Blind Placebo Controlled Crossover Trial Research Articles

Immunomodulatory effects of fucoidan in recreationally active adult males undertaking 3-weeks of intensified training

ABSTRACT The aim of the current study was to determine whether daily fucoidan supplementation (Undaria pinnatifida extract containing >85% fucoidan, 1 g/day) for three-weeks in a double blind-placebo controlled cross-over trial (ACTRN12621000872831) could modulate alterations in faecal (calprotectin, lysozyme and IgA) and salivary (lactoferrin, lysozyme and IgA) markers of mucosal immune competence typically observed in response to both acute physical activity, and a period of intensified exercise training, in healthy recreationally active men (n = 12). Participants responded positively to the intensified training with 16–19% improvement in mean power that was not different between supplement groups. Faecal biomarkers and concentrations of lactoferrin, lysozyme and IgA from resting saliva samples were largely stable over the supplementation period. Concentrations of salivary biomarkers varied significantly over time in response to acute exercise, however differences between supplementation groups were modest. For salivary lysozyme, there was a trend for a lower magnitude of increase post-exercise (p = 0.08) and limited return towards pre-exercise in response to fucoidan. For salivary IgA, a greater acute exercise response was noted for IgA in response to fucoidan (~2.7-fold higher; p = 0.02). Different dosage and supplementation protocols and inclusion of additional immune markers should be considered in subsequent assessments of any potential benefits of fucoidan supplementation in healthy active adults.

Null effect of ginsenoside Rb1 on improving glycemic status in men during a resistance training recovery.

BackgroundGinsenoside Rb1, a principle active ingredients of Panax ginseng, has been shown to lower blood glucose in animals and increase insulin secretion in cultured insulinoma cells. The aim of this study was to determine the effects of daily ginsenoside Rb1 supplementation on circulating glucose and insulin levels in men during a 5-day recovery period after an acute bout of resistance exercise.MethodsTwelve gymnasts (20.5 ± 0.3 years of age) participated in this double blind placebo-controlled crossover trial. They were challenged by a lower-limb resistance exercise at a weight load of 85 % one-repetition maximal (1-RM) for 10 repetitions, six sets of the movement. Rb1 (1 ng/kg) or Placebo was orally delivered to participants daily during a 5-day recovery period after challenge. Circulating insulin, glucose and heart rate variability (HRV) were measured under fasted condition in the morning at Days 1, Day 3, and Day 5 during recovery.ResultsNo significant effect of Rb1 on circulating glucose and insulin levels were found among participants during the 5-day recovery period. A persistent elevation in sympathetic nervous activity, indicated by increased HRV-low frequency/high frequency (HRV-LF/HF) power, during the Rb1 trial was observed.ConclusionsThe result of the study suggests that the null effect of Rb1 supplementation on lowering glucose and insulin levels of participants may be associated with chronic sympathetic activation.

Abstract P641: Angiotensin Receptor Blocker Improves Pressure Natriuresis in Select African-Americans

Objective: Hypertension in ~30-60% of African-Americans (AAs) is resistant to single or combination therapy, indicating the necessity for novel screening strategies in this population. Our research supports a strategy that identifies a subset of AAs (approximately 1 in 3) who increase their retained sodium load during mental stress (MS) with an accompanying volume-mediated increase in blood pressure (BP) that remains elevated until the volume expansion diminishes. We hypothesize is due to activation of the renin-angiotensin system (RAS). Design and Method: We conducted a double blind placebo controlled crossover trial comparing the effects of irbesartan to placebo on sodium handling and consequent BP during MS. Subjects included 213 AA adults, of which 168 (78%) completed the study. After 7 days of vehicle (placebo or irbesartan) subjects underwent a 3 hr protocol comprised of 1 hr rest, 1 hr competitive video games, and 1 hr recovery. Blood and urine were obtained after each hour and BP every 15 mins. A 1 week washout ensued before subjects crossed over to repeat with the alternate vehicle. Subjects were divided into those who exhibited expected increases in urinary sodium excretion (U Na V) (Excreters) or reduced U Na V (Retainers) during MS as defined by previous data. Statistical analysis was performed using crossover methods with a pooled analysis that assumes equal variances and the Satterthwaite test of treatment difference (Stest) that assumes unequal variances. Results: Both statistical tests revealed that U Na V increased significantly for retainers (n=55) on irbesartan (p<0.002 and p<0.015, mean ± SD (pooled =7.15 ± 6.78, Stest =7.15)) normalizing the sodium response to MS. Irbesartan also enhanced U Na V during MS in excreters (n=113) with significant differences (p<0.001 and p<0.001, mean ± SD (pooled = 4.18 ± 9.03, Stest =4.18)). Overall SBP response was significantly reduced with treatment (p< 0.001 and p< 0.001, mean ± SD (pooled = -5.08 ± 3.19, Stest = -5.08)). Conclusion: Agents that block the RAS are not usually considered effective in AAs. However, our results suggest identification and treatment of AAs who increase their retained sodium load during MS with these agents will reduce the percentage of AAs with hypertension resistant to standard therapy.

