GABAergic modulation in central sensitization in humans: a randomized placebo-controlled pharmacokinetic-pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers

Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.

The treatment of chronic progressive multiple sclerosis with cladribine.

A 2-year, placebo-controlled, double-blind, crossover study was started in 1992 to evaluate cladribine, an immunosuppressive drug, in the treatment of chronic progressive multiple sclerosis. In the first year patients were given cladribine 0.10 mg/kg per day for 7 days as four monthly courses for a total of 2.8 mg/kg or placebo. During the second year patients treated with placebo during the first year were given i.v. infusions of 0.10 mg, 0.05 mg, and 0.05 mg of cladribine per kg of body weight per day for 7 consecutive days in three successive monthly courses, for a total dose of 1.4 mg/kg. Patients who had been treated previously with cladribine were crossed over to placebo. Analysis of the results revealed a favorable influence on the neurological performance scores, both in the Kurtze extended disability status and the Scripps neurological rating scale, and on MRI findings in patients treated with cladribine. In the first year the most striking finding was that while clinical deterioration continued in the placebo-treated patients, the condition of patients who received cladribine stabilized or even improved slightly. Toxicity and therapeutic response were dose-related.

The Effect of Fructose vs. Glucose Beverages on Low-Grade Systemic Inflammation

Thesis (Ph.D.)--University of Washington, 2016-04

Lithium for schizophrenia revisited: A systematic review and meta-analysis of randomized controlled trials

Background: Clinicians frequently use lithium to augment antipsychotic medication in schizophrenia. Therefore, we undertook a systematic review and meta-analysis of the use of lithium in the treatment of schizophrenia. Data sources and study selection: Randomized controlled trials examining lithium (as a sole or an adjunctive compound) in participants with schizophrenia or related disorders were searched in the register of the Cochrane Schizophrenia Group. No language restrictions were applied. The Boolean phrase [lithium* or lithicarb or eskalith or lithobid or lithane or cibalith-s or quilonum or hypnorex] was used to locate articles. The search strategy initially identified 90 references. The authors of the included studies were contacted to obtain original patient data. The data were combined in a meta-analysis. The main outcome parameters were the number of patients with a clinically significant response and the number of patients leaving the studies early. Results: The meta-analysis includes 20 studies (N = 611). The evidence shows that lithium as a sole agent is ineffective in the treatment of schizophrenia. Eleven trials examined the augmentation of antipsychotics with lithium. More patients who received lithium augmentation than those who received antipsychotics alone were classified as responders. However, the superiority was not consistent across different response thresholds, and when patients with prominent affective symptoms were excluded from the analysis, the advantage of lithium augmentation was not significant (p = .07). Significantly more patients taking lithium left the trials early, suggesting a lower acceptability of lithium augmentation compared with that of taking antipsychotics alone. Conclusion: Despite some evidence in favor of lithium augmentation, the overall results are inconclusive. A large trial of lithium augmentation of antipsychotic medications will be required in order to detect a benefit of small effect size in patients with schizophrenia who lack affective symptoms.

An n-of-1 trial service in clinical practice: Testing the effectiveness of stimulants for attention-deficit/hyperactivity disorder

OBJECTIVE. We sought to describe the clinical use of n-of-1 trials for attention-deficit/hyperactivity disorder in publicly and privately funded family and specialized pediatric practice in Australia. METHODS. We used a within-patient randomized, double-blind, crossover comparison of stimulant (dexamphetamine or methylphenidate) versus placebo or alternative stimulant using 3 pairs of treatment periods. Trials were conducted from a central location using mail and telephone communication, with local supervision by the patients' clinicians. PATIENTS. Our study population included children with clinically diagnosed attention-deficit/ hyperactivity disorder who were aged 5 to 16 years and previously stabilized on an optimal dose of stimulant. They were selected because treatment effectiveness was uncertain. MAIN OUTCOME MEASURES. Our measures included number of patients recruited, number of doctors who used the service, geographic spread, completion rates, response rate, and post-n-of-1 trial decisions. RESULTS. Forty-five doctors across Australia requested 108 n-of-1 trials, of which 86 were completed. In 69 drug-versus-placebo comparisons, 29 children responded better to stimulant than placebo. Immediately posttrial, 19 of 25 drug-versus-placebo responders stayed on the same stimulant, and 13 of 24 nonresponders ceased or switched stimulants. In 40 of 63 for which data were available, posttrial management was consistent with the trial results. For all types of n-of-1 trials, management changed for 28 of 64 children for whom information was available. DISCUSSION. Attention-deficit/hyperactivity disorder n-of-1 trials can be implemented successfully by mail and telephone communication. This type of trial can be valuable in clarifying treatment effect when it is uncertain, and in this series, they had a noticeable impact on short-term management.

