Absorption Kinetics of Berberine and Dihydroberberine and Their Impact on Glycemia: A Randomized, Controlled, Crossover Pilot Trial

Berberine is a natural alkaloid used to improve glycemia but displays poor bioavailability and increased rates of gastrointestinal distress at higher doses. Recently, dihydroberberine has been developed to combat these challenges. This study was designed to determine the rate and extent to which berberine appeared in human plasma after oral ingestion of a 500 mg dose of berberine (B500) or 100 mg and 200 mg doses of dihydroberberine (D100 and D200). In a randomized, double-blind, crossover fashion, five males (26 ± 2.6 years; 184.2 ± 11.6 cm; 91.8 ± 10.1 kg; 17.1 ± 3.5% fat) completed a four-dose supplementation protocol of placebo (PLA), B500, D100, and D200. The day prior to their scheduled visit, participants ingested three separate doses with breakfast, lunch, and dinner. Participants fasted overnight (8–10 h) and consumed their fourth dose with a standardized test meal (30 g glucose solution, 3 slices white bread) after arrival. Venous blood samples were collected 0, 20, 40, 60, 90, and 120 minutes (min) after ingestion and analyzed for BBR, glucose, and insulin. Peak concentration (CMax) and area under the curve (AUC) were calculated for all variables. Baseline berberine levels were different between groups (p = 0.006), with pairwise comparisons indicating that baseline levels of PLA and B500 were different than D100. Berberine CMax tended to be different (p = 0.06) between all conditions. Specifically, the observed CMax for D100 (3.76 ± 1.4 ng/mL) was different than PLA (0.22 ± 0.18 ng/mL, p = 0.005) and B500 (0.4 ± 0.17 ng/mL, p = 0.005). CMax for D200 (12.0 ± 10.1 ng/mL) tended (p = 0.06) to be different than B500. No difference in CMax was found between D100 and D200 (p = 0.11). Significant differences in berberine AUC were found between D100 (284.4 ± 115.9 ng/mL × 120 min) and PLA (20.2 ± 16.2 ng/mL × 120 min, p = 0.007) and between D100 and B500 (42.3 ± 17.6 ng/mL × 120 min, p = 0.04). Significant differences in D100 BBR AUC (284.4 ± 115.9 ng/mL×120 min) were found between PLA (20.2 ± 16.2 ng/mL × 120 min, p = 0.042) and B500 (42.3 ± 17.6 ng/mL × 120 min, p = 0.045). Berberine AUC values between D100 and D200 tended (p = 0.073) to be different. No significant differences in the levels of glucose (p = 0.97) and insulin (p = 0.24) were observed across the study protocol. These results provide preliminary evidence that four doses of a 100 mg dose of dihydroberberine and 200 mg dose of dihydroberberine produce significantly greater concentrations of plasma berberine across of two-hour measurement window when compared to a 500 mg dose of berberine or a placebo. The lack of observed changes in glucose and insulin were likely due to the short duration of supplementation and insulin responsive nature of study participants. Follow-up efficacy studies on glucose and insulin changes should be completed to assess the impact of berberine and dihydroberberine supplementation in overweight, glucose intolerant populations.

Improving Wellness of Operating Room Personnel: A Light-Based Intervention on Perceived Nursing-Related Stress

Background: Nursing is an emotionally demanding and physically draining occupation. Well-being of health care workers is essential to achieve success in care and have good cooperation relationships with other health professionals.Objective: The purpose of this study was to evaluate the effectiveness of a light-based intervention on perceived nursing-related stress in health care personnel working in an operating room environment.Methods: A total of 84 nurses participated in this randomized, cross-over controlled study. Intervention consisted of 4 weeks of bright blue-enriched light exposure using a LED head-mounted portable device (n = 42) or no light exposure (n = 42) separated by a 2-week washout period in a crossover fashion. Participants completes questionnaires for the Nursing Stress Scale (NSS).Results: Intervention and control groups were comparable in terms of demographics, with a median age of 34 (IQR: 27–49) and 69 (82%) female. The mean baseline NSS score was similar in both groups before intervention. The NSS score of the intervention group was significantly lower after intervention than the baseline score: the NSS score difference before and after intervention was 15.1 (SD 7.6) (p < 0.001) and 19.7 (SD 7.5) (p < 0.001) during the two successive periods of intervention, respectively. The cross-group comparison after intervention showed a significantly higher NSS score difference after intervention in the intervention group than the control group: 15.1 (SD 7.6) vs. 1.4 (SD 8.4) (p < 0.001) and 19.7 (SD 7.5) vs. 1.7 (SD 8.9) (p < 0.001) during the two successive periods of intervention, respectively.Conclusion: Alternative person-directed initiatives should be considered to improve the well-being of the health workforce in operating rooms, especially during the coronavirus pandemic.

