Placebo-controlled Crossover Clinical Trial Research Articles

Efficacy and Safety of Sodium Oxybate in Isolated Focal Laryngeal Dystonia: A Phase IIb Double-Blind Placebo-Controlled Cross-Over Randomized Clinical Trial.

To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double-blind placebo-controlled 2-period cross-over clinical trial in patients with isolated laryngeal dystonia (LD). The study was conducted from January 2018 to December 2021, pausing during the COVID-19pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol-responsive (EtOH+) and alcohol-non-responsive (EtOH-) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures. Compared to baseline, EtOH+ but not EtOH- patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6-26.9; p = 0.008; EtOH-: 98.75% CI = -6.2 to 18.7; p = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75-5.80; p = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7-48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness. Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2024.

Efficacy and Safety of Wilac L Probiotic Complex Isolated from Kimchi on the Regulation of Alcohol and Acetaldehyde Metabolism in Humans.

Alcohol-related hangovers impact both physical and mental wellness, largely due to acetaldehyde levels produced through alcohol metabolism. The present study investigated the efficacy and safety of the Wilac L probiotic complex (Levilactobacillus brevis WiKim0168 and Leuconostoc mesenteroides WiKim0172 isolated from kimchi) in improving hangovers post-alcohol consumption. This study was conducted as a randomized, double-blind, crossover placebo-controlled clinical trial from August 2023 to February 2024. Subjects (n = 26) were randomized into six test groups consuming three products, the Wilac L probiotic complex, Wilac L35 (Wilac L probiotic complex with Pyrus pyrifolia Nakai), or placebo, in different orders with crossover after a wash-out interval of 7-10 days. Blood alcohol and acetaldehyde concentrations were measured 0, 0.25, 0.5, 1, 2, 4, 6, and 15 h after alcohol consumption. The blood acetaldehyde levels measured with Wilac L probiotic complex supplementation were significantly lower than the control at 0.25 (p = 0.0381), 0.5 (p = 0.0498), and 1 h (p = 0.0260) post-consumption. The blood acetaldehyde levels after Wilac L35 consumption compared to the control are significant at 0.25 (p = 0.0115), 0.5 (p = 0.0054), 1 (p = 0.0285), 2 (p = 0.0113), and 6 h (p = 0.0287) post-consumption. No significant adverse events were reported. The Wilac L probiotic complex is associated with decreased blood acetaldehyde levels and improved subjective hangover symptoms.

Effects of GSH on Alcohol Metabolism and Hangover Improvement in Humans: A Randomized Double-Blind Placebo-Controlled Crossover Clinical Trial.

The definition of alcohol hangovers refers to a combination of mental and physical side effects that occur after drinking. One of the ways that hangovers can be ameliorated is by promoting the rapid and effective elimination of acetaldehyde to alleviate the discomfort it causes. This study aimed to investigate the effects of GSH (yeast extract containing 50 mg of glutathione) on the hangover-relieving effect. A randomized double-blind placebo-controlled crossover clinical trial was conducted with 40 participants who reported experiencing hangover symptoms. Participants consumed alcohol at a rate of 0.78 g per kg body weight with 40% whiskey, adjusted according to their weight. Alcohol and acetaldehyde concentrations in serum were analyzed at 0, 0.25, 1, 2, 4, 6, and 15 h after alcohol consumption. In the GSH group, the serum alcohol concentration decreased, although this change was not statistically significant. The serum acetaldehyde concentration was significantly lower in the GSH group in comparison to the placebo group (at 0.25, 1, 4, and 6 h (p < 0.01) and at 0.5, 2, and 15 h (p < 0.001) after alcohol consumption). However, there was no significant difference between the two groups on questionnaires such as the Acute Hangover Scale and the Alcohol Hangover Severity Scale. Overall, we consider the discovery that GSH lowered acetaldehyde concentration, a crucial factor in alcohol metabolism, to be more considerable. Therefore, GSH administration effectively reduces acetaldehyde levels in serum. This result suggests that this effect may contribute to the relief of hangover symptoms.

