Placebo-controlled Crossover Study Research Articles

As-Needed Pilocarpine for Radiation-Induced Xerostomia in Head and Neck Cancers.

This study aimed to evaluate the efficacy of as-needed pilocarpine for the management of radiation-induced xerostomia. Additionally, the study sought to assess the side effects associated with an as-needed regimen. A randomized, double-blinded, placebo-controlled crossover study was conducted on patients who had undergone radiation therapy for head and neck cancers and developed xerostomia. Participants took pilocarpine or placebo as needed for symptom relief at 2 weeks per treatment, which included a one-week washout period. The primary outcome measure was the severity of dry mouth symptoms, quantified using the Xerostomia Inventory (XI). The primary outcome was the change in the XI score. Among the 20 participants who completed the crossover study, there was a significant reduction in XI scores during the treatment phase with pilocarpine compared to the scores during the placebo phase. The mean difference in XI scores was -18.05 (95% CI: -17.17, -6.13, p < 0.001), with a-49.77 ± 3.22% change (p < 0.001). Only one participant withdrew due to pilocarpine side effects. As-needed pilocarpine administration is effective in relieving symptoms of radiation-induced xerostomia, with fewer side effects and reduced treatment costs compared to fixed-dose regimens. This study guides the potential shift toward flexible dosing strategies in clinical practice, promoting enhanced patient-centered, tailored care and adherence. According to the Oxford Center for Evidence-Based Medicine 2011 level of evidence guidelines Laryngoscope, 134:4542-4548, 2024.

Examining the effect of salbutamol use in ozone air pollution by people with exercise-induced bronchoconstriction.

Previous studies based on animal models have raised concerns about salbutamol use in ozone air pollution with regard to ozone related lung injury. We conducted a double-blind, randomized, placebo-controlled crossover study including 18 subjects diagnosed with EIB by a eucapnic voluntary hyperpnea (EVH) test. Participants completed 30 min of standardized moderate to vigorous exercise in four conditions: ozone plus salbutamol; room air plus salbutamol; ozone plus placebo medication; and room air plus placebo medication. Spirometry, fraction of exhaled nitric oxide, and symptoms were measured before, immediately after, 30 min after and 1 h after exercise. Measurements between the four conditions were compared using percent change from pre to post exercise. There was a statistically significant difference between the salbutamol and placebo medication groups for spirometric variables including FEV1 (Estimate = 6.3, 95% CI: 4.23-8.37, p < 0.001). No differences were observed between ozone and room air exposures. There were no significant differences in FeNO response between experimental conditions. We found that salbutamol improved pulmonary function in individuals with EIB when exercising in ozone and did not increase eosinophilic airway inflammation as indicated by FeNO. This evidence suggests that it is safe for people with EIB to continue to use salbutamol as proscribed when ozone levels are elevated.

The impact of exogenous ketone body suppletion on energy and pH balance in skeletal muscle during exercise in chronic heart failure patients: a prospective randomized double-blind cross-over study

Abstract Background Heart Failure (HF) is characterized by impediments in exercise capacity. Disruptions in the energy metabolism of skeletal muscle contribute to this condition. Pre-clinical and clinical evidence showed that reductions in carbohydrate and FA metabolism in HF may be partially overcome by a compensatory increase in ketone body oxidation and suggest that suppletion of ketone bodies (KB) may improve energy metabolism in HF. Purpose We tested the effect of exogenous KB suppletion on energy and pH balance during cycling exercise using 31P Magnetic Resonance (MR) Spectroscopy of the exercising quadriceps muscle in patients with HF. Methods In a randomized, double-blind, placebo-controlled cross-over study, 14 stable HF patients with reduced ejection fraction and diminished exercise capacity underwent maximal exercise testing in a MR scanner fitted with a cycling ergometer after KB or placebo treatment. Phosphocreatine (PCr) and inorganic phosphate (Pi) resonance amplitudes and frequencies were measured continuously in the quadriceps muscle during rest, exercise and recovery using in-vivo 31P MR spectroscopy (Figure 1). Results Patients had a median age of 66 [53 – 75] years, were 14% female, had a median LVEF of 37% [27 – 40] and circulating NT-pro BNP levels of 411 [182 – 946] pg/mL. Peak oxygen uptake (VO2) was 18.2 [15.2 – 20.3] ml/kg/min, which is 68% [62 – 78%] of predicted. After treatment, exercise performance in terms of cycling duration and workload were comparable between treatment arms (Figure 2). Quadriceps acidification during exercise was larger after KB suppletion compared to placebo (ΔpH: -0.2 [-0.3 - -0.1] vs -0.1 [-0.3 - -0.1] respectively; p=0.041) while quadriceps energy depletion during exercise was not altered by treatment (ΔPi/PCr 0.77 [0.55 – 2.51] vs 0.66 [0.46 – 0.81] respectively; p=0.087). Post-exercise mitochondrial oxidative function was similar between treatment arms (KB: PCr resynthesis rate 48 sec [25 – 59] versus placebo: 42 sec [36 – 63]; p=0.767). Conclusions Ketone body suppletion increased acidification and did not improve energy balance in skeletal muscle during exercise or mitochondrial function during recovery in patients with chronic HF. These results question the value of ketone bodies as treatment to boost muscular energy metabolism during exercise in HF.31P MRS Spectrum during exercise in HFExercise and energy parameters