Effects of oral vitamin C on monocyte:Endothelial cell adhesion in healthy subjects

Monocyte recruitment and retention in the vasculature is influenced by oxidative stress and is involved in cardiovascular disease (CVD). Individuals with low plasma ascorbate are at elevated risk of CVD. It is unknown whether vitamin C supplementation affects monocyte adhesion to endothelial cells (ECs) in healthy non-smokers. In a randomised double-blind crossover study the effect of vitamin C supplementation (six weeks, 250 mg/day) was determined in subjects with normal (HIC) and below average (LOC) plasma vitamin C concentration at baseline (mean = 67μM, n = 20, mean = 32μM, n = 20, respectively). LOC subjects showed 30% greater monocyte adhesion to ECs. This was significantly reduced by 37% (P < 0.02) following vitamin C supplementation to levels of HIC monocyte adhesion. No differences in plasma malondialdehyde concentrations were observed between groups or after supplementation. In conclusion, vitamin C supplementation normalises monocyte adhesion in subjects with low plasma vitamin C (LOC). This process may be related to a direct effect on monocytes, independent of lipid peroxidation. © 2002 Elsevier Science (USA). All rights reserved.

Vitamin C supplementation in normal subjects reduces constitutive ICAM-1 expression

Regulation of monocyte adhesion molecule gene expression is via redox sensitive transcription factors. We have investigated whether dietary antioxidant supplementation with vitamin C (250mg/day) can modulate monocyte ICAM-1 expression in healthy male subjects with low plasma vitamin C at baseline. In a randomised, double-blind, crossover study, monocyte ICAM-1 mRNA was analysed using quantitative reverse transcriptase PCR. Protein was determined by flow cytometry (monocytes) and ELISA (plasma). Monocyte numbers were unaltered by supplementation. Subjects with low plasma vitamin C (<50μM) prior to supplementation expressed higher levels of monocyte ICAM-1mRNA, and showed a significant (50%) reduction in ICAM-1mRNA expression after 6 weeks of 250mg/day vitamin C supplementation (p<0.05). This was paralleled by a reduction in sICAM-1 (p<0.05). For the first time, these results show that dietary vitamin C can modulate monocyte ICAM-1 gene expression in vivo, where regulation of gene expression represents a novel mechanism for benefit from dietary antioxidants. © 2003 Elsevier Inc. All rights reserved.

Dietary supplementation with vitamin C but not vitamin E reduces constitutive expression of ICAM-1 in peripheral blood monocytes of normal subjects with low plasma vitamin C levels

Monocytes play a central role in inflammatory responses through systemic antigen presentation and cytokine secretion. Regulation of monocyte adhesion molecule and inflammatory gene expression is via redox sensitive transcription factors. Therefore we have investigated the hypothesis that dietary antioxidant supplementation with vitamins C (250mg/d) or E (400iU/d) for six weeks can modulate monocyte ICAM-1 expression in healthy male subjects with low plasma vitamin C at baseline. In a randomised, double-blind, crossover study, ICAM-1 mRNA and protein was analysed using quantitative RTPCR with ELISA measurement of PCR products and by flow cytometry and ELISA respectively. Monocyte numbers were unaltered by supplementation. Subjects with low plasma vitamin C (<50uM) prior to supplementation expressed higher levels of monocyte ICAM-1 mRNA, and showed a significant (50%) reduction in ICAM-1 mRNA expression after 6 weeks of 250mg/d vitamin C supplementation compared to subjects with normal plasma vitamin C. This was paralleled by a reduction in plasma sICAM-1. Vitamin E supplementation had no effect on ICAM-1 expression. For the first time, these results show that dietary vitamin C can modulate monocyte ICAM-1 gene expression in vivo, where regulation of gene expression represents a novel mechanism for benefit from dietary antioxidants.