Atomoxetine on neurogenic orthostatic hypotension: a randomized, double-blind, placebo-controlled crossover trial

PurposeWe previously reported that single doses of the norepinephrine transporter inhibitor, atomoxetine, increased standing blood pressure (BP) and ameliorated symptoms in patients with neurogenic orthostatic hypotension (nOH). We aimed to evaluate the effect of atomoxetine over four weeks in patients with nOH.MethodsA randomized, double-blind, placebo-controlled crossover clinical trial between July 2016 and May 2021 was carried out with an initial open-label, single-dose phase (10 or 18 mg atomoxetine), followed by a 1-week wash-out, and a subsequent double-blind 4-week treatment sequence (period 1: atomoxetine followed by placebo) or vice versa (period 2). The trial included a 2-week wash-out period. The primary endpoint was symptoms of nOH as measured by the orthostatic hypotension questionnaire (OHQ) assessed at 2 weeks.ResultsA total of 68 patients were screened, 40 were randomized, and 37 completed the study. We found no differences in the OHQ composite score between atomoxetine and placebo at 2 weeks (−0.3 ± 1.7 versus −0.4 ± 1.5; P = 0.806) and 4 weeks (−0.6 ± 2.4 versus −0.5 ± 1.6; P = 0.251). There were no differences either in the OHSA scores at 2 weeks (3 ± 1.9 versus 4 ± 2.1; P = 0.062) and at 4 weeks (3 ± 2.2 versus 3 ± 2.0; P = 1.000) or in the OH daily activity scores (OHDAS) at 2 weeks (4 ± 3.0 versus 5 ± 3.1, P = 0.102) and 4 weeks (4 ± 3.0 versus 4 ± 2.7, P = 0.095). Atomoxetine was well-tolerated.ConclusionsWhile previous evidence suggested that acute doses of atomoxetine might be efficacious in treating nOH; results of this clinical trial indicated that it was not superior to placebo to ameliorate symptoms of nOH.Trial registrationClinicalTrials.gov; NCT02316821.

Quercetin intervention reduced hepatic fat deposition in patients with nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled crossover clinical trial

BackgroundNonalcoholic fatty liver disease (NAFLD) has become a growing public health problem worldwide. However, there is still lack of effective treatment strategies except lifestyle intervention. ObjectivesTo evaluate whether quercetin improves intrahepatic lipid content in patients with NAFLD. MethodsIn this randomized, double-blind, placebo-controlled crossover trial, 41 patients with NAFLD were randomly assigned to receive the quercetin (500 mg) or placebo capsules for 12 wk, then switched interventions for another 12 wk after a 4-wk washout period. The primary outcome was intrahepatic lipid content evaluated by magnetic resonance imaging estimated proton density fat fraction. The secondary outcomes were liver function measurements, etc. Safety outcomes included blood routine. ResultsA total of 36 patients completed the trial. In intention-to-treat analyses, the quercetin intervention moderately decreased the intrahepatic lipid contents from 11.5% ± 6.4% to 9.6% ± 5.8%, compared with the placebo intervention (decreased by 0.1% ± 2.6%, P = 0.013 and adjusted P value is 0.028). Body weight and body mass index were mildly reduced by 1.5 ± 2.6 kg and 0.5 ± 0.9 kg/m2 after the quercetin intervention (P < 0.05 and both adjusted P values are 0.038), whereas the reductions were only 0.2 ± 1.8 kg and 0.1 ± 0.7 kg/m2 after the placebo intervention. The intrahepatic lipid content reductions were noticeably positively associated with the body weight losses after the quercetin and placebo interventions (r = 0.557 and 0.412, P < 0.001 and P = 0.007, respectively). Subgroup analyses found that the reduction of intrahepatic lipid contents in females (3.0% ± 3.7%) was about twice as large as that in males (1.4% ± 2.5%) with a trend of statistical significance (P = 0.113 and adjusted P value is 0.061). There were no significant differences in other secondary and safety outcomes. No adverse events associated with study intervention were found. ConclusionsTwelve weeks treatment of quercetin could reduce intrahepatic lipid contents in patients with NAFLD, possibly explained by a slightly larger body weight loss in the quercetin group. Trial RegistrationThe trial is registered at www.chictr.org.cn as ChiCTR2100047904.

Short-Term Effects of Adding Topical Ketorolac to Intravitreal Bevacizumab in Diabetic Macular Edema: A Crossover Randomized Clinical Trial.