Ursodeoxycholic Acid for Trans Intestinal Cholesterol Excretion Stimulation: A Randomized Placebo Controlled Crossover Study.

The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE. We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m2, and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (-118.7% versus +2.3%, P<0.001). The fecal neutral sterols did not change (-5.8% versus +18.8%, P=0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus -3.64%, P=0.002) when compared with placebo. UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.

Effect of nutrient support on structural and functional parameters of facial skin

Aims: to study the effect of oral administration of biologically active supplement "VITABEAUTY® Hyaluronic Acid + Resveratrol" on structural and functional parameters of facial skin. Materials and methods: a simple blind placebo-controlled cross-over study was conducted in which 40 female patients aged 30 to 45 years with signs of dryness, decreased hydration and elasticity of facial skin, the first signs of aging and wrinkles took part. The observation was carried out for 10 weeks. The dietary supplement and placebo were taken according to the following scheme: during the first 4 weeks of the study patients received placebo, then the subjects took "VITABEAUTY® Hyaluronic Acid + Resveratrol" for the next 6 weeks. Results: the study participants were not aware of whether they were taking placebo or the dietary supplement "VITABEAUTY® Hyaluronic Acid + Resveratrol" at the moment. Objective assessment of skin condition was carried out 4 and 10 weeks after the beginning of the study in strictly fixed points of anatomical formations of the face: medial part of the forehead and central zone of the right cheek. The software and hardware complex MultiskinTestCenterMC 900 (Courage + Khazakaelectronic GmbH, Germany) was used to evaluate the study of skin functional properties. Moisture content was investigated by the corneometry method based on the measurement of the electrical capacitance of dielectric medium using the "Corneometer®" sensor. Conclusions: sebumetry was assessed by photometric method using a transparent film that fixes the amount of sebum on the epidermis surface using a "Sebumeter®" sensor. The state of epidermis barrier function was investigated by measuring the transepidermal water loss (TEWA) using the sensor "TewametereTM300". The elastic properties of the skin were studied by assessing the degree of skin retraction and straightening under negative pressure of 400 mbar using a "Cutometer®" sensor. Topographic features of the skin were studied using the method of video dermascopy. Also during the study, patients subjectively evaluated the effectiveness of VITABEAUTY® Hyaluronic Acid + Resveratrol supplementation.

Effects of 8days intake of hydrogen-rich water on muscular endurance performance and fatigue recovery during resistance training.