Link between increased gut hormones signaling satiety and reduced food reward following gastric bypass surgery for obesity

CONTEXT: Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. OBJECTIVE: To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression. DESIGN: These were randomized, placebo-controlled, double-blind, crossover experimental medicine studies. PATIENTS: Two groups, more than 5 months after RYGB for obesity (n = 7-11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies. INTERVENTION: Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task. MAIN OUTCOME MEASURES: Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups. RESULTS: Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1. CONCLUSIONS: Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food.

Air Pollution and High Density Lipoprotein Structure and Function

Thesis (Ph.D.)--University of Washington, 2016-06

Comparison of two oral probiotic preparations in a randomized crossover trial highlights a potentially beneficial effect of Lactobacillus paracasei NCC2461 in patients with allergic rhinitis.

BACKGROUND: There is promising but conflicting evidence to recommend the addition of probiotics to foods for prevention and treatment of allergy. Based on previous studies with fermented milk containing Lactobacillus paracasei NCC2461, we aimed to compare the effect of a powder form of the latter probiotic with the effect of a blend of Lactobacillus acidophilus ATCC SD5221 and Bifidobacterium lactis ATCC SD5219 in patients with allergic rhinitis. METHODS: A double-blind, randomized, cross-over study, involving 31 adults with allergic rhinitis to grass pollen, was performed outside the grass pollen season (registration number: NCT01233154). Subjects received each product for 4-weeks in two phases separated by a wash-out period of 6 to 8 weeks. A nasal provocation test was performed before and after each 4-week product intake period, and outcome parameters (objective and subjective clinical symptoms; immune parameters) were measured during and/or 24 hours after the test. RESULTS: Out of the 31 subject enrolled, 28 completed the study. While no effect was observed on nasal congestion (primary outcome), treatment with NCC2461 significantly decreased nasal pruritus (determined by VAS), and leukocytes in nasal fluid samples, enhanced IL-5, IL-13 and IL-10 production by peripheral blood mononuclear cells in an allergen specific manner and tended to decrease IL-5 secretion in nasal fluid, in contrast to treatment with the blend of L. acidophilus and B. lactis. CONCLUSIONS: Despite short-term consumption, NCC2461 was able to reduce subjective nasal pruritus while not affecting nasal congestion in adults suffering from grass pollen allergic rhinitis. The associated decrease in nasal fluid leukocytes and IL-5 secretion, and the enhanced IL-10 secretion in an allergen specific manner may partly explain the decrease in nasal pruritus. However, somewhat unexpected systemic immune changes were also noted. These data support the study of NCC2461 consumption in a seasonal clinical trial to further demonstrate its potentially beneficial effect.

Rivastigmine for HIV-associated neurocognitive disorders: A randomized crossover pilot study.

OBJECTIVE: To assess the efficacy and safety of rivastigmine for the treatment of HIV-associated neurocognitive disorders (HAND) in a cohort of long-lasting aviremic HIV+ patients. METHODS: Seventeen aviremic HIV+ patients with HAND were enrolled in a randomized, double-blind, placebo-controlled, crossover study to receive either oral rivastigmine (up to 12 mg/day for 20 weeks) followed by placebo (20 weeks) or placebo followed by rivastigmine. Efficacy endpoints were improvement on rivastigmine in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and individual neuropsychological scores of information processing speed, attention/working memory, executive functioning, and motor skills. Measures of safety included frequency and nature of adverse events and abnormalities on laboratory tests and on plasma concentrations of antiretroviral drugs. Analyses of variance with repeated measures were computed to look for treatment effects. RESULTS: There was no change on the primary outcome ADAS-Cog on drug. For secondary outcomes, processing speed improved on rivastigmine (Trail Making Test A: F(1,13) = 5.57, p = 0.03). One measure of executive functioning just failed to reach significance (CANTAB Spatial Working Memory [strategy]: F(1,13) = 3.94, p = 0.069). No other change was observed. Adverse events were frequent, but not different from those observed in other populations treated with rivastigmine. No safety issues were recorded. CONCLUSIONS: Rivastigmine in aviremic HIV+ patients with HAND seemed to improve psychomotor speed. A larger trial with the better tolerated transdermal form of rivastigmine is warranted. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that rivastigmine is ineffective for improving ADAS-Cog scores, but is effective in improving some secondary outcome measures in aviremic HIV+ patients with HAND.