To evaluate the short-term additive effects of topical ketorolac to intravitreal bevacizumab (IVB) in the management of center-involved diabetic macular edema (CI-DME). In a randomized double-masked placebo-controlled crossover clinical trial, eyes with CI-DME and the best-corrected visual acuity (BCVA) between (20/40) and (20/400) were included. These eyes should have had at least one intravitreal anti-VEGF injection in the preceding two months. They were randomized into two groups; while both groups received two IVB injections with a six-week interval, one group received topical ketorolac every 6 hr in the first interval and artificial tears every 6 hr as a placebo in the second interval and the other group received the same medications using a crossover method. The main outcome measures were changes in BCVA and central macular thickness (CMT). Fifty-seven eyes of 35 patients with CI-DME were included in the study. The mean BCVA improvement was -0.09 0.47 logMAR in the periods of receiving ketorolac and -0.03 0.12 logMAR in the periods of placebo treatment, respectively (P = 0.99). Corresponding changes in CMT were -13.1 170.1 and +11.7 157.7 µm in the ketorolac and placebo periods, respectively (P = 0.322). The treatment effect was not statistically significant regarding both BCVA and CMT changes. Statistical analysis also disclosed that the carryover effect was insignificant for BCVA and CMT. Although the period effect was not significant for BCVA, it was at a meaningful level for CMT changes (P = 0.012). This crossover clinical trial demonstrated that in the course of DME treatment with IVB injections, topical ketorolac did not have any additive beneficial effect at least during a six-week period.

Immunomodulatory effects of supercritical CO2 extracted oils from Portulaca oleracea and Perilla frutescens (PPCE) in healthy individuals: a randomized double-blind clinical trial.

The human immune system plays a crucial role in defending the body against various infections, viruses, and external substances, contributing to overall well-being. However, an imbalance in the immune system can lead to increased susceptibility to infections, impacting overall health. Preclinical investigations suggest the potential application of Portulaca oleracea L. and Perilla frutescens var. japonica Hara seed complex extract (PPCE) as a potent biological response modifier in terms of immunity. However, the safety and efficacy of PPCE in boosting immune function have not been investigated clinically. The present study aims to evaluate the safety and efficacy of PPCE on the immune system in healthy adults. An 8-week randomized, double-blinded, placebo-controlled cross-over clinical trial was adopted for the study. Study participants were administered either 1080 mg day-1 of a PPCE supplement or a placebo. The study assessed the Natural Killer (NK) cell activity as the primary outcome measure. Serum concentrations of cytokines (IL-6, IL-12, IFN-γ, TNF-α) and a questionnaire-based assessment of upper airway infection were the secondary outcomes. At the end of the 8 weeks, NK cell activity significantly improved in the PPCE group compared to the placebo group (p < 0.05). Similarly, the concentrations of IFN-γ and IL-12 significantly increased (p < 0.05). However, there were no significant differences between the two groups in the cytokines IL-6 and TNF-α. Additionally, no adverse effects were observed during the trial. These findings suggest that PPCE supplementation is safe and potentially benefits immune stimulation by enhancing NK cell activity and inducing the production of Th-1 type cell-stimulating cytokines like IL-12 in healthy individuals.

Acute effects of a chewable beetroot-based supplement on cognitive performance: a double-blind randomized placebo-controlled crossover clinical trial

BackgroundDietary nitrate (NO3−) has been shown to be useful as an ergogenic aid with potential applications in health and disease (e.g., blood pressure control). However, there is no consensus about the effects of dietary NO3− or beetroot (BR) juice supplementation on cognitive function.ObjectiveThe aim of this study was to evaluate the effects of a single dose of a chewable BR-based supplement on cognitive performance.MethodsA double-blind randomized placebo-controlled two-period crossover clinical trial was carried out based on the extension of the CONSORT guidelines for randomized crossover trials. A total of 44 participants (24 F; 20 M; 32.7 [12.5] years; 66.3 [9.0] kg; 170 [9.2] cm; 22.8 [1.4] kg/m2) were randomly allocated to receive first either four BR-based chewable tablets (BR-CT) containing 3 g of a Beta vulgaris extract (RedNite®) or four tablets of a placebo (maltodextrin). A 4-day washout period was used before crossover. Ninety minutes after ingestion of the treatments, a neuropsychological testing battery was administered in each period. The trial was registered at clinicaltrials.gov NCT05509075.ResultsSignificant improvements with moderate effect size were found on memory consolidation at the short and long term only after BR-CT supplementation via the Rey Auditory Verbal Learning Test immediate (+ 20.69%) and delayed (+ 12.34%) recalls. Likewise, enhancement on both frontal lobe functions (+ 2.57%) and cognitive flexibility (+ 11.16%) were detected after BR-CT. There was no significant change (p < 0.05) on verbal memory of short-term digits, working memory and information processing speed. Mixed results were found on mood and anxiety through the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI-Y1 and STAI-Y2); however, sequence and period effects were seen on STAI-Y2.ConclusionsThe acute administration of a chewable BR-based supplement improves certain aspects of cognitive function in healthy females and males, particularly memory capacity and frontal skills.

