Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients

Hyperkalemia is a common life-threatening problem in hemodialysis patients. Because glycyrrhetinic acid (GA) inhibits the enzyme 11beta-hydroxy-steroid dehydrogenase II and thereby increases cortisol availability to the colonic mineralocorticoid receptor, it has the potential to lower serum potassium concentrations. To test this, 10 patients in a 6 month prospective, double-blind, placebo-controlled crossover study were given cookies or bread rolls supplemented with glycyrrhetinic acid or placebo. Twenty-four-hour blood pressure measurements were performed at baseline and week 6 and 12 of each treatment period. The ratio of plasma cortisol/cortisone was significantly increased in all patients on GA as compared to baseline or placebo, indicating appropriate enzyme inhibition. Nine of the 10 patients had a persistent decrease in predialysis serum potassium concentration. On GA, mean predialysis serum potassium was significantly lower than at baseline or on placebo. On placebo, serum potassium was significantly elevated above the upper limit of normal in 76% compared to 30% of measurements during GA treatment. Furthermore, on this treatment the frequency of severe hyperkalemia significantly decreased from 9% to 0.6%. No differences were found in parameters reflecting sodium retention. Although these studies show that prolonged GA supplementation persistently lowers serum potassium in dialysis patients, a long-term toxicity study will be mandatory before we recommend the routine use of this treatment.

Reduction in total plasma ghrelin levels following catecholamine depletion: relation to bulimic and depressive symptoms

There is increasing preclinical and clinical evidence of the important role played by the gastric peptide hormone ghrelin in the pathogenesis of symptoms of depression and eating disorders. To investigate the role of ghrelin and its considered counterpart, peptide tyrosine tyrosine (PYY), in the development of bulimic and depressive symptoms induced by catecholamine depletion, we administered the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine (AMPT) in a randomized, double-blind, placebo-controlled crossover, single-site experimental trial to 29 healthy controls and 20 subjects with fully recovered bulimia nervosa (rBN). We found a decrease between peprandial and postprandial plasma ghrelin levels (p < 0.0001) and a postprandial rise in plasma PYY levels (p < 0.0001) in both conditions in the entire study population. Plasma ghrelin levels decreased in the entire study population after treatment with AMPT compared to placebo (p < 0.006). AMPT-induced changes in plasma ghrelin levels were negatively correlated with AMPT-induced depressive symptoms (p < 0.004). Plasma ghrelin and plasma PYY levels were also negatively correlated (p < 0.05). We did not observe a difference in ghrelin or PYY response to catecholamine depletion between rBN subjects and healthy controls, and there was no correlation between plasma ghrelin and PYY levels and bulimic symptoms induced by catecholamine depletion. These findings suggest a relationship between catecholamines and ghrelin with depressive symptoms.

Behavioral responses to catecholamine depletion in unmedicated, remitted subjects with bulimia nervosa and healthy subjects

BACKGROUND: Bulimia nervosa (BN) has been associated with dysregulation of the central catecholaminergic system. An instructive way to investigate the relationship between catecholaminergic function and psychiatric disorder has involved behavioral responses to experimental catecholamine depletion (CD). The purpose of this study was to examine a possible catecholaminergic dysfunction in the pathogenesis of bulimia nervosa. METHODS: CD was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 18 remitted female subjects with BN (rBN) and 31 healthy female control subjects. The study design consisted of a randomized, double blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were bulimic symptoms assessed by the Eating Disorder Examination-Questionnaire. Measures were assessed before and 26, 30, 54, 78, 102 hours after the first AMPT or placebo administration. RESULTS: In the experimental environment (controlled environment with a low level of food cues) rBN subjects had a greater increase in eating disorder symptoms during CD compared with healthy control subjects (condition × diagnosis interaction, p < .05). In the experimental environment, rBN subjects experienced fewer bulimic symptoms than in the natural environment (uncontrolled environment concerning food cues) 36 hours after the first AMPT intake (environment × diagnosis interaction, p < .05). Serum prolactin levels increased significantly, and to a comparable degree across groups, after AMPT administration. CONCLUSIONS: This study suggests that rBN is associated with vulnerability for developing eating disorder symptoms in response to reduced catecholamine neurotransmission after CD. The findings support the notion of catecholaminergic dysfunction as a possible trait abnormality in BN.