A randomised crossover study investigating the effects of galacto-oligosaccharides on the faecal microbiota in men and women over 50 years of age

Faecal microbial changes associated with ageing include reduced bifidobacteria numbers. These changes coincide with an increased risk of disease development. Prebiotics have been observed to increase bifidobacteria numbers within humans. The present study aimed to determine if prebiotic galacto-oligosaccharides (GOS) could benefit a population of men and women of 50 years and above, through modulation of faecal microbiota, fermentation characteristics and faecal water genotoxicity. A total of thirty-seven volunteers completed this randomised, double-blind, placebo-controlled crossover trial. The treatments – juice containing 4 g GOS and placebo – were consumed twice daily for 3 weeks, preceded by 3-week washout periods. To study the effect of GOS on different large bowel regions, three-stage continuous culture systems were conducted in parallel using faecal inocula from three volunteers. Faecal samples were microbially enumerated by quantitative PCR. In vivo, following GOS intervention, bifidobacteria were significantly more compared to post-placebo (P = 0·02). Accordingly, GOS supplementation had a bifidogenic effect in all in vitro system vessels. Furthermore, in vessel 1 (similar to the proximal colon), GOS fermentation led to more lactobacilli and increased butyrate. No changes in faecal water genotoxicity were observed. To conclude, GOS supplementation significantly increased bifidobacteria numbers in vivo and in vitro. Increased butyrate production and elevated bifidobacteria numbers may constitute beneficial modulation of the gut microbiota in a maturing population.

The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial

Rationale: There has recently been increasing interest in the potential of flavanols, plant derived compounds found in foods such as fruit and vegetables, to ameliorate age-related cognitive decline. Research suggests that cocoa flavanols improve memory and learning, possibly as a result of their anti-inflammatory and neuroprotective effects. These effects may be mediated by increased cerebral blood flow (CBF), thus stimulating neuronal function. Objectives: The present study employed arterial spin labelling (ASL) functional magnetic resonance imaging (FMRI) to explore the effect of a single acute dose of cocoa flavanols on regional CBF. Methods: CBF was measured pre and post consumption of low (23mg) or high (494mg) 330ml equicaloric flavanol drinks matched for caffeine, theobromine, taste and appearance according to a randomised counterbalanced crossover double-blind design in eight males and ten females, aged 50-65 years. Changes in perfusion from pre to post consumption were calculated as a function of each drink. Results: Significant increases in regional perfusion across the brain were observed following consumption of the high flavanol drink relative to the low flavanol drink, particularly in the anterior cingulate cortex (ACC) and the central opercular cortex of the parietal lobe. Conclusions: Consumption of cocoa flavanol improves regional cerebral perfusion in older adults. This provides evidence for a possible acute mechanism by which cocoa flavanols are associated with benefits for cognitive performance.

Pleiotropic Effects With Equivalent Low-density Lipoprotein Cholesterol Reduction: Comparative Study Between Simvastatin and Simvastatin/Ezetimibe Coadministration

Background: Coadministration of any statin with ezetimibe is as effective as using high doses of the same statin in the reduction Of tow-density lipoprotein cholesterol (LDL-c). There may be other effects called pleiotropics. Objective: To compare the effectiveness of 2 different treatments that obtain equivalent LDL-c reductions (80 mg of simvastatin, once a clay and coadministration of 10 mg of simvastatin and 10 mg of ezetimibe, once a day) over endothelial function and inflammation. Methods: Twenty-three randomized patients with hypercholesterolemia in a 2 X 2 crossover protocol were Studied. Endothelial function was analyzed by ultrasound assessment of endothelial dependent flow-mediated vasodilation of the brachial artery, and inflammation was estimated by high-sensitivity C-reactive protein (hs-CRP). Results: LDL-c reduction was similar between the 2 treatments with simvastatin/ezetimibe and with simvastatin (P < 0.001); no difference between treatments was found (P = 0.968). Both treatments improved significantly the endothelial function [3.61% with simvastatin/ezetimibe (P = 0.003) and 5.08%. with simvastatin (P < 0.001)]; no difference was found between the 2 treatments (P = 0.291). hs-CRP had a 23% reduction with simvastatin/ezetimibe (P = 0.004) and a 30% reduction with simvastatin alone (P = 0.01), with no significant difference between the 2 treatments (P = 0.380). Conclusion: The 2 forms of treatment presented similar pleiotropic effects: improvement in endothelial function and decrease in hsCRP levels.