Exercise-induced oxidative stress and inflammation can impair muscular function in humans. The antioxidant and anti-inflammatory properties of molecular hydrogen (H2) highlight its potential to be as an effective nutritional supplement to support muscular function performance in healthy adults. However, the effects of H2 supplementation on muscular endurance performance in trained individuals have not been well characterized. This study aimed to assess the effects of intermittent hydrogen-rich water (HRW) supplementation before, during, and after resistance training on muscular endurance performance, neuromuscular status, and subjective perceptual responses after a 48-h recovery period. This randomized, double-blinded, placebo-controlled cross-over study included 18 trained men aged 19.7 ± 0.9years. Participants in this study were instructed to consume 1,920mL of HRW or pure water (Placebo) daily for 7days. Additionally, participants were required to supplement with HRW or pure water five times during the training day (1,260mL total). This included drinking 210mL 30min and 1min before training, 210mL between training sets, 210mL immediately after training, and 420mL 30min into the recovery period. Participants performed half-squat exercises with the load set at 70% of one repetition maximum for six sets (half-squat exercise performed to repetitions failure each set). We measured the power output and number of repetitions in the free barbell half-squat used to assess muscular endurance performance in participants. The countermovement jump (CMJ) height, total quality recovery scale (TQRS), and muscle soreness visual analog scale (VAS) scores were measured to assess fatigue recovery status after training, as well as at 24 and 48h of recovery. The total power output (HRW: 50,866.7 ± 6,359.9W, Placebo: 46,431.0 ± 9,376.5W, p = 0.032) and the total number of repetitions (HRW:78.2 ± 9.5 repetitions, Placebo: 70.3 ± 9.5 repetitions, p = 0.019) in the H2 supplemented group were significantly higher than in the placebo group. However, there was no statistically significant difference (p< 0.05) between the H2 and placebo groups in CMJ, TQRS, and VAS. Eight days of intermittent HRW intake could significantly improve muscular endurance performance in trained individuals, making it a promising strategy for athletes or fitness enthusiasts looking to boost muscular endurance during resistance training or competitions. However, it should be noted that HRW intake alone may not be adequate to accelerate recovery from muscle soreness or fatigue following high-intensity training.

The glucagon-like peptide-1 and other endocrine responses to alcohol ingestion in women with versus without metabolic surgery.

Glucagon-like peptide-1 (GLP-1)-based therapies, effective in treating obesity and type 2 diabetes, hold potential for reducing alcohol-seeking behaviour. However, the understanding of how alcohol consumption affects endogenous GLP-1 responses-important for understanding GLP-1-based therapies' potential in addressing alcohol misuse-is limited, given the absence of placebo-controlled studies examining these effects. This study aimed to determine the acute effects of alcohol ingestion on GLP-1 and other peptides and evaluate whether metabolic surgery, which increases GLP-1 responses, blood alcohol concentrations (BAC) and alcohol misuse risk, influences this effect. Additionally, we assessed the acute effects of alcohol on plasma glucose and insulin concentrations. Using a placebo-controlled crossover study, we examined hormonal and glucose responses after oral alcohol consumption (0.5g/kg of fat-free mass) versus placebo drinks in 18 women who underwent metabolic surgery <5years ago and in 14 non-operated controls (equivalent in age, body mass index [BMI], race and alcohol consumption patterns). Women had a mean (SD) age of 41 (10) years and a BMI of 33 (5) kg/m2. Compared with the control group, the surgery group exhibited a higher peak BAC (0.99 [0.20] g/L vs. 0.75 [0.16] g/L; P < 0.005). Alcohol decreased GLP-1 by 34% (95% CI, 16%-52%) in both groups and decreased ghrelin more in the control (27%) than in the surgery group (13%). Alcohol modestly decreased plasma glucose and transiently increased insulin secretion in both groups (P < 0.05). However, alcohol lowered blood glucose concentrations to the hypoglycaemic range in 28% of the women in the surgery group versus none in the control group. These findings provide compelling evidence that acute alcohol consumption decreases GLP-1, a satiation signal, elucidating alcohol's 'apéritif' effect. This study also highlights the potential increase in alcohol-related hypoglycaemic effects after metabolic surgery.

Does Colostrum Bovinum Supplementation Affect Swimming Performance in Endurance-Trained Males? A Randomized Placebo-Controlled Crossover Study.