The Role of BDNF, Leptin and Catecholamines in Reward Learning in Bulimia Nervosa

Background: A relationship between bulimia nervosa (BN) and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin. Methods: Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted BN (rBN) and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT). The plasma levels of BDNF and leptin were measured twice during the placebo and the AMPT condition, immediately before and 1 h after a standardized breakfast. Results: AMPT-induced differences in plasma BDNF levels were positively correlated with the AMPT-induced differences in reward learning in the whole sample (p = 0.05). Across conditions, plasma BDNF levels were higher in rBN subjects compared to controls (diagnosis effect; p = 0.001). Plasma BDNF and leptin levels were higher in the morning before compared to after a standardized breakfast across groups and conditions (time effect; p < 0.0001). The plasma leptin levels were higher under catecholamine depletion compared to placebo in the whole sample (treatment effect; p = 0.0004). Conclusions: This study reports on preliminary findings that suggest a catecholamine-dependent association of plasma BDNF and reward learning in subjects with rBN and controls. A role of leptin in reward learning is not supported by this study. However, leptin levels were sensitive to a depletion of catecholamine stores in both rBN and controls.

TMS- EEG Signatures of GABAergic Neurotransmission in the Human Cortex

Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs). It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (<50 ms after TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ∼100 ms after TMS). However, the physiological underpinnings of TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine acting as allosteric-positive modulator at α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the N45 represents activity of α1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia.

Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients

Background: Cyclosporin A (CsA)-treated renal transplant recipients (RTR) exhibit relative hyperhomocystinemia and vascular dysfunction. Folate supplementation lowers homocysteine and has been shown to improve vascular function in healthy subjects and patients with coronary artery disease. The aim of this study was to assess the effects of 3 months of folate supplementation (5 mg/day) on vascular function and structure in RTR. Methods: A double-blind, placebo-controlled crossover study was conducted in 10 CsA-treated RTR. Vascular structure was measured as carotid artery intima media thickness (IMT) and function was assessed as changes in brachial artery diameter during reactive hyperemia (RE) and in response to glyceryl trinitrate (GTN). Function data were analyzed as absolute and percent change from baseline and area under the diameter/time curve. Blood samples were collected before and after supplementation and analyzed for total plasma homocysteine, folate, vitamin B-12 and asymmetric dimethyl arginine (ADMA) in addition to regular measures of hemoglobin, hematocrit, mean corpuscular volume (MCV) and serum creatinine. Results: Folate supplementation significantly increased plasma folate by 687% (p < 0.005) and decreased homocysteine by 37% (p < 0.05) with no changes (p > 0.05) in vitamin B 12 or ADMA. There were no significant (p > 0.05) changes in vascular structure or function during the placebo or the folate supplementation phases; IMT; placebo pre mean +/- SD, 0.52 +/- 0.12, post 0.50 +/- 0.11; folate pre 0.55 +/- 0.17, post 0.49 +/- 10.20 mm 5% change in brachial artery diameter (RH, placebo pre 10 +/- 8, post 6 +/- 5; folate pre 9 +/- 7, post 7 +/- 5; GTN, placebo pre 18 +/- 10, post 17 +/- 9, folate pre 16 +/- 9, post-supplementation 18 +/- 8). Conclusion: Three months of folate supplementation decreases plasma homocysteine but has no effect on endothelial function or carotid artery IMT in RTR.