Impact of Glucosamine Supplementation on Gut Health

Glucosamine (GLU) is a natural compound found in cartilage, and supplementation with glucosamine has been shown to improve joint heath and has been linked to reduced mortality rates. GLU is poorly absorbed and may exhibit functional properties in the gut. The purpose of this study was to examine the impact of glucosamine on gastrointestinal function as well as changes in fecal microbiota and metabolome. Healthy males (n = 6) and females (n = 5) (33.4 ± 7.7 years, 174.1 ± 12.0 cm, 76.5 ± 12.9 kg, 25.2 ± 3.1 kg/m2, n = 11) completed two supplementation protocols that each spanned three weeks separated by a washout period that lasted two weeks. In a randomized, double-blind, placebo-controlled, crossover fashion, participants ingested a daily dose of GLU hydrochloride (3000 mg GlucosaGreen®, TSI Group Ltd., USA) or maltodextrin placebo. Study participants completed bowel habit and gastrointestinal symptoms questionnaires in addition to providing a stool sample that was analyzed for fecal microbiota and metabolome at baseline and after the completion of each supplementation period. GLU significantly reduced stomach bloating and showed a trend towards reducing constipation and hard stools. Phylogenetic diversity (Faith’s PD) and proportions of Pseudomonadaceae, Peptococcaceae, and Bacillaceae were significantly reduced following GLU consumption. GLU supplementation significantly reduced individual, total branched-chain, and total amino acid excretion, with no glucosamine being detected in any of the fecal samples. GLU had no effect on fecal short-chain fatty acids levels. GLU supplementation provided functional gut health benefits and induced fecal microbiota and metabolome changes.

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression

Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were −0.75 points on the HDRS-21 at 2 hours (P = 0.73), −1.41 points at 24 hours (P = 0.52), −4.35 points at week 1 (P = 0.05), and −5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were −0.87 points at 2 hours (P = 0.69), −1.93 points at 24 hours (P = 0.37), −2.44 points at week 1 (P = 0.25), and −7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Local Passive Heat for the Treatment of Hypertension in Autonomic Failure

BackgroundSupine hypertension affects a majority of patients with autonomic failure; it is associated with end‐organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP‐lowering effect in patients with autonomic failure and could be used to treat their supine hypertension.Methods and ResultsIn Protocol 1 (n=22), the acute effects of local heat (40–42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by −19±4 mm Hg (versus 3±4 with sham,P<0.001) owing to decreases in stroke volume (−18±5% versus −4±4%,P=0.013 ) and cardiac output (−15±5% versus −2±4%,P=0.013). In Protocol 2 (proof‐of‐concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water‐perfused heating pad placed under the torso from 10 pmto 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change −28±6 versus −2±6 mm Hg,P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57,P=0.072) and an improvement in the morning upright systolic BP (r=−0.76,P=0.007).ConclusionsLocal heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long‐term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension.RegistrationURL:https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

Caffeine Timing Improves Lower-Body Muscular Performance: A Randomized Trial

Little is known about the optimal time to consume caffeine prior to exercise to maximize the ergogenic benefits of the substance.Purpose: To determine the optimal pre-exercise time interval to consume caffeine to improve lower-body muscular performance. A secondary aim was to identify the presence of any sex differences in responses to timed caffeine administration.Methods: Healthy, resistance-trained males (n = 18; Mean±SD; Age: 25.1 ± 5.7 years; Height: 178.4 ± 7.1 cm; Body mass: 91.3 ± 13.5 kg; Percent body fat: 20.7 ± 5.2; Average caffeine consumption: 146.6 ± 100.3 mg/day) and females (n = 11; Mean ± SD; Age: 20.1 ± 1.6 years; Height: 165.0 ± 8.8 cm; Body mass: 65.8 ± 10.0 kg; Percent bodyfat: 25.8 ± 4.2; Average caffeine consumption: 111.8 ± 91.7 mg/day) participated in this investigation. In a randomized, double-blind, placebo-controlled, crossover fashion, participants consumed 6 mg·kg−1 caffeine or placebo solution at three time points: 2 h prior (2H), 1 h prior (1H), or 30 min prior (30M) to exercise testing. During three visits, caffeine was randomly administered at one time point, and placebo was administered at the other two time points. During one visit, placebo was administered at all three time points. Next, participants performed isometric mid-thigh pulls (IMTP), countermovement vertical jumps (CMVJ), and isometric/isokinetic knee extensor testing (ISO/ISOK).Results: Caffeine administered at 1H significantly improved absolute CMVJ and ISO performance relative to placebo. Mean CMVJ jump height was significantly higher during 1H compared to 30M. However, only caffeine administered at 30M significantly improved absolute measures of isokinetic performance. Analysis of the pooled caffeine conditions revealed that muscular performance was more consistently augmented by caffeine in males compared to females.Conclusions: Pre-exercise caffeine timing significantly modulated participant responses to the substance, with 1H exerting the most consistent ergogenic benefits relative to other time points, particularly compared to 2H. Male participants were found to respond more consistently to caffeine compared to female participants. These results suggest that active individuals can maximize the ergogenic effects of caffeine by consuming the substance ~1 h prior to the point when peak muscular performance is desired.