Background/Objectives: Colostrum Bovinum (COL) is recognized for its unique composition and potential ergogenic and immunological benefits. Unlike mature milk, COL is rich in immunoglobulins, lactoferrin, and various growth factors, making it one of the most potent natural immune stimulants. The purpose of this study was to evaluate the effects of 12-weeks of COL supplementation on swimming-specific performance (SSP) and exercise adaptations in endurance-trained male athletes. Methods: Twenty-eight male triathletes and swimmers (age: 31.1 ± 10.2 years; body mass: 81.9 ± 9.0 kg; height: 1.82 ± 0.06 m) participated in a randomized, double-blind, placebo (PLA)-controlled crossover study and received 25 g∙day-1 of COL or PLA for 12 weeks. The study assessed the effects of COL on SSP (8 × 100 m performed at various intensities) and exercise adaptations [heart rate (HR) and blood lactate concentrations ([La-])]. Four main study visits were conducted-before and after COL (COLPRE and COLPOST) and PLA (PLAPRE and PLAPOST) supplementation. Results: COL had no significant effect on SSP. Still, the total time of the SSP test was about ~3.04 s shorter after COL supplementation, and ~7.13 s longer after PLA supplementation. Neither COL nor PLA supplementation affected HR during the SSP test. Post-exercise blood [La-] was significantly reduced after both COL and PLA supplementation. The analysis of SSP results in the consecutive study visits revealed possible existence of the practice effect. Conclusions: Colostrum Bovinum and high-quality milk protein (PLA) seem to be comparably effective in evoking exercise adaptation in endurance-trained male athletes. Long-term crossover supplementation protocols in athletes must consider the impact of possible practice effect when interpreting the outcomes related to exercise performance, but not biochemical or physiological markers of exercise adaptation.

Effect of hormone therapy on personality traits: preliminary evidence in older men and women.

Findings concerning the effects of hormone therapy (HT) on cognition and dementia are mixed, with some trials suggesting increased harm at older ages. Personality, like cognition, changes with dementia, but no clinical trials to date have examined the effects of HT on personality traits. This study aimed to determine the effects of HT on personality traits in older men and women. Secondary data analysis was performed from randomized, double-blind, placebo-controlled cross-over studies of menopausal HT in women and testosterone therapy (TT) in men. Participants were community-dwelling cognitively normal adults (mean age = 75.2 years), including 29 men and 22 women. Three months of hormone intervention (for women, 0.625 mg/day conjugated equine estrogen with or without 2.5 mg/day medroxyprogesterone acetate; for men, 200 mg intramuscular testosterone enanthate every 2 weeks) were crossed over with 3 months of identical placebo with a 3-month washout between intervention phases. The main outcome measure was neuroticism and conscientiousness personality domains and facets assessed with the Revised NEO Personality Inventory (NEO-PI-R) after the active and placebo intervention phases. In linear mixed-effect models, HT in women decreased conscientiousness (p < 0.01) and the conscientiousness facet of achievement striving (p < 0.01), and increased vulnerability, a facet of neuroticism (p < 0.05). Testosterone in men decreased conscientiousness (p < 0.05) and the conscientiousness facet of dutifulness (p < 0.05), and increased vulnerability (p < 0.05). In a preliminary study of healthy older adults, HT and TT formulations produced adverse changes in vulnerability and conscientiousness facets that parallel personality changes in dementia.

Multi-modal and bi-directional effects of a synthetic Δ9-Tetrahydrocannabinol (THC) analogue, Nabilone, on spatio-temporal binding windows: Evidence from the projected hand illusion.

Abnormally widened spatial and temporal binding windows (SBW/TBWs; length of space/time whereby stimuli are considered part of the same percept) are observed in schizophrenia. TBW alterations have been associated with altered sense of agency (hereafter referred to as agency), and an associative relationship between embodiment (body ownership) and agency has been proposed. SBWs/TBWs are investigated separately, but no evidence exists of these being separate in mechanism, system or function. The underlying neural substrate of schizophrenia remains unclear. The literature claims either pro-psychotic or anti-psychotic effects of Δ9-Tetrahydrocannabinol (THC) in patients and healthy individuals, but major support for cannabis in the aetiology of schizophrenia is associative, not causal. To clarify if THC is pro- or anti-psychotic, this single-blind, placebo-controlled within-subjects cross-over study tested several hypotheses. 1) Competing hypotheses that a synthetic THC analogue, Nabilone (NAB, 1-2 mg), would alter measures of agency and embodiment in healthy volunteers (n = 32) similarly, or opposite, to that of in patients with schizophrenia. 2) That there would be significant associations between any NAB-induced alterations in individual agency and embodiment measures in the Projected Hand Illusion (PHI). 3) That there is a unitary spatio-temporal binding window (STBW). A large proportion of individuals did not experience the PHI. Multimodal and bi-directional effects of NAB on the PHI were observed. Evidence of a unitary spatio-temporal binding window (STBW) was observed. NAB widened the STBW in some but narrowed it in others as a function of space and delay. No associations were found between agency and embodiment.