Evidencia sobre la eficacia de cannabinoides en el dolor neuropático oncológico

Contexto: La eficacia de los cannabinoides en el dolor neuropático es desconocida. El control del dolor es determinante en los pacientes ya que genera un impacto negativo en la calidad de vida de los pacientes. Objetivo: El presente trabajo pretende demostrar la evidencia sobre la eficacia de los medicamentos cannabinoides en el control del dolor neuropático oncológico, mediante la evaluación de la literatura disponible. Metodología: Se realizó una revisión sistemática de literatura incluyendo estudios experimentales, observacionales y revisiones sistemáticas en un periodo de 15 años. Se incluyeron todos los estudios desde el años 2000 con evidencia IB según la escala de evidencia de Oxford. Resultados: Cuatro estudios cumplieron criterios para su inclusión, sin embargo la evidencia es baja y no permite recomendar o descartar los cannabinoides como terapia coadyuvante en control del dolor neuropático oncológico. La combinación de THC/CDB (Sativex®) parece ser un medicamento seguro pues no se reportaron muertes asociadas a su uso, sin embargo la presentación de eventos adversos a nivel gastrointestinal y neurológico podría aumentar el riesgo de interacciones medicamentosas y tener un impacto negativo en la calidad de vida de los pacientes oncológicos. Conclusiones: No hay suficiente literatura y la evidencia no es suficiente para recomendar o descartar el uso de los cannabinoides en dolor neuropático oncológico. Futuros estudios deben realizarse para analizar el beneficio de estos medicamentos. Aunque ética y socialmente hay resistencia para el uso de los cannabinoides, actualmente hay una gran discusión política en el mundo y en Colombia para su aceptación como terapia en el control del dolor.

Changes in the phenolic content of low density lipoprotein after olive oil consumption in men. A randomized crossover controlled trial

Olive oil decreases the risk of CVD. This effect may be due to the fatty acid profile of the oil, but it may also be due to its antioxidant content which differs depending on the type of olive oil. In this study, the concentrations of oleic acid and antioxidants (phenolic compounds and vitamin E) in plasma and LDL were compared after consumption of three similar olive oils, but with differences in their phenolic content. Thirty healthy volunteers participated in a placebo-controlled, double-blind, crossover, randomized supplementation trial. Virgin, common, and refined olive oils were administered during three periods of 3 weeks separated by a 2-week washout period. Participants were requested to ingest a daily dose of 25 ml raw olive oil, distributed over the three meals of the day, during intervention periods. All three olive oils caused an increase in plasma and LDL oleic acid (P,0·05) content. Olive oils rich in phenolic compounds led to an increase in phenolic compounds in LDL (P,0·005). The concentration of phenolic compounds in LDL was directly correlated with the phenolic concentration in the olive oils. The increase in the phenolic content of LDL could account for the increase of the resistance of LDL to oxidation, and the decrease of the in vivo oxidized LDL, observed in the frame of this trial. Our results support the hypothesis that a daily intake of virgin olive oil promotes protective LDL changes ahead of its oxidation.

Preemptive dexamethasone and etoricoxib for pain and discomfort prevention after periodontal surgery: A double-masked, crossover, controlled clinical trial

Background: Several anti-inflammatory drugs have been used to reduce pain and discomfort after periodontal surgeries. This study evaluates the efficacy of using etoricoxib and dexamethasone for pain prevention after open-flap debridement surgery. Methods: For this prospective, double-masked, crossover, placebo-controlled, randomized clinical trial, open-flap debridement surgeries were performed on 15 patients (eight males and seven females, age range 20 to 56 years: mean age ± SD: 40 ± 9.7 years) who presented with chronic periodontitis after nonsurgical periodontal therapy at three quadrants. Each patient underwent three surgical procedures at intervals of 30 days and received one of the following premedication protocols 1-hour before surgery: group 1 = placebo, group 2 = 8 mg dexamethasone, and group 3 = 120 mg etoricoxib. Rescue medication (750 mg acetaminophen) was given to each patient who was instructed to take it when necessary. Pain intensity and discomfort were evaluated by a 101-point numeric rate scale and a four-point verbal rate scale, respectively, hourly for the first 8 hours after surgery and three times a day on the following 3 days. Results: The results demonstrate that groups 2 and 3 present reduced postoperative pain-intensity levels compared to group 1. There were statistically significant differences at the 4, 5, 6, 7, and 8 hour-periods after surgery (Friedman test; P<0.05). Furthermore, rescue-medication intake was significantly lower for groups 2 and 3 than for group 1 (analysis of variance; P<0.02). Conclusion: The adoption of a preemptive medication protocol using etoricoxib or dexamethasone may be considered effective for pain and discomfort prevention after open-flap debridement surgeries.

