(max) was observed (estimated ratio 0.69; 90% CI: 0.56, 0.85) and the median acetaminophen t(max) occurred 15 minutes later compared with placebo. The overall exposure of acetaminophen following a 1 g dose was comparable for subjects taking liraglutide or placebo, and the clinical impact of the lower C(max) and delay in absorption of acetaminophen was considered to be transient and small, and without clinical relevance. No adjustment for acetaminophen is recommended when used concomitantly with liraglutide.

Stratified Multivariate Mann–Whitney Estimators for the Comparison of Two Treatments with Randomization Based Covariance Adjustment

Methodology for comparing two randomly assigned treatments for strictly ordinal response variables has been discussed throughout the literature on multivariate Mann–Whitney estimators with stratification adjustment. Although such estimators can be computed directly as weighted linear combinations of within-stratum Mann–Whitney estimators, consistent estimation of their covariance matrix is done using methods for multivariate U-statistics. The scope of these methods includes ways of managing randomly missing data and ways to invoke randomization-based covariance adjustment for no differences between treatments for background or baseline covariables. The assessment of treatment differences can be done using confidence intervals or statistical tests for the adjusted Mann–Whitney estimators. The methods in this article are illustrated using three examples. The first example is a randomized clinical trial with eight strata and a univariate ordinal response variable. The second example is a randomized clinical trial with four strata, two covariables, and four ordinal response variables. The third example is a randomized two-period crossover clinical trial with four strata, three covariables (as age, screening, first baseline), three response variables (as first period response, second baseline, second period response), and missing data. For these examples, the results are interpretable through the probability of better outcomes for one treatment over the other.

Randomized cross‐over trial comparing inpatient and outpatient administration of high‐dose cisplatin

Treatment with high-dose cisplatin (HDC) previously required inpatient (IP) admission with overnight hospitalization, but recently practice has shifted to outpatient (OP) therapy. We aimed to determine whether it is preferable to give HDC as an IP or OP using a two-period cross-over trial. Eligible patients were starting chemotherapy with ≥2 cycles of HDC (≥100 mg/dose) and were suitable for OP treatment. All patients received an IP cycle and OP cycle: the order was randomly allocated. Pre-hydration, anti-emetics and chemotherapy were identical for IP and OP. Post-hydration varied by group (3 L normal saline (NS) for IP, 2 L NS for OP). The primary outcome was patient preference for IP versus OP treatment. Secondary outcomes included aspects of health-related quality of life, adverse events (dose delays and reductions, elevated creatinine and unplanned readmissions) and resource use. Fifty-nine patients were randomized, 53 completed two cycles of HDC. Most patients preferred OP treatment (36 vs 13, P = 0.002). There were no significant differences in patients' ratings of nausea, vomiting, fatigue, anxiety, depression or overall quality of life. Adverse events were few and unrelated to IP versus OP treatment. Nursing time was longer for IP than OP (163 vs 104 min, P < 0.001). OP treatment was preferred by most patients, appeared safe and used less resources.

Contribution of N-Glucuronidation to Efavirenz Elimination In Vivo in the Basal and Rifampin-Induced Metabolism of Efavirenz

In this study, the contribution of efavirenz N-glucuronidation to efavirenz elimination in vivo was assessed. In a two-period placebo-controlled crossover trial design, a single 600-mg oral dose of efavirenz was administered to healthy volunteers (n = 10) pretreated with placebo pills or 600 mg/day rifampin orally for 10 days. Urine and plasma concentrations of efavirenz and 8-hydroxyefavirenz were measured by the liquid chromatography-tandem mass spectrometry method after enzymatic hydrolysis with β-glucuronidase (conjugated and unconjugated) and without enzymatic hydrolysis (unconjugated). Pharmacokinetic parameters of efavirenz within the placebo- or rifampin-treated group obtained after enzymatic hydrolysis did not show any statistically significant difference compared with those obtained without enzymatic hydrolysis (P > 0.05; paired t test, two-tailed). The amount of efavirenz excreted over 12 h was significantly larger after enzymatic hydrolysis in both the placebo (P = 0.007) and rifampin (P = 0.0001) treatment groups, supporting the occurrence of direct N-glucuronidation of efavirenz, but the relevance of this finding is limited because the amount of efavirenz excreted as unchanged or conjugated in urine is less than 1% of the dose administered. In both the placebo- and rifampin-treated groups, plasma concentrations of 8-hydroxyefavirenz and the amount excreted over 12 h were significantly larger (P < 0.00001) after enzymatic hydrolysis than without enzymatic hydrolysis. These findings suggest that although the occurrence of direct efavirenz N-glucuronidation is supported by the urine data, the abundance of efavirenz N-glucuronide in plasma is negligible and that the contribution of the N-glucuronidation pathway to the overall clearance of efavirenz seems minimal.