Effects of fructan and gluten on gut microbiota in individuals with self-reported non-celiac gluten/wheat sensitivity—a randomised controlled crossover trial

BackgroundIndividuals with non-celiac gluten/wheat sensitivity (NCGWS) experience improvement in gastrointestinal symptoms following a gluten-free diet. Although previous results have indicated that fructo-oligosaccharides (FOS), a type of short-chain fructans, were more likely to induce symptoms than gluten in self-reported NCGWS patients, the underlying mechanisms are unresolved.MethodsOur main objective was therefore to investigate whether FOS-fructans and gluten affect the composition and diversity of the faecal microbiota (16S rRNA gene sequencing), faecal metabolites of microbial fermentation (short-chain fatty acids [SCFA]; gas chromatography with flame ionization detector), and a faecal biomarker of gut inflammation (neutrophil gelatinase-associated lipocalin, also known as lipocalin 2, NGAL/LCN2; ELISA). In the randomised double-blind placebo-controlled crossover study, 59 participants with self-reported NCGWS underwent three different 7-day diet challenges with gluten (5.7 g/day), FOS-fructans (2.1 g/day), and placebo separately (three periods, six challenge sequences).ResultsThe relative abundances of certain bacterial taxa were affected differently by the diet challenges. After the FOS-fructan challenge, Fusicatenibacter increased, while Eubacterium (E.) coprostanoligenes group, Anaerotruncus, and unknown Ruminococcaceae genera decreased. The gluten challenge was primarily characterized by increased abundance of Eubacterium xylanophilum group. However, no differences were found for bacterial diversity (α-diversity), overall bacterial community structure (β-diversity), faecal metabolites (SCFA), or NGAL/LCN2. Furthermore, gastrointestinal symptoms in response to FOS-fructans were generally not linked to substantial shifts in the gut bacterial community. However, the reduction in E. coprostanoligenes group following the FOS-fructan challenge was associated with increased gastrointestinal pain. Finally, correlation analysis revealed that changes in gastrointestinal symptoms following the FOS-fructan and gluten challenges were linked to varying bacterial abundances at baseline.ConclusionsIn conclusion, while FOS-fructans induced more gastrointestinal symptoms than gluten in the NCGWS patients, we did not find that substantial shifts in the composition nor function of the faecal microbiota could explain these differences in the current study. However, our results indicate that individual variations in baseline bacterial composition/function may influence the gastrointestinal symptom response to both FOS-fructans and gluten. Additionally, the change in E. coprostanoligenes group, which was associated with increased symptoms, implies that attention should be given to these bacteria in future trials investigating the impact of dietary treatments on gastrointestinal symptoms.Trial registrationClinicaltrials.gov as NCT02464150.

Tramadol Effects on Brain Activity During Cognitive and Emotional Empathy for Pain: A Randomized Controlled Study

Pain is perceived not only by personal experience but also vicariously. Pain empathy is the ability to share and understand other’s intentions and emotions in their painful conditions, which can be divided into cognitive and emotional empathy. It remains unclear how centrally acting analgesics would modulate brain activity related to pain empathy and which component of pain empathy would be altered by analgesics. In this study, we examined the effects of the analgesic tramadol on the brain activity for pain empathy in healthy adults. We used 2 tasks to assess brain activity for pain empathy. In experiment 1, we used a well-established picture-based pain empathy task involving passive observation of other’s pain. In experiment 2, we developed a novel pain empathy task to assess brain activity during cognitive and emotional empathy for pain separately in a single task. We conducted a double-blind, placebo-controlled within-subject crossover study with functional magnetic resonance imaging for 33 participants in experiment 1 and 31 participants in experiment 2, respectively. In experiment 1, we found that tramadol decreased activation in the supramarginal gyrus during observation of other's pain compared with placebo. Supramarginal gyrus activation correlated negatively with the thermal pain threshold. In experiment 2, we found that tramadol decreased activation in angular gyrus in cognitive empathy for pain compared with placebo but did not change brain activity in emotional empathy for pain. PerspectiveCentrally acting analgesics such as tramadol may have not only analgesic effects on self-experienced pain but also on the complex neural processing of pain empathy.