In Vitro and In Vivo Evaluation of Two Hydroxychloroquine Tablet Formulations: HPLC Assay Development

The relative in vitro and in vivo evaluation of two hydroxychloroquine (HCQ) products was conducted. In vitro studies involved assay, content uniformity and dissolution test, and a two-way crossover fashion were used for in vivo studies. Blood samples were collected at appropriate intervals and HCQ levels were measured using a validated reversed-phase high-performance liquid chromatography (HPLC) method. The drug and the internal standard, chloroquine (CQ), were extracted from blood with diethyl ether, separated and dried under nitrogen gas. Residues were reconstituted in the mobile phase and analyzed at 340 nm on a μ-bondapack C18 (250 × 4.6 mm) HPLC column with acetonitrile:methanol:KH2PO4 (10:10:80) mixture containing 0.01% triethylamine. The standard curve was linear within 50–1,500 ng/mL HCQ (R2 = 0.9996), relative errors were 1.6 to 5%, and the CV% ranged from 7 to 15.4. The resolution factor and RSD were 1.62 and 0.35% and in vitro data of both products met the USP requirements. The 90% confidence intervals for the ratios of the AUC0–96, Cmax and Tmax and their corresponding logarithmically transformed values of generic product over those of Plaquenil® were within the acceptable limit of 0.80–1.20 and 0.80–1.25, respectively. Therefore, the generic HCQ was bioequivalent to the innovator formulation.

Ergogenic Effects of Bihemispheric Transcranial Direct Current Stimulation on Fitness: a Randomized Cross-over Trial

Several types of routines and methods have been experimented to gain neuromuscular advantages, in terms of exercise performance, in athletes and fitness enthusiasts. The aim of the present study was to evaluate the impact of biemispheric transcranial direct current stimulation on physical fitness indicators of healthy, physically active, men. In a randomized, single-blinded, crossover fashion, seventeen subjects (age: 30.9 ± 6.5 years, BMI: 24.8±3.1 kg/m2) underwent either stimulation or sham, prior to: vertical jump, sit & reach, and endurance running tests. Mixed repeated measures anova revealed a large main effect of stimulation for any of the three physical fitness measures. Stimulation determined increases of lower limb power (+ 5%), sit & reach amplitude (+ 9%) and endurance running capacity (+ 12%) with respect to sham condition (0.16<ηp2 < 0.41; p<0.05). Ratings-of-perceived-exertion, recorded at the end of each test session, did not change across all performances. However, in the stimulated-endurance protocol, an average lower rate-of-perceived-exertion at iso-time was inferred. A portable transcranial direct current stimulation headset could be a valuable ergogenic resource for individuals seeking to improve physical fitness in daily life or in athletic training.

High-impact Routines to Ameliorate Trunk and Lower Limbs Flexibility in Women

Several types of routines and methods have been experimented to gain neuro/muscular advantages, in terms of overall range of motion, in athletes and fitness enthusiasts. The aim of the present study was to evaluate the impact of different routines on trunk- and lower limbs flexibility in a sample of young women. In a randomized-crossover fashion, eleven subjects underwent to: hamstrings stretching [S]; hamstrings stretching plus whole-body vibration [S+WBV]; partial-body cryotherapy [Cryo]; rest [Control]. Standing hamstrings stretch performance and sit-and-reach amplitude resulted to be improved with [S+WBV] compared to all other protocols (p<0.05). [Cryo] ameliorated the active knee extension performance with respect to all other interventions (p<0.05). These flexibility improvements were obtained without a loss in the trunk position sense proprioception. These results represent the first evidence that a single session of either vibration or cryotherapy can ameliorate flexibility without losing the trunk position sense proprioception in young women.

Noninvasive Neurally Adjusted Ventilator Assist Ventilation in the Postoperative Period Produces Better Patient-Ventilator Synchrony but Not Comfort

Background. Noninvasive neurally adjusted ventilatory assist (NAVA) has been shown to improve patient-ventilator interaction in many settings. There is still scarce data with regard to postoperative patients indicated for noninvasive ventilation (NIV) which this study elates. The purpose of this trial was to evaluate postoperative patients for synchrony and comfort in noninvasive pressure support ventilation (NIV-PSV) vs. NIV-NAVA. Methods. Twenty-two subjects received either NIV-NAVA or NIV-PSV in an object-blind, prospective, randomized, crossover fashion (observational trial). We evaluated blood gases and ventilator tracings throughout as well as comfort of ventilation at the end of each ventilation phase. Results. There was an effective reduction in ventilator delays (p<0.001) and negative pressure duration in NIV-NAVA as compared to NIV-PSV (p<0.001). Although we used optimized settings in NIV-PSV, explaining the overall low incidence of asynchrony, NIV-NAVA led to reductions in the NeuroSync-index (p<0.001) and all types of asynchrony except for double triggering that was significantly more frequent in NIV-NAVA vs. NIV-PSV (p=0.02); ineffective efforts were reduced to zero by use of NIV-NAVA. In our population of previously lung-healthy subjects, we did not find differences in blood gases and patient comfort between the two modes. Conclusion. In the postoperative setting, NIV-NAVA is well suitable for use and effective in reducing asynchronies as well as a surrogate for work of breathing. Although increased synchrony was not transferred into an increased comfort, there was an advantage with regard to patient-ventilator interaction. The trial was registered at the German clinical Trials Register (DRKS no.: DRKS00005408).