Effects of sumac supplementation on metabolic markers in adults with metabolic syndrome: a triple-blinded randomized placebo-controlled cross-over clinical trial

BackgroundDespite the prior evidence of the impacts of sumac on glycemic indices, lipid profile and visceral fat, there is a lack of evidence regarding the efficacy of sumac in cases with metabolic syndrome (MetS). Therefore, we aimed to assess the effect of sumac supplementation on MetS markers among adults with this syndrome.MethodsIn this triple-blinded randomized placebo-controlled cross-over clinical trial 47 adults with MetS were randomly assigned to receive 500 mg sumac or placebo (lactose) capsule, twice a day. Each phase took 6 weeks and there was a 2-week washout between phases. All clinical evaluations and laboratory tests were conducted before and after each phase.ResultsAt the baseline of the study, mean (± SD) age, weight, and waist circumference of participants were respectively 58.7 (± 5.8) yr, 79.9 (± 14.3) kg, and 107.6 (± 10.8) cm. Intention to treat analysis (ITT) analyses revealed that sumac supplementation decreased systolic blood pressure by 5 mmHg (128.8 ± 21.4 at the baseline vs. 123.2 ± 17.6 after 6 weeks intervention, P = 0.001). The comparison of changes in two trial arms showed that sumac supplementation significantly reduced systolic blood pressure (sumac group -5.59 ± 10.6 vs. control group 0.76 ± 10.5, P = 0.004), but did not change anthropometric indices or diastolic blood pressure. Similar results were also found in the per-protocol analyses.ConclusionsThis cross-over trial revealed that sumac supplementation could reduce systolic blood pressure in men and women with MetS. Daily intake of 1000 mg sumac, as an adjuvant therapy, may be beneficial in management of MetS in adults.

Eicosapentaenoic and Docosahexaenoic Acid Supplementation Increases HDL Content in n-3 Fatty Acids and Improves Endothelial Function in Hypertriglyceridemic Patients.

High-density lipoproteins (HDLs) are known to enhance vascular function through different mechanisms, including the delivery of functional lipids to endothelial cells. Therefore, we hypothesized that omega-3 (n-3) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content of HDLs would improve the beneficial vascular effects of these lipoproteins. To explore this hypothesis, we performed a placebo-controlled crossover clinical trial in 18 hypertriglyceridemic patients without clinical symptoms of coronary heart disease who received highly purified EPA 460 mg and DHA 380 mg, twice a day for 5 weeks or placebo. After 5 weeks of treatment, patients followed a 4-week washout period before crossover. HDLs were isolated using sequential ultracentrifugation for characterization and determination of fatty acid content. Our results showed that n-3 supplementation induced a significant decrease in body mass index, waist circumference as well as triglycerides and HDL-triglyceride plasma concentrations, whilst HDL-cholesterol and HDL-phospholipids significantly increased. On the other hand, HDL, EPA, and DHA content increased by 131% and 62%, respectively, whereas 3 omega-6 fatty acids significantly decreased in HDL structures. In addition, the EPA-to-arachidonic acid (AA) ratio increased more than twice within HDLs suggesting an improvement in their anti-inflammatory properties. All HDL-fatty acid modifications did not affect the size distribution or the stability of these lipoproteins and were concomitant with a significant increase in endothelial function assessed using a flow-mediated dilatation test (FMD) after n-3 supplementation. However, endothelial function was not improved in vitro using a model of rat aortic rings co-incubated with HDLs before or after treatment with n-3. These results suggest a beneficial effect of n-3 on endothelial function through a mechanism independent of HDL composition. In conclusion, we demonstrated that EPA and DHA supplementation for 5 weeks improved vascular function in hypertriglyceridemic patients, and induced enrichment of HDLs with EPA and DHA to the detriment of some n-6 fatty acids. The significant increase in the EPA-to-AA ratio in HDLs is indicative of a more anti-inflammatory profile of these lipoproteins.