The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma

To investigate the effect of prior administration of a bronchodilator on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids. A single-centre, randomized, open-label, two-period cross-over trial was carried out in 41 nondiabetic subjects with asthma treated with inhaled steroids, with reversible bronchoconstriction (Rev+; n= 25) or without reversible bronchoconstriction (Rev-; n= 16). A dose of 0.10 U kg(-1) inhaled human insulin was administered on each dosing day with or without prior administration of the bronchodilator terbutaline (in random order). Prior administration of terbutaline led to a 44% increase in absorption of insulin over 6 h for the Rev+ group compared with no prior administration of bronchodilator [ratio (95% confidence interval) 1.44 (1.13, 1.82), P= 0.004], whereas no effect was seen for the Rev- or the whole group. The maximum insulin concentration (C(max)) increased by 34% for the Rev+ group (P = 0.018) and 17% for the whole group (P= 0.046), whereas no significant effect of prior terbutaline administration was seen for Rev-. The time to C(max) was not significantly different for the Rev+ group, whereas it was approximately 30% longer after bronchodilator administration for the Rev- group (P= 0.044) and the whole group (P= 0.032). In people with asthma and reversible bronchoconstriction, the administration of a bronchodilator prior to administration of inhaled insulin led to increased absorption of insulin, whereas no effect on insulin absorption in subjects without significant reversibility could be detected.

Increased intake of Maillard reaction products reduces phosphorous digestibility in male adolescents

ObjectiveTo examine the effects of consuming diets rich in Maillard reaction products (MRPs) on phosphorus bioavailability in male adolescents. MethodsA 2-wk randomized two-period crossover trial was performed among healthy male adolescents aged 11–14 y (n = 20), with a 40-d washout period. The diets consumed were rich (brown diet) or poor (white diet) in MRPs. Three-day balances were performed on the last of each dietary period, and fasting blood samples were obtained. Dietary phosphorus utilization was examined by phosphorus intake in diet and phosphorus output in feces and urine, as measured colorimetrically by the vanadomolibdate procedure. Serum phosphorus, parathyroid hormone, and total alkaline phosphatase were determined. ResultsA tendency to increase daily phosphorus fecal excretion was observed subsequent to the brown diet consumption compared with the white diet (P = 0.10), which led to significant reductions in phosphorus apparent absorption (P = 0.03) and fractional absorption (P = 0.04). Values of apparent phosphorus retention and bioavailability tended to decrease after the high-MRP diet. Serum parameters analyzed remained unchanged between diets and were within normal values. ConclusionThe consumption of a rich-MRP diet in male adolescents had a negative influence on dietary phosphorus absorption, tending to decrease the phosphorus balance. Given the actual dietary habits of adolescents, possible long-term repercussions of this kind of diet should be studied.

Mixture of Arnebia euchroma and Matricaria chamomilla (Marhame-Mafasel) for pain relief of osteoarthritis of the knee – a two-treatment, two-period crossover trial

IntroductionOsteoarthritis is the most prevalent chronic non-infective joint arthritis. Because of its chronic disease nature, local drugs are preferred due to lower complications. In the present study, the new herbal pomade Marhame-Mafasel for knee osteoarthritis was used in a double-blind crossover trial.The aim of the study was to assess the efficacy and safety of Marhame-Mafasel pomade, which consists of several medical herbs including Arnebia euchroma and Matricaria chamomilla, in osteoarthritis of the knee.Material and methodsThis study was a placebo-controlled double-blind crossover trial. Forty-two patients with pain associated with osteoarthritis of the knee (diagnosed by criteria of the European League against Rheumatism and physical examination) were drawn from patients attending the Clinic of Mostafa-Khomeini Hospital. In this study we assessed efficacy (analgesic effect and improved function) of herbal pomade Marhame-Mafasel, which was used locally in patients with primary osteoarthritis of the knee over three weeks. The instrument of the study was the Western Ontario and McMaster Universities (WOMAC) LK3.1 standard questionnaires.ResultsThe participants in each group were 21 patients; 30 (71.4%) were women and 12 (28.6%) of them were men. The participants were between 40 and 76 years old. Six patients had mild arthritis, 15 had moderate arthritis and 21 had severe arthritis. The positive analgesic effect of the herbal pomade Marhame-Mafasel in primary knee osteoarthritis was proven. The herbal joint pomade Marhame-Mafasel had a significantly greater mean change in score compared to the placebo group for osteoarthritis severity (p < 0.05).ConclusionsHerbal pomade Marhame-Mafasel in comparison to placebo has more effect on reduction of pain of primary knee osteoarthritis.