A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial

BackgroundChronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans.MethodsTen healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ± 3.8) were randomized in a double-masked, placebo-controlled, crossover study to separate 36-hour inpatient visits (placebo versus intravenous-LPS 0.6 ng/kg). We measured clinical symptoms via the McGill pain questionnaire and serial vital signs. Plasma and serum were collected for measurement of cytokines, C-reactive protein, insulin and glucose, serial whole blood & subcutaneous adipose tissue mRNA expression were measured by real-time PCR. HOMA-IR, a well-validated measure of IR was calculated to estimate insulin resistance, and frequently sampled intravenous glucose tolerance testing (FSIGTT) was performed to confirm an insulin resistant state. We performed ANOVA and within subject ANOVA to understand the differences in cytokines, adipose tissue inflammation and IR before and after LPS or placebo.ResultsThere was no significant difference between placebo and LPS in clinical responses of symptom scores, body temperature or heart rate. However, low-dose endotoxemia induced a rapid and transient 25-fold induction of plasma TNF-alpha and 100-fold increase in plasma IL-6 (Figure 1B) (p < 0.001 for both) both peaking at two hours, followed by modest inflammation in adipose tissue with increases in mRNA levels of several inflammatory genes known to modulate adipose and systemic insulin resistance. Adipose tissue mRNA levels of IL-6 (peak 6-fold, ANOVA F = 27.5, p < 0.001) and TNF-alpha (peak 1.8-fold, F = 2.9, p = 0.01) increased with MCP-1 (peak 10-fold, F = 5.6, p < 0.01) and fractalkine (CX3CL1) (peak 15-fold, F = 13.3, p < 0.001). Finally, HOMA-IR was 32% higher following LPS compared to placebo (p < 0.01) and insulin sensitivity declined by 21% following LPS compared to placebo (p < 0.05).ConclusionsWe present a low dose human endotoxemia model of inflammation which induces adipose tissue inflammation and systemic insulin resistance in the absence of overt clinical response. Such a model has the potential for broad and safe application in the study of novel therapeutics and genomic influences in cardio-metabolic disease.

Blood pressure lowering effect of a pea protein hydrolysate in hypertensive rats and humans.

The blood pressure lowering effect of a pea protein hydrolysate (PPH) that contained <3 kDa peptides, isolated by membrane ultrafiltration from the thermolysin digest of pea protein isolate (PPI), was examined using different rat models of hypertension as well as hypertensive human subjects. The PPH showed weak in vitro activities against renin and angiotensin converting enzyme (ACE) with inhibitory activities of 17 and 19%, respectively, at 1 mg/mL test concentration. Oral administration of the PPH to spontaneously hypertensive rats (SHR) at doses of 100 and 200 mg/kg body weight led to a lowering of hourly systolic blood pressure (SBP), with a maximum reduction of 19 mmHg at 4 h. In contrast, orally administered unhydrolyzed PPI had no blood pressure reducing effect in SHR, suggesting that thermolysin hydrolysis may have been responsible for releasing bioactive peptides from the native protein. Oral administration of the PPH to the Han:SPRD-cy rat (a model of chronic kidney disease) over an 8-week period led to 29 and 25 mmHg reductions in SBP and diastolic blood pressure, respectively. The PPH-fed rats had lower plasma levels of angiotensin II, the major vasopressor involved in development of hypertension, but there was no effect on plasma activity or renal mRNA levels of ACE. However, renal expression of renin mRNA levels was reduced by approximately 50% in the PPH-fed rats, suggesting that reduced renin may be responsible for the reduced levels of angiotensin II. In a 3-week randomized double blind placebo-controlled crossover human intervention trial (7 volunteers), significant (p<0.05) reductions (over placebo) in SBP of 5 and 6 mmHg were obtained in the second and third weeks, respectively, for the PPH group. Therefore, thermolysin derived bioactive peptides from PPH reduced blood pressure in hypertensive rats and human subjects, likely via effects on the renal angiotensin system.

