Double-blind Placebo-controlled Crossover Study Research Articles

Enhanced Bioavailability and Immune Benefits of Liposome-Encapsulated Vitamin C: A Combination of the Effects of Ascorbic Acid and Phospholipid Membranes

The bioavailability of vitamin C, or ascorbic acid, depends on limiting transport mechanisms that may be bypassed by liposome-encapsulation. The goal for this study was to evaluate the uptake, antioxidant, and immune-modulating effects of liposome-encapsulated vitamin C (LEC) using Lypo-Spheric® technology, compared to three controls: ascorbic acid (AA), the phospholipid fraction composing the liposome, and placebo. A double-blinded placebo-controlled cross-over study design involved twelve healthy participants attending four clinic visits. At each visit, a baseline blood draw was performed, followed by consumption of 1 g LEC, 1 g AA, the phospholipid component of LEC, or placebo. Additional blood draws were performed at 2, 4, and 6 h. Consuming LEC and AA increased blood levels of vitamin C; the levels were significantly higher after consuming LEC at all timepoints when compared to AA (p < 0.01). LEC consumption increased serum antioxidant capacity (p < 0.01 at 2 h) and protection. Consuming LEC increased IFN-γ levels at 6 h, while consuming the phospholipid fraction rapidly decreased inflammatory cytokines IL-6, MCP-1, and MIP-1α at 2 h. Consuming LEC provided enhanced vitamin C bioavailability and antioxidant protection compared to AA. Consuming the phospholipids had anti-inflammatory effects. The results suggest that LEC provides antioxidant and immune benefits above AA, useful in preventive medicine.

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.

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.

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.

Ketamine reduces the neural distinction between self- and other-produced affective touch: a randomized double-blind placebo-controlled study

A coherent sense of self is crucial for social functioning and mental health. The N-methyl-D-aspartate antagonist ketamine induces short-term dissociative experiences and has therefore been used to model an altered state of self-perception. This randomized double-blind placebo-controlled cross-over study investigated the mechanisms for ketamine’s effects on the bodily sense of self in the context of affective touch. Thirty healthy participants (15 females/15 males, age 19–39) received intravenous ketamine or placebo while performing self-touch and receiving touch by someone else during functional MRI – a previously established neural measure of tactile self-other-differentiation. Afterwards, tactile detection thresholds during self- and other-touch were assessed, as well as dissociative states, interoceptive awareness, and social touch attitudes. Compared to placebo, ketamine administration elicited dissociation and reduced neural activity associated with self-other-differentiation in the right temporoparietal cortex, which was most pronounced during other-touch. This reduction correlated with ketamine-induced reductions in interoceptive awareness. The temporoparietal cortex showed higher connectivity to somatosensory cortex and insula during other- compared to self-touch. This difference was augmented by ketamine, and correlated with dissociation strength for somatosensory cortex. These results demonstrate that disrupting the self-experience through ketamine administration affects neural activity associated with self-other-differentiation in a region involved in touch perception and social cognition, especially with regard to social touch by someone else. This process may be driven by ketamine-induced effects on top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. These findings provide further evidence for the intricate relationship of the bodily self with the tactile sense.

Subcutaneous injection of lidocaine around ischemic ankle provides safe and effective foot analgesia in patients with critical limb ischemia.

It is often difficult to alleviate foot pain associated with critical limb ischemia (CLI) using common analgesics. Neuraxial block is contraindicated in anticoagulant therapy. This study was designed to determine the response to subcutaneous injection of lidocaine around the network of peripheral nerves around the ankle in patients with CLI pain on anticoagulants and antiplatelets. Sixteen patients with CLI pain in the foot were enrolled in this double-blind placebo-controlled crossover study. Patients were randomized to receive either 2% lidocaine or saline via catheters inserted into the subcutaneous area around the ankle. After recurrence of pain, the patients were crossed over to receive the alternative treatment. Pain was assessed with a numerical rating scale (NRS) before and 15min after injection. Patients used a descriptive scale to grade pain control and were asked to determine the duration of analgesia in each arm of the study. No serious complications including protracted bleeding occurred. Lidocaine significantly decreased the NRS on movement from 10 (6, 10) [median (range)] to 2 (0, 10) (p < .001), and the differences in the Δ change in NRS between lidocaine and placebo were significant (p = .009). Of the 16 patients, 14 patients were very satisfied after lidocaine but only one described the same after saline. The effect of lidocaine and placebo lasted 11 (0, 28) and 1 (0, 22) h, respectively. Subcutaneous injection of lidocaine around the ischemic ankle affectively alleviated pain in patients with CLI without serious adverse effects under anticoagulant therapy.