Intake of Maillard reaction products reduces iron bioavailability in male adolescents

The effects of diets with different Maillard reaction products (MRPs) content on biological iron utilization were compared using in vitro/in vivo assays. Diets were rich (brown diet, BD) or poor (white diet) in MRP. In vitro studies included iron solubility after in vitro digestion of diets and iron transport across Caco-2 cells. In the human assay 18 healthy adolescent males (11-14 years) participated in a 2-wk randomized two-period crossover trial. Subjects collected urine and faeces on the last 3 days of each dietary period, and fasting blood samples were obtained after periods. In vitro dietary iron availability was significantly lower with the BD than the white diet (9.52 and 12.92%, respectively), as a consequence of the lower iron solubility after the in vitro digestion, but not as a result of decreased transport of the remaining soluble iron. The BD consumption increased iron fecal excretion ( approximately 1.4-fold) and significantly decreased its bioavailability ( approximately 2.7-fold), mainly due to the effects found at digestive level. Serum biochemical parameters related to iron metabolism remained unaltered. It is concluded the presence of MRP in the diet negatively affects iron bioavailability. As iron deficiency may be related to learning impairment and to reductions of cognitive and physical functions, possible long-term effects of excessive MRP intake during adolescence warrant attention.

Relative bioavailability of generic and branded 250-mg and 500-mg oral chlorphenesin carbamate tablets in healthy Korean volunteers: A single-dose, randomized-sequence, open-label, two-period crossover trial

Background: Chlorphenesin carbamate is a skeletal muscle relaxant approved in Korea for use in the treatment of pain and discomfort related to skeletal muscle trauma and inflammation. Objective: The aim of this study was to assess the bioequivalence of a generic formulation of chlorphenesin carbamate at doses of 250 and 500 mg and 2 branded formulations of the same doses in healthy Korean adults. Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Korean male and female volunteers. Subjects were assigned to receive, in a randomized sequence, a single dose of the generic (test) and branded (reference) formulations of chlorphenesin carbamate at a dose of 250 or 500 mg. Blood samples were drawn at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, and 15 hours after administration. Pharmacokinetic properties (C max, T max, AUC 0−t AUC 0-∞, t 1/2, and ke) were determined using HPLC. The formulations were to be considered bioequivalent if the 90% CIs of the treatment ratios of the geometric means of C max and AUC 0−t were within a predetermined range of log 0.80 to log 1.25 based on regulatory criteria. Tolerability was assessed by monitoring for adverse events (AEs) on physical examination and/or e-mail and personal interview at the beginning and end of each study period. Results: Twenty-eight subjects (22 men, 6 women) received chlorphenesin carbamate at the 250-mg dose, and 24 male subjects received the 500-mg dose. The mean (SD) ages of the subjects were 24.0 (2.6) and 24.0 (1.9) years in the 250- and 500-mg groups, respectively. No significant differences were found between the test and reference formulations (90% CIs: C max, 1.0048–1.1153 with the 250-mg dose and 0.9630–1.1189 with the 500-mg dose; AUC 0−t, 0.9882–1.0546 and 0.9842–1.0578, respectively). No clinically significant AEs (upper gastric pain, abdominal bloating, pyrexia, edema, nausea, heartburn, constipation, headache, dizziness, drowsiness, or fatigue) were reported throughout the study. Conclusion: In this single-dose study in these healthy Korean subjects, the generic and branded formulations of chlorphenesin carbamate 250 and 500 mg met the regulatory criteria for bioequivalence. All formulations were well tolerated.

A simple analysis of a simple crossover trial with a dichotomous outcome measure

For the two-treatment two-period crossover trial with a dichotomous outcome measure a simple and straightforward analysis is proposed: compute the treatment difference for each of the treatment sequences AB and BA, and then average over the sequence groups. The mean difference is used in the statistical test and in the computation of the 95 per cent confidence interval. The method is generalized to the case of a crossover trial including more than two treatments.