A candidate probiotic with unfavourable effects in subjects with irritable bowel syndrome: a randomised controlled trial

BackgroundSome probiotics have shown efficacy for patients with irritable bowel syndrome (IBS). Lactobacillus (L.) plantarum MF1298 was found to have the best in vitro probiotic properties of 22 strains of lactobacilli. The aim of this study was to investigate the symptomatic effect of L. plantarum MF1298 in subjects with IBS. Primary outcome was treatment preference and secondary outcomes were number of weeks with satisfactory relief of symptoms and IBS sum score.MethodsThe design was a randomised double blind placebo-controlled crossover trial. 16 subjects with IBS underwent two three-week periods of daily intake of one capsule of 1010 CFU L. plantarum MF 1298 or placebo separated by a four-week washout period.ResultsThirteen participants (81%; 95% CI 57% to 93%; P = 0.012) preferred placebo to L. plantarum MF1298 treatment. The mean (SD) number of weeks with satisfactory relief of symptoms in the periods with L. plantarum MF1298 and placebo were 0.50 (0.89) and 1.44 (1.26), respectively (P = 0.006). IBS sum score was 6.44 (1.81) in the period with L. plantarum MF1298 treatment compared with 5.35 (1.77) in the period with placebo (P = 0.010). With a clinically significant difference in the IBS sum score of 2 in disfavour of active treatment, the number needed to harm was 3.7, 95% CI 2.3 to 10.9.ConclusionsThis trial shows for the first time an unfavourable effect on symptoms in subjects with IBS after intake of a potential probiotic.The trial registration numberClinical trials NCT00355810.

A Double Blind Placebo Controlled Crossover Trial of Sertraline To Prevent Depression during Combination Therapy for Hepatitis C Infection

A Double Blind Placebo Controlled Crossover Trial of Sertraline To Prevent Depression during Combination Therapy for Hepatitis C Infection

Androgen Replacement in Adolescents and Young Women with Hypopituitarism

The aim of this study was to test the hypothesis that young women with androgen deficiency due to hypopituitarism would benefit from androgen replacement in the form of dehydroepiandrosterone (DHEA). Five young women, age 15.2-23.1 years, with panhypopituitarism were studied in a 12-month double blind placebo-controlled crossover trial of DHEA replacement in a dose 50 mg/day (Belmar Pharmacy, Lakewood, CO). All had growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) and antidiuretic hormone deficiencies. Gonadotropin deficiency was complete in three and partial in two. The patients were evaluated at baseline, 6 months and 12 months. Serum hormone levels, body composition, lumbar bone mineral density (BMD), exercise capacity and tests of psychological function were performed. DHEA replacement restored serum DHEA levels to normal, 359.8+/-337 ng/dl (12.5+/-11.7 nmol/l). The Life Situation Survey showed significantly better life satisfaction on DHEA than placebo (110 vs 102, p = 0.05). Trends for improved maximal oxygen uptake (VO2), and decreased percent body fat did not reach statistical significance. In conclusion, androgen replacement with DHEA should be considered in young women with panhypopituitarism. Further studies over longer periods in larger groups of patients are necessary to better evaluate the effects of DHEA replacement on BMD, muscle strength and body composition.

Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial

Objective To evaluate the effect of the oral synthetic δ-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis.Design Randomised double blind placebo controlled crossovertrial.Setting Outpatient clinic, University Hospital...

Effect of BCAA Intake During Exercise on Skeletal Muscle Protein Metabolism in Young Individuals

1372 PURPOSE: To determine the effect of branched-chain amino acids (BCAA) intake during cycling exercise on the net balance of amino acid concentrations across the working muscles in young individuals. METHODS: Eight healthy young volunteers (4 males and 4 females, means ± SD, 26 ± 2 yrs, 178 ± 10 cm, 73 ± 11 kg) were studied by a double blind placebo-controlled cross-over trial. The subjects performed 3 bouts of 20-min cycling exercise (5-min break between each bout) at intensity of 126 ± 37 W corresponding to 50% of maximal work intensity. Either a BCAA drink (2000 mg BCAA and 20 g carbohydrate, 500 mL) or an iso-calorie placebo drink (500 mL) was given at 10 min of the 1st exercise bout. Arterial and venous blood samples st were taken from arteria radialis and vena femoralis. Blood flow in arteria femoralis was determined by ultrasound Doppler technique. Blood sampling and blood flow measurements were performed at rest, every 10 min during each exercise bout, and every 15 min during 60-min recovery period. Net balance of plasma phenylalanine concentration [Phe] (μmol/min) as an index for skeletal muscle protein metabolism, was calculated by the use of the following formula: Net balance of [Phe] = ([Phe]artery − [Phe]vein) × blood flow × (1-hematocrit). RESULTS: No difference in blood flow was observed between BCAA and placebo group at rest (0.43 ± 0.19 vs. 0.55 ± 0.25 L/min) and the end of 3rd exercise bout (3.60 ± 1.37 rd vs. 3.48 ± 1.58 L/min). Plasma BCAA concentration increased from 10 min, and peaked at 25 min (75.8 % increase compared to rest), and remained significant increase until 75 min (41.7 %) after BCAA ingestion. In placebo group, the arterial plasma BCAA concentration remained constant throughout the experiment. Negative balance of [Phe] across leg muscles was observed during the exercise bouts in both groups. Cumulative [Phe] release from the leg muscles during the exercise bouts after BCAA ingestion tended to be lower than that after placebo ingestion (−33.5 ± 27.1 vs. −60.6 ± 51.3μmol/60 min, P < 0.10). The cumulative [Phe] release during 3rd exercise bout in BCAA group was less than that rd in placebo group (−5.0 ± 21.0 vs. −35.9 ± 37.4μmol/25 min, P < 0.05). CONCLUSION: These results suggest that BCAA intake at onset of exercise is effective to suppress skeletal muscle proteolysis induced by dynamic exercise.

Effect of Protein-Carbohydrate Intake During Exercise on Skeletal Muscle Protein Metabolism in Elderly Individuals