Effects of Descurainia sophia on Oxidative Stress Markers and Thirst Alleviation in Hemodialysis Patients: A Randomized Double-Blinded Placebo-Controlled Cross-Over Clinical Trial.

Patients undergoing hemodialysis (HD) are regularly exposed to oxidative stress and inflammation and may suffer from thirst distress with no definitive treatment to address these complications. Descurainia sophia (DS) has been used to alleviate thirst in traditional Persian medicine. This study aimed to assess the effectiveness of DS on oxidation factors and thirst score in HD patients. This study was conducted on fifty-three HD patients referred to Tehran Shahid Modarres hospital. The patients were randomly divided into two groups: Group 1 received DS for six weeks, then underwent four weeks of washout period followed by six weeks of placebo treatment, while group 2 received placebo initially followed by treatment with DS. Biochemistry, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured in four phases: at the beginning, before washout, after washout, and at the end of the study. The patient's body weight was recorded at the start of each session to assess interdialytic weight gain. Thirst scores also were measured using a visual analog scale. A total of 53 patients, including 23 (43.4%) male and 30 (56.6%) female subjects, were included in the study. The results showed a reduction in thirst score (p=0.001), cholesterol levels (p=0.046), triglycerides (0.003), and MDA (p < 0.001) following the four-week administration of DS treatment in HD patients. The mean levels of TAC were increased (p < 0.001), and calcium, as well as Na+, remained unchanged (p > 0.05). Also, a significant decrease in the patient's weight was observed (p value <0.001). This effect persisted after shifting to a placebo. However, the two groups had no significant difference (p value = 0.539). DS powder-mixed syrup may benefit HD patients by facilitating free radical scavenging and alleviating thirst distress with minimal adverse effects. The seeds could therefore be utilized as a complementary therapy for hemodialysis patients.

Water-Soluble Tomato Concentrate, a Potential Antioxidant Supplement, Can Attenuate Platelet Apoptosis and Oxidative Stress in Healthy Middle-Aged and Elderly Adults: A Randomized, Double-Blinded, Crossover Clinical Trial.

Increased oxidative stress and platelet apoptotic in middle-aged and elderly adults are important risk factors for atherosclerotic cardiovascular disease (ASCVD). Therefore, it is of great significance to control the oxidative stress and platelet apoptosis in middle-aged and elderly adults. Previous acute clinical trials have shown that water-soluble tomato concentrate (WSTC) from fresh tomatoes could exert antiplatelet benefits after 3 h or 7 h, but its effects on platelet apoptosis and oxidative stress are still unknown, especially in healthy middle-aged and elderly adults. This current study aimed to examine the efficacies of WSTC on platelet apoptosis and oxidative stress in healthy middle-aged and elderly adults via a randomized double-blinded placebo-controlled crossover clinical trial (10 weeks in total). A total of 52 healthy middle-aged and elderly adults completed this trial. The results showed that WSTC could increase the serum total antioxidant capacity levels (p < 0.05) and decrease the serum malondialdehyde levels (p < 0.05) after a 4-week WSTC supplementation in healthy middle-aged and elderly adults. Platelet endogenous reactive oxygen species generation (p < 0.05), mitochondrial membrane potential dissipation (p < 0.05) and phosphatidylserine exposure (p < 0.05) were attenuated. In addition, our present study also found that WSTC could inhibit platelet aggregation and activation induced by collagen or ADP after intervention (p < 0.05), while having no effects on adverse events (p > 0.05). The results suggest that WSTC can inhibit oxidative stress and its related platelet apoptosis, which may provide a basis for the primary prevention of WSTC in ASCVD.

Non-invasive instrumental evaluation of Coenzyme Q10 phytosome on endothelial reactivity in healthy non-smoking young volunteers: A double-blind, randomized, placebo-controlled cross-over clinical trial

Non-invasive instrumental evaluation of Coenzyme Q10 phytosome on endothelial reactivity in healthy non-smoking young volunteers: A double-blind, randomized, placebo-controlled cross-over clinical trial

Levetiracetam in Alzheimer's Disease: Do Epileptologists Already Have the Cure?