Budesonide Reverses Lung Hyperinflation in Childhood Asthma: a Controlled Study

Budesonide (800 mg bid, for 2 months) was administered to 12 asthmatic children (mean age, 11.293.3 years) with lung hyperinflation (TGV]130% predicted and:or RV]140% predicted) in a randomised, placebo controlled, double blind, crossover study. Body plethysmography (panting frequency controlled at 1·s 1) was performed at the beginning, 2 months afterwards (before crossover) and at the end of the study. Budesonide significantly reduced TGV (2.3590.90 l BTPS or 126924% predicted) compared with placebo (2.5491.08 l BTPS, P 0.014 or 140921% predicted, PB0.05). In addition, budesonide significantly increased mean specific conductance (0.0690.02 cm H2O 1 l s 1 to 0.0790.01 cm H2O 1 l s 1, PB0.05). It was concluded that budesonide reduced lung hyperinflation most likely by decreasing airway inflammation.

Double-blinded, randomized controlled trial comparing real versus placebo acupuncture to improve tolerance of diagnostic esophagogastroduodenoscopy without sedation: a study protocol

Background Sedation prior to performance of diagnostic esophagogastroduodenoscopy (EGDE) is widespread and increases patient comfort. But 98% of all serious adverse events during EGDEs are ascribed to sedation. The S3 guideline for sedation procedures in gastrointestinal endoscopy published in 2008 in Germany increases patient safety by standardization. These new regulations increase costs because of the need for more personnel and a prolonged discharge procedure after examinations with sedation. Many patients have difficulties to meet the discharge criteria regulated by the S3 guideline, e.g. the call for a second person to escort them home, to resign from driving and working for the rest of the day, resulting in a refusal of sedation. Therefore, we would like to examine if an acupuncture during elective, diagnostic EGDEs could increase the comfort of patients refusing systemic sedation. Methods/Design A single-center, double blinded, placebo controlled superiority trial to compare the success rates of elective, diagnostic EGDEs with real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic EGDE who refuse a systemic sedation are eligible. 354 patients will be randomized. The primary endpoint is the rate of successful EGDEs with the randomized technique. Intervention: Real or placebo acupuncture before and during EGDE. Duration of study: Approximately 24 months. Discussion Organisation/Responsibility The ACUPEND - Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Interdisciplinary Endoscopy Center (IEZ) of the University Hospital Heidelberg is responsible for design and conduct of the trial, including randomization and documentation of patients' data. Data management and statistical analysis will be performed by the independent Institute for Medical Biometry and Informatics (IMBI) and the Center of Clinical Trials (KSC) at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg.

The butterbur extract petasin has no effect on skin test reactivity induced by different stimuli: a randomized, double-blind crossover study using histamine, codeine, methacholine, and aeroallergen solutions

BACKGROUND: Petasin (Ze 339) was recently introduced on the market as a potent herbal antiallergic drug for treatment of respiratory allergies such as hay fever. Few clinical studies have been performed so far addressing the clinical effectiveness of Ze 339. OBJECTIVE: To evaluate the antiallergic properties of Ze 339 using skin prick tests with different stimuli, such as codeine, histamine, methacholine, and a relevant inhalant allergen. METHODS: A randomized, double-blind, placebo-controlled study was performed in which Ze 339 was compared to acrivastine, a short-acting antihistamine, in 8 patients with respiratory allergy and in 10 nonatopic, healthy volunteers. Antiallergic activity of Ze 339 was determined by analyzing inhibitory potency in skin prick tests with codeine, histamine, methacholine, and an inhalant allergen. Wheal-and-flare reactions were assessed 90 minutes after a double dose of Ze 339, acrivastine, or placebo. An interval of at least 3 days was left between the skin tests. RESULTS: Acrivastine was identified as the only substance that significantly inhibited skin test reactivity to all solutions analyzed in all study subjects. In contrast, no significant inhibition could be demonstrated for Ze 339 with any test solution. Moreover, the results of Ze 339 did not differ significantly from placebo. CONCLUSIONS: In this study we found no antiallergic, particularly antihistaminic, effect of Ze 339 in skin tests using a variety of stimuli often used to evaluate immediate skin test reactivity. The mechanism by which Ze 339 is effective in the treatment of seasonal allergic rhinitis still needs to be elucidated.