2210 Dynamic exercise-induced skeletal muscle protein metabolism and the effect of nutrient supplementation on the protein metabolism have not been well demonstrated in elderly individuals. PURPOSE: This study aimed at evaluating the effect of a protein-carbohydrate supplement taken during cycling exercise on the net balance of amino acid concentrations across the working muscles in elderly subjects. METHODS: Six healthy elderly volunteers (4 males and 2 females, means ± SD, 64 ± 3 yrs, 175 ± 6 cm, 74 ± 8 kg) were studied by a double blind placebo-controlled cross-over trial. The subject performed 3 bouts of 20-min cycling exercise (5-min break between each bout) at intensity of 89 ± 14 W corresponding to 50% of maximal work intensity. Either a nutrient supplement containing 10.0 g protein and 16.5 g carbohydrate (PROT) or a non-calorie placebo (CONT) was given at 10 min of the 1st exercise bout. Arterial and venous blood samples were taken from arteria radialis and vena femoralis, respectively. Blood flow in arteria femoralis was determined by ultrasound Doppler technique. Blood sampling and blood flow measurements were performed at rest, every 10 min during each exercise bout, and every 15 min during 60-min recovery period. Net balance of plasma phenylalanine concentration [Phe] (μmol min−1) as an index for skeletal muscle protein metabolism, was calculated by the use of the following formula: Net balance of [Phe] = ([Phe]artery – [Phe]vein) × blood flow × (1-hematocrit). RESULTS: No difference in blood flow was observed between PROT and CONT, at rest (0.39 ± 0.21vs. 0.37 ± 0.21 L min−1) and the end of 3rd exercise bout (2.48 ± 0.56 rd vs. 2.65 ± 0.22 L min−1). In PROT, the arterial plasma concentration of total amino acids at rest was 2.42 ± 0.14 mmol L-1. After 35 min of PROT ingestion, the total amino acids concentration reached 3.33 ± 0.23 mmol L-1. The concentrations remained unchanged to the end of 3rd exercise bout (3.28 ± 0.26 mmol L-1) and returned to the resting level by the end of 60-min of recovery (2.40 ± 0.11 mmol L-1). In CONT, the arterial plasma concentration of total amino acids at rest was 2.31 ± 0.11 mmol L-1, and remained constant throughout the experiment. In CONT, negative balance of [Phe] was observed during the exercise bouts. In PROT, a significantly larger net balance of [Phe] across leg muscles was observed at 35-min cycling as compared with CONT (1.23 ± 1.49vs. −1.98 ± 1.90μmol min-1, P<0.05). CONCLUSION: Skeletal muscle proteolysis was indicated to occur during dynamic exercise at 50% of maximal intensity in elderly individuals, and such response was diminished by ingesting a protein-carbohydrate supplement at onset of exercise.

Intravenous adenosine alleviates neuropathic pain: a double blind placebo controlled crossover trial using an enriched enrolment design

Adenosine analogs produce analgesic actions in nociceptive paradigms and alleviate manifestations of neuropathic pain in nerve injury models in rodents. In humans, previous work indicates an analgesic effect for adenosine administered intravenously in postoperative and neuropathic pain. In this double blind placebo controlled crossover trial, we used an enriched enrolment design to determine the effects of intravenous adenosine (50μg/kg/min over 60min) on neuropathic pain. In Phase 1 of the trial, adenosine was administered in an open label manner, while in Phase 2 adenosine was administered in a double blind placebo controlled manner to 23 adenosine responders who had experienced a 30% or greater response in the open trial. Outcome measures included the McGill pain questionnaire (MPQ), which generates a pain rating index (PRI), and contains a visual analog scale (VAS) of pain intensity, the neuropathy pain scale (NPS), and a VAS for pain relief. Subjects also graded the degree of allodynia and hyperalgesia using a VAS. Adenosine led to a significant reduction in spontaneous pain according to the MPQ-PRI, the MPQ-VAS and the VAS for pain relief. The NPS showed a pattern similar to the MPQ-PRI, with statistically significant reductions in scales 1 (intensity), 3 (hot), 6 (sensitive), 7 (itchy) and 9 (unpleasant). Adenosine also led to a significant reduction in pinprick hyperalgesia, but not in allodynia. Three patients from Phase 1 of the trial experienced long term resolution of their pain following intravenous adenosine (5,16,25 months). The results of this study support previous reports that indicate intravenous adenosine alleviates neuropathic pain and hyperalgesia.

Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread

Plant sterols may be a useful additive therapy in the treatment of hypercholesterolaemic patients. The purpose of this study was to determine the effect of a fat spread enriched with vegetable oil sterols on plasma lipid, lipoprotein and apolipoprotein concentrations. A randomised double blind placebo-controlled crossover trial with two consecutive periods of 8 weeks was conducted. 30 patients with heterozygous familial hypercholesterolaemia treated concurrently with an HMG-CoA reductase inhibitor (statin) and 32 patients with type IIa primary hypercholesterolaemia with a total cholesterol concentration >6.5 mmol/l not taking lipid-lowering drug therapy were recruited from a hospital lipid clinic. The active treatment was a fortified fat spread (25 g/day) providing 2.5 g of plant sterols. The control spread was indistinguishable in taste and appearance. Comparison at the end of the two 8-week trial periods showed a statistically significant reduction in total and LDL-cholesterol with use of the fortified spread but the results were confounded by a carry-over effect, which was partly explained by changes in the background diet. Because a carry-over effect was present, further analyses were restricted to the parallel arms of the first treatment period and were conducted on an intention to treat basis. After 4 weeks, LDL-cholesterol had decreased by 0.04 mmol/l ([0.8%] 95% confidence interval −0.44–0.37 NS) in the placebo group and decreased by −0.76 mmol/l ([15.0%] 95% CI −1.03–−0.48, P<0.0001) in the active treatment group. After 8 weeks, the corresponding results were 0.0 mmol/l ([0.0%] 95% CI −0.26–0.24 NS) and −0.51 mmol/l ([10.0%] 95% CI −0.73–−0.29 P<0.0001). There were no significant changes in apolipoprotein AI or B concentrations in the placebo group, but there was a small but statistically significant increase in apolipoprotein AI and a decrease in apolipoprotein B in the active treatment group. HDL cholesterol and triglyceride concentrations were unchanged. There was no difference in response between patients with statin-treated familial hypercholesterolaemia and patients with type IIa hyperlipoprotienaemia. We conclude that a fortified fat spread enriched with vegetable oil sterols reduces LDL-cholesterol by 10–15% with no difference in response between hypercholesterolaemic patients prescribed statins and those not taking lipid-lowering drug therapy.

A double blind, placebo controlled, crossover trial of d-ribose in McArdle's disease

To determine whether seven days oral d-ribose would improve exercise tolerance in a group of 5 patients with McArdle's disease, we performed a double blind placebo controlled crossover trial. Subjects performed weekly treadmill exercise tests with expired gas analysis until their times were reproducible. They then received 60 g d-ribose daily or placebo for seven days. Exercise testing was repeated on completion of this period. A seven day washout period then followed. Subjects then performed a new baseline exercise test prior to starting the other solution. Again after seven days the exercise test was repeated. There was no significant difference between pre-treatment exercise tests for peak oxygen consumption or level of leg fatigue. Patients did not like taking the ribose and d-Ribose does not appear to be of benefit to patients with McArdle's disease.

The effect of ultrasound on in vitro liberation and in vivo penetration of benzyl nicotinate

The effect of ultrasound on the in vitro liberation of benzyl nicotinate from polyacrylate gel and the in vivo penetration of benzyl nicotinate solution through the skin was investigated. An ultrasonic apparatus used in medical therapy was employed for ultrasonic treatment. Sonication of the gels accelerates the liberation and enhances the apparent diffusion coefficient of benzyl nicotinate. The liberation can be described by the square root law. The influence of ultrasound on the percutaneous absorption of benzyl nicotinate was investigated in healthy volunteers in a blind placebo-controlled crossover trial. In our experiments, ultrasonic treatment alone does not result in reddening of the skin. For recording the reddening of the skin on application of benzyl nicotinate a reflection photometry method was used. The parameters determined, i.e., lag time and intensity of redness, indicate a behaviour dependent on the concentration of benzyl nicotinate. Increasing concentrations reduce the lag time and increase the intensity of redness, both parameters tending towards a limit. Ultrasonic treatment of the skin in ther-apeutic doses of 0.2, 0.5 and 1.0 W/cm 2 reduces the lag time as a function of power after application of the benzyl nicotinate. Repetitions of the ultrasonic treatment confirm the reversibility of the changes in skin permeability. Thus, phonophoresis of benzyl nicotinate gels has two effects; acceleration of nicotinate liberation from gel and enhancement of percutaneous nicotinate permeation.

A double blind trial of botulinum toxin "A" in torticollis, with one year follow up.

A double blind placebo controlled crossover trial was performed of botulinum toxin "A" in 20 patients with spasmodic torticollis. There was a statistically significant benefit for those treated with toxin; 12 on toxin improved objectively, compared with four on placebo (p less than 0.04). After a follow up period of one year, 16 still seemed to benefit from repeated toxin injections. The main side effect was dysphagia, which appeared to be dose related in individual patients.