Effect of Single-Dose Imipramine on Anal Sphincter Tone in Healthy Women: A Randomized, Placebo-Controlled Study Using Anal Acoustic Reflectometry

Introduction and HypothesisDespite the high prevalence of fecal incontinence, existing treatment options may be inadequate. Drugs that enhance the tone of the anal sphincter complex could potentially be an effective pharmacological approach. This study investigated the effect of the tricyclic antidepressant imipramine on anal sphincter tone in healthy women, employing anal acoustic reflectometry as the evaluating method.MethodsIn a double-blind, randomized, placebo-controlled crossover study, 16 healthy female volunteers were randomized to one of two treatment sequences. The participants attended two study visits separated by at least 7 days’ washout. At each visit, they received a single dose of 50 mg imipramine or matching placebo, in alternating order. We assessed the anal opening pressure under the resting state and during voluntary squeezing of the pelvic floor. Measurements were performed pre-dose and 1 h after drug administration, corresponding to the estimated time of peak plasma concentration of imipramine.ResultsAll participants completed the study. In total, 44% of the participants reported at least one adverse effect, primarily anticholinergic. Compared with placebo, imipramine increased anal opening pressure by 15.2 cmH2O (95% confidence interval [CI] 2.0–28.2 cmH2O, p = 0.03) in the resting state and 15.1 (95% CI 4.2–26.0 cmH2O, p = 0.01) cmH2O during squeezing.ConclusionsThe findings indicate that imipramine increases anal sphincter tone in healthy women. However, further research is required to evaluate its clinical impact on individuals with fecal incontinence. This research also demonstrates the effectiveness of using anal acoustic reflectometry for assessing pharmacological effects on anal sphincter function.

Gaba-producing lactobacilli boost cognitive reactivity to negative mood without improving cognitive performance: A human Double-Blind Placebo-Controlled Cross-Over study

BackgroundPsychobiotic bacteria are probiotics able to influence stress-related behavior, sleep, and cognitive outcomes. Several in vitro and human studies were performed to assess their physiological potential, to find strains having psychotropic activity in humans, and to elucidate the metabolic pathways involved. In our previous in vitro study, we identified two strains Levilactobacillus brevis P30021 and Lactiplantibacillus plantarum P30025, able to produce GABA and acetylcholine, being promising candidates to provide an effect on mood and cognitive performance. AimTo investigate the effects of probiotics in the alleviation on the cognitive performance of moderately stressed healthy adults. Secondary outcomes were related to mood improvement, production of GABA, glutamate, acetylcholine, and choline and modification of the microbiota composition. MethodsA 12-week randomized, double-blind, placebo-controlled, cross-over study investigated the effects of a probiotic formulation (Levilactobacillus brevis P30021 and Lactiplantibacillus plantarum P30025) on psychological, memory, and cognition parameters in 44 (Probiotic = 44, Placebo = 43) adults with a mean age of 29 ± 5.7 years old by CogState Battery test. Subjects-inclusion criteria was a mild-moderate (18.7 ± 4.06) stress upon diagnosis using the DASS-42 questionnaire. ResultsProbiotic treatment had no effect on subjective stress measures. The probiotic formulation showed a significant beneficial effect on depressive symptoms by reducing cognitive reactivity to sad mood (p = 0.034). Rumination significantly improved after intake of the probiotic (p = 0.006), suggesting a potential benefit in reducing the negative cognitive effects associated with depression and improving overall mental health. When stratifying the treated subjects according to the response, we found an increase in the abundance of the probiotic genera in the gut microbiota of positive responders (p = 0.009 for Lactiplantibacillus and p = 0.004 for L.brevis). No relevant correlations were observed between the neurotransmitter concentration in the faecal sample, scores of LEIDS, DASS-42, and cognitive tests. ConclusionWe highlight the potential of this probiotic preparation to act as psycobiotics for the relief of negative mood feelings. The assessment of the psychotropic effects of dietary interventions in human participants has many challenges. Further interventional studies investigating the effect of these psychobiotic bacteria in populations with stressed-related disorders are required including longer period of intervention and larger sample size in order to verify the effects of the treatment on further stress-related indicators.