Consumption of a flaxseed-rich food is not more effective than a placebo in alleviating the climacteric symptoms of postmenopausal women

Our objective in this work was to test the effects of daily intake of bread produced with partially defatted ground flaxseed on the climacteric symptoms and endometrial thickness of postmenopausal women. A double-blind, placebo-controlled, randomized clinical trial was performed with 38 women who had been postmenopausal for 1–10 y and consumed 2 slices of bread containing 25 g of flaxseed (46 mg lignans) or wheat bran (<1 mg lignans; control) every day for 12 consecutive weeks. The outcome variables were the daily number of hot flashes, the Kupperman Menopausal Index (KMI), and endometrial thickness. The plasma lipid profile (total cholesterol and HDL, LDL, and VLDL cholesterol fractions and triglycerides) and the hormones estradiol, follicle-stimulating hormone, thyroid-stimulating hormone, and free thyroxine also were measured. Food intake was evaluated by means of 2 24-h recalls, before and after the treatment. Twenty patients in the study group and 18 in the control group completed the study. The general characteristics did not differ between the 2 groups at the start of the study. Both had significant, but similar, reductions in hot flashes and KMI after 3 mo of treatment. Moreover, endometrial thickness was not affected in either group. Our findings clearly show that although flaxseed is safe, its consumption at this level (46 mg lignans/d) is no more effective than placebo for reducing hot flashes and KMI

Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis

Background: Although meta-analyses have shown that placebo responses are large in Major Depressive Disorder (MDD) trials; the placebo response of devices such as repetitive transcranial magnetic stimulation (rTMS) has not been systematically assessed. We proposed to assess placebo responses in two categories of MDD trials: pharmacological (antidepressant drugs) and non-pharmacological (device-rTMS) trials. Methodology/Principal Findings: We performed a systematic review and meta-analysis of the literature from April 2002 to April 2008, searching MEDLINE, Cochrane, Scielo and CRISP electronic databases and reference lists from retrieved studies and conference abstracts. We used the keywords placebo and depression and escitalopram for pharmacological studies; and transcranial magnetic stimulation and depression and sham for non-pharmacological studies. All randomized, double-blinded, placebo-controlled, parallel articles on major depressive disorder were included. Forty-one studies met our inclusion criteria-29 in the rTMS arm and 12 in the escitalopram arm. We extracted the mean and standard values of depression scores in the placebo group of each study. Then, we calculated the pooled effect size for escitalopram and rTMS arm separately, using Cohen's d as the measure of effect size. We found that placebo response are large for both escitalopram (Cohen's d-random-effects model-1.48; 95% C.I. 1.26 to 1.6) and rTMS studies (0.82; 95% C.I. 0.63 to 1). Exploratory analyses show that sham response is associated with refractoriness and with the use of rTMS as an add-on therapy, but not with age, gender and sham method utilized. Conclusions/Significance: We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself.

Treatment of vitamin D deficiency increases lower limb muscle strength in institutionalized older people independently of regular physical activity: a randomized double-blind controlled trial

Aims: To investigate the effects of a 6-month supplementation with calcium and cholecalciferol on biochemical parameters and muscle strength of institutionalized elderly. Methods: This prospective, double-blind, placebo-controlled, randomized trial included Brazilian institutionalized people 6 60 years of age receiving a 6-month supplementation ( December to May) of daily calcium plus monthly placebo (calcium/placebo group) or daily calcium plus oral cholecalciferol (150,000 IU once a month during the first 2 months, followed by 90,000 IU once a month for the last 4 months; calcium/vitamin D group). Fasting blood samples for 25-(OH) D, PTH and calcium determination were collected (n = 56) and muscle tests were performed ( n = 46) to measure the strength of hip flexors (SHF) and knee extensors (SKE) before ( baseline) and after the 6-month intervention ( 6 months). Results: Due to seasonal variations, serum 25( OH) D significantly enhanced in both groups after treatment, but the calcium/vitamin D group had significantly higher 25-(OH) D levels than the calcium/placebo group (84 vs. 33%, respectively; p < 0.0001). No cases of hypercalcemia were observed. While the calcium/placebo group showed no improvement in SHF and SKE at 6 months (p = 0.93 and p = 0.61, respectively), SHF was increased in the calcium/vitamin D group by 16.4% (p = 0.0001) and SKE by 24.6% (p = 0.0007). Conclusions: The suggested cholecalciferol supplementation was safe and efficient in enhancing 25(OH)D levels and lower limb muscle strength in the elderly, in the absence of any regular physical exercise practice. Copyright (C) 2009 S. Karger AG, Basel