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial Vossel K, Ranasinghe KG, Beagle AJ, et al. JAMA Neurol. 2021;78(11):1345-1354. doi:10.1001/jamaneurol.2021.3310.Importance:Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).Objective:To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.Design, setting, and participants:The Levetiracetam for Alzheimer’s Disease–Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.Interventions:Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.Main outcomes and measures:The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer’s Disease Assessment Scale—Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.Results:Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, .07 points; 95% CI, −.18 to .32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, .2–14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = .11; P = .02). There were no treatment discontinuations because of adverse events.Conclusions and relevance:In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.

Non-invasive instrumental evaluation of coenzyme Q10 phytosome on endothelial reactivity in healthy non-smoking young volunteers: a double-blind, placebo-controlled cross-over clinical trial

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): University of Bologna Background Coenzyme Q10 (CoQ10) is a natural antioxidant compound that prevents the vascular damage induced by free radicals and the activation of inflammatory signaling pathways. Supplementation with CoQ10 is safe though its bioavailability is generally low, as far as variable depending on the pharmaceutical form of preparation. Recently, the development of phytosome technology has improved the bioavailability of CoQ10 and definitely facilitated its effective use in clinical. Purpose and Methods The present double-blind, randomized, placebo-controlled, cross-over clinical study aimed to investigate the effect on endothelial reactivity and total antioxidant capacity (TAC) of either acute and chronic supplementation with CoQ10 phytosome in a sample of 20 healthy young not smoking subjects. Results The immediate acute effect of dietary supplementation with CoQ10 phytosome on pulse volume (PV) was sustained in the actively treated group in comparison with placebo and the baseline (p&amp;lt; 0.05). Chronic supplementation of the tested pharmaceutical formulation of CoQ10 significantly improved mean arterial pressure and TAC compared to placebo and baseline values (p&amp;lt; 0.05 for both comparisons). In the actively treated group, the effect on dietary supplementation with CoQ10 phytosome on PV was also sustained when compared to the baseline (P&amp;lt;0.05).

Effects of trazodone on behavioral and physiological signs of stress in dogs during veterinary visits: a randomized double-blind placebo-controlled crossover clinical trial.

To determine whether a single dose of trazodone administered to dogs before a veterinary visit reduced their behavioral and physiologic signs of stress and owners' stress during veterinary visits. 20 dogs and their owners. In this randomized double-blinded placebo-controlled crossover clinical trial, dogs with a history of anxiety during veterinary visits were scheduled for 2 veterinary visits 1 week apart and randomly assigned to receive a single oral dose of either trazodone (9 to 12 mg/kg) or a placebo 90 minutes before transport to the veterinary clinic for alternate visits between September 21 and November 3, 2019. For each visit, we collected and assessed owner-completed surveys of dog stress score (DSS) and owner stress score; various investigator-reported scores, including from video-recorded behavior analyses; and patient-related physiologic data. Dogs treated with trazodone versus placebo had lower mean DSSs, assessed by owners for physical examination and assessed by video analysis for time spent in the examination room; lower mean SD of normal-to-normal intervals, root mean square of successive heartbeat interval difference, and respiratory rate; and higher mean heart rate. No meaningful differences were observed in other behavioral or physiologic outcomes, including serum cortisol concentrations. A single dose of trazodone before transport reduced signs of stress during veterinary visits for dogs in the present study and may be useful as an anti-anxiety medication for similarly affected dogs, potentially resulting in higher-quality clinical examinations and improved patient welfare.

Noninvasive instrumental evaluation of coenzyme Q10 phytosome on endothelial reactivity in healthy nonsmoking young volunteers: A double-blind, randomized, placebo-controlled crossover clinical trial.