A pilot study to detect the effects of a green-lipped mussel (Perna canaliculus) nutraceutical on working farm dogs with musculoskeletal abnormalities using accelerometry

ABSTRACT Aims To obtain preliminary data on changes in gait from the use of a green-lipped mussel (Perna canaliculus) extract product in working farm dogs with musculoskeletal abnormalities using accelerometry. Methods: New Zealand working farm dogs (n = 32) with signs of musculoskeletal abnormalities were enrolled in a double-blinded, placebo-controlled cross-over study. Each dog was allocated to one of six groups to receive three trial substances (180 mg full fat green-lipped mussel extract (GLME180); 220 mg full fat green-lipped mussel extract (GLME220); placebo) in one of the six possible different orders. Each trial substance was administered orally once a day for an 8-week period, with a 4-week washout in between each. Dogs wore a collar-mounted triaxial accelerometer for the study duration. Diet and activity were not controlled. Accelerations were recorded continuously and analysed (n = 27) in 10-second activity epochs partitioned into daytime and night-time periods. Analysis of activity during the daytime period was limited to epochs when dogs were gaiting faster than a walk. The median and IQR of activity were determined for the daytime and night-time. Additionally, the 75th and 90th percentiles of daytime activity for each 24-hour period were determined. Mixed effects linear regression models were constructed to determine if each trial substance altered the response variables. Results During the daytime, the 90th percentile was higher when dogs were given GLME220 compared with the placebo (β coefficient 2.6; 95% CI = 0.25–4.94; p = 0.03). Dogs that started the trial with the GLME products had a higher 90th percentile activity compared with dogs that began with the placebo (β coefficient 26.26; 95% CI = 0.45–52.06; p = 0.046). The 75th percentile for activity was not affected by the GLME product. The daytime IQR was larger when dogs were given the GLME180 product compared with the placebo (β coefficient 1.25; 95% CI = 0.12–2.37; p = 0.03). Night-time median activity and the IQR was greater in dogs that started the trial with the GLME products than in dogs that began with the placebo. The night-time IQR for activity was greater for GLME180 than for the placebo. Conclusions Administration of a low dose of the GLME-containing product increased peak activity in working farm dogs with signs of musculoskeletal abnormalities and may improve their performance. Clinical relevance Even mildly affected working farm dogs might benefit from support of their musculoskeletal abnormalities, and this particular GLME-based product shows promise as an adjunct to other management strategies.

The Effect of Low-Dose Colchicine on the Phenotype and Function of Neutrophils and Monocytes in Patients with Chronic Coronary Artery Disease: A Double-Blind Randomized Placebo-Controlled Cross-Over Study.

Recent landmark trials showed that colchicine provides a substantial benefit in reducing major cardiovascular events in patients with coronary artery disease. Yet, its exact mechanism of action is still poorly understood. This study aimed to unravel the effect of colchicine on monocyte and neutrophil phenotype and function. A randomized double-blind placebo-controlled cross-over intervention study was executed in patients with a history of myocardial infarction. In neutrophils, colchicine treatment decreased CD62L expression and NGAL release upon ex vivo stimulation and increased PMA-induced ROS production. The effects of colchicine on monocytes were limited to a decrease in HLA-DR expression in the intermediate and nonclassical monocytes. Also, on the level of RNA expression, colchicine did not affect monocyte phenotype, while affecting various immunomodulating genes in neutrophils. Overall, our study suggests that treatment with colchicine affects neutrophil function, particularly by reducing neutrophil recruitment, lowering concentrations of NGAL, and changing the expression of various genes with immunomodulatory potential, whereas the effect on monocytes is limited.

Effects of levcromakalim in patients with migraine aura without headache: An experimental study.

Levcromakalim has previously been shown to induce attacks of migraine with aura in certain individuals. In this study, we tested the migraine-inducing effect of levcromakalim in a cohort of participants with migraine aura without headache. In a double-blind, randomized, placebo-controlled cross-over study, eight adult participants with migraine with aura received intravenous infusions of levcromakalim and saline. Headache, aura and associated symptoms were evaluated for 24 h following administration of the study drug. The primary endpoint was occurrence of migraine-like attacks with or without aura in the 24-h observation period. Five participants (62.5%) developed migraine of any type following levcromakalim compared with three participants (37.5%) following placebo. No participants developed aura following levcromakalim. Our findings suggest that the aura-inducing effect of levcromakalim is likely not based on direct induction of cortical spreading depression but may involve activation of the trigeminovascular system. This hypothesis should be further explored in future studies. NCT04905654.