Coenzyme Q10 (CoQ10 ) is a natural antioxidant compound that prevents the vascular damage induced by free radicals and the activation of inflammatory signaling pathways. Supplementation with CoQ10 is safe though its bioavailability is generally low, as far as variable depending on the pharmaceutical form of preparation. Recently, the development of phytosome technology has improved the bioavailability of CoQ10 and definitely facilitated its effective use in clinical practice. The present double-blind, randomized, placebo-controlled, crossover clinical study aimed to investigate the effect on endothelial reactivity and total antioxidant capacity (TAC) of either acute and chronic supplementation with CoQ10 phytosome in a sample of 20 healthy young nonsmoking subjects. CoQ10 phytosome supplementation acutely improved endothelial reactivity in comparison with baseline and placebo (+4.7% ± 0.9% vs. -0.1%± 0.3% p< 0.05). Middle-term supplementation of the tested pharmaceutical formulation of CoQ10 significantly improved mean arterial pressure (-2.2± 1.1 mmHg vs. 0.2± 0.7 mmHg, p< 0.05 vs. placebo) and TAC (+29.6% ± 3.2% vs. +1.9% ± 0.8%, p< 0.05 vs. placebo). Endothelial reactivity improved compared with baseline following middle-term dietary supplementation with CoQ10 phytosome (+5.7% ± 1.1%, p< 0.05).

Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity

Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD). To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD. The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination. Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence. The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity. Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events. In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD. ClinicalTrials.gov Identifier: NCT02002819.

Effects of Mixing Energy Drinks With Alcohol on Driving-Related Skills.

BackgroundEnergy drinks (EDs) reduce sleepiness and fatigue and improve driving performance whereas alcohol does just the opposite. Although it is a trendy combination among young people, the effects of alcohol mixed with EDs on driving performance have been poorly studied. The aim was to assess if there is an interaction between the effects of both drinks on driving-related skills as well as perceptions about driving ability.MethodsWe conducted a randomized, double-blind, and placebo-controlled 4-way crossover clinical trial. Participants were 16 healthy volunteers. Interventions of 60 g of ethanol and 750 mL of Red Bull (RB) were administered in 2 separated doses. Conditions were alcohol + RB placebo, alcohol + RB, alcohol placebo + RB, and both placebos. Objective performance was assessed using a tracking test and simple reaction time, N-Back, and movement estimation tasks. Additionally, willingness to drive, other subjective effects, and ethanol and caffeine blood concentrations were also measured.ResultsAlcohol increased the time outside the road in the tracking test and increased simple reaction time, but the addition of RB had no main or interaction effects on performance. Nonetheless, driving-related skills after alcohol + RB were better than after alcohol alone. Willingness to drive increased with the combination of drinks. RB also reduced alcohol-induced sedation whereas drunkenness did not change. These effects were seen even though alcohol + RB increased alcohol (14.8%) and caffeine plasma concentrations (17.6%).ConclusionsMixing EDs with alcohol predisposes consumers to drive under alcohol influence, perhaps in part because EDs counteract its detrimental effects on driving-related skills. Clinicaltrials.gov: NCT02771587.

Regulation of Alcohol and Acetaldehyde Metabolism by a Mixture of Lactobacillus and Bifidobacterium Species in Human.

Excessive alcohol consumption is one of the most significant causes of morbidity and mortality worldwide. Alcohol is oxidized to toxic and carcinogenic acetaldehyde by alcohol dehydrogenase (ADH) and further oxidized to a non-toxic acetate by aldehyde dehydrogenase (ALDH). There are two major ALDH isoforms, cytosolic and mitochondrial, encoded by ALDH1 and ALDH2 genes, respectively. The ALDH2 polymorphism is associated with flushing response to alcohol use. Emerging evidence shows that Lactobacillus and Bifidobacterium species encode alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) mediate alcohol and acetaldehyde metabolism, respectively. A randomized, double-blind, placebo-controlled crossover clinical trial was designed to study the effects of Lactobacillus and Bifidobacterium probiotic mixture in humans and assessed their effects on alcohol and acetaldehyde metabolism. Here, twenty-seven wild types (ALDH2*1/*1) and the same number of heterozygotes (ALDH2*2/*1) were recruited for the study. The enrolled participants were randomly divided into either the probiotic (Duolac ProAP4) or the placebo group. Each group received a probiotic or placebo capsule for 15 days with subsequent crossover. Primary outcomes were measurement of alcohol and acetaldehyde in the blood after the alcohol intake. Blood levels of alcohol and acetaldehyde were significantly downregulated by probiotic supplementation in subjects with ALDH2*2/*1 genotype, but not in those with ALDH2*1/*1 genotype. However, there were no marked improvements in hangover score parameters between test and placebo groups. No clinically significant changes were observed in safety parameters. These results suggest that Duolac ProAP4 has a potential to downregulate the alcohol and acetaldehyde concentrations, and their effects depend on the presence or absence of polymorphism on the ALDH2 gene.