Effect of reboxetine and citalopram on anal opening pressure in healthy women: A randomized, double-blind, placebo-controlled crossover study.

In placebo-controlled clinical trials, reboxetine, a selective noradrenaline reuptake inhibitor, increases urethral pressure and relieves stress urinary incontinence symptoms in women. Considering the close connection in neural regulation of the external urethral and anal sphincters, we hypothesized that reboxetine may also enhance anal sphincter pressure. Conversely, it is believed that selective serotonin reuptake inhibitors may contribute to fecal incontinence by reducing anal sphincter pressure. In this study, we investigated the effect of reboxetine and citalopram on anal opening pressure in healthy female volunteers. In a double-blind, three-way crossover trial, 24 female participants received single doses of 40 mg citalopram, 8 mg reboxetine, and matching placebos, with a minimum of 8-day washout between sessions. Using anal acoustic reflectometry, we measured anal opening pressure during both resting and squeezing conditions at the estimated time of peak plasma concentration for both study drugs. Compared with placebo, reboxetine increased anal opening pressure with 23.4 cmH2O (95% confidence interval [CI] 16.5-30.2, p < 0.001) during rest and with 22.5 cmH2O (95% CI 15.2-29.8, p < 0.001) during squeeze. Citalopram did not change anal opening pressure statistically significantly compared to placebo. An 8-mg dose of reboxetine increased anal opening pressure substantially in healthy women, suggesting potential benefits for fecal incontinence symptoms. In contrast, a 40-mg dose of citalopram showed a marginal and statistically insignificant effect on anal opening pressure, indicating that selective serotonin reuptake inhibitors do not contribute to fecal incontinence by reducing anal sphincter tone.

Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial.

Obstructive sleep apnea (OSA) is a highly prevalent disorder with serious health consequences but limited therapeutic options. For a subset of those with OSA, a key underlying mechanism is hypersensitive chemoreflex control of breathing. There is no approved therapy that targets this endotypic trait. Here we determine whether the P2X3 receptor antagonist gefapixant, which is predicted to attenuate hypersensitive carotid chemoreflexes, reduces OSA severity in patients with chemoreflex-dependent OSA. In a randomized placebo-controlled cross-over study, 24 patients with moderate-to-severe OSA (aged 39-68 years, non-CPAP users) whose disorder was partially responsive to supplemental oxygen (chemoreflex-dependent OSA) were treated with gefapixant 180 mg (or placebo) administered as tablets taken orally before bedtime for 7 days and assessed via overnight polysomnography. The primary analysis examined whether gefapixant treatment resulted in a greater reduction in the apnea-hypopnea index (AHI) from baseline than placebo. Gefapixant did not lower the AHI significantly more than placebo; the estimated ratio of the AHI on gefapixant versus placebo was 0.92 [90% CI: 0.73, 1.17]. Notably, nocturnal hypoxemia was increased (ratio of total sleep time with SpO2 <90% on gefapixant versus placebo = 2.08 [90% CI: 1.53, 2.82]), consistent with reduced chemoreflex output. Commonly reported adverse events with gefapixant included ageusia, dysgeusia, oral hypoaesthesia, nausea, somnolence, and taste disorders. Gefapixant, while generally well tolerated, did not reduce OSA severity in patients with chemoreflex-dependent OSA. P2X3 receptor antagonism is unlikely to provide an avenue for therapeutic intervention in OSA. Registry: ClinicalTrials.gov; Name: Safety and Tolerability of Gefapixant (MK-7264) in Participants With Obstructive Sleep Apnea (MK-7264-039); URL: https://clinicaltrials.gov/study/NCT03882801; Identifier: NCT03882801.

Effects of Intranasal Naloxone on Hypoglycemia-Associated Autonomic Failure (HAAF) in Susceptible Individuals.

Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally, yet is not feasible therapeutically. To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF. Randomized, double-blinded, placebo-controlled crossover study. Academic research center. Healthy non-diabetic volunteers. Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2. Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies. Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.