Impact of curcumin supplementation on exercise performance and muscle damage after a soccer match: a double-blind placebo-controlled cross-over study.

Curcumin ingestion can mitigate muscle damage, soreness, and inflammation following a laboratory-based eccentric exercise. Similar effects were observed in recent field-based studies wherein responses were evaluated after a soccer match. However, various potential confounding factors, such as matching opponent skill levels and daily training conditions, may have influenced the outcomes. In the present study, we investigated whether curcumin intake ameliorates changes in muscle damage markers following a soccer match while controlling for the potential confounding factors. Fifteen collegiate athletes were tested in a randomized, double-blind, cross-over manner. They were recruited from the same college soccer team and thus followed the same daily training regimen and competition levels. Furthermore, athletes positioning during matches were counterbalanced. They consumed either 180mg/day of curcumin or a placebo starting 1h before the match and continuing for 2days after a match (two 45-min plays and a 15-min half-time). Muscle soreness, jump performance (including countermovement jump and rebound jump index), and inflammatory and muscle damage markers (high-sensitive C-reactive protein, serum creatine kinase activity, and urinary N-terminal fragment of titin concentration) were evaluated before and after the match. The washout period between matches was set at 1week. After the match, all markers showed similarity between the placebo and curcumin conditions (all P > 0.208). These findings indicate that ingesting 180mg/day of curcumin may not expedite recovery from muscle damage elicited by soccer matches in collegiate soccer players.

Role of zonisamide in advanced Parkinson’s disease: a randomized placebo-controlled study

BackgroundZonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD.MethodsPD patients with Hoehn and Yahr stage ≥ 2 (“On” state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III “On”, while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson’s disease questionnaire-39 at the final assessment.ResultsSixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group (p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation.ConclusionZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL.Trial registrationClinicaltrials.gov, NCT04182399, in 24/11/2019.

The efficacy and safety of cannabidiol as adjunct treatment for drug-resistant idiopathic epilepsy in 51 dogs: A double-blinded crossover study.

Approximately 30% of dogs with idiopathic epilepsy (IE) are drug-resistant. Recent studies have suggested cannabidiol (CBD) may be an effective anticonvulsant in dogs with IE. To evaluate the addition of CBD to antiseizure drugs (ASDs) on seizure frequency and to report adverse events in dogs with drug-resistant IE. Fifty-one dogs. Dogs having at least 2 seizures per month while receiving at least 1 ASD were included in the trial. Double-blinded placebo-controlled crossover study. The 5 mg/kg/day dosage met futility requirements after 12 dogs, and a dosage of 9 mg/kg/day was used in the next 39 dogs. Dogs were randomly assigned to receive CBD or placebo for 3 months, with a 1-month washout period between oils. Total numbers of seizures and seizure days were recorded. Diagnostic testing was performed periodically throughout the trial. At the 9 mg/kg/day dose, the decrease in total seizure frequency was significant compared with placebo. A 24.1% decrease in seizure days occurred in dogs receiving CBD and a 5.8% increase occurred in dogs receiving placebo (P ≤ .05). No significant difference was found in the number of responders (≥50% decrease in total seizures or seizure days). Liver enzyme activities increased at both dosages. Decreased appetite and vomiting were more common in the CBD phase (P ≤ .05). Cannabidiol decreased total seizures and seizure dayscompared to placebo when administered to dogs PO at 9 mg/kg/day. Liver enzymes should be monitored with administration of CBD in dogs.

Abstract P209: Six Weeks Oral Losartan Treatment Improves Endothelium-dependent Dilation In Normotensive Women With A History Of Preeclampsia

Women with a history of preeclampsia have a 4-fold increased risk of cardiovascular disease compared to women who had a healthy pregnancy. These women demonstrate microvascular endothelial dysfunction, mediated by reduced nitric oxide (NO)-dependent dilation and increased sensitivity to angiotensin II. We hypothesized that systemic angiotensin II type 1 receptor (AT 1 R) inhibition would improve endothelium- and NO-dependent dilation in the microvasculature of women with a history of preeclampsia. Seven normotensive (seated SBP 118±6; DBP 78±6 mmHg) women (33±6 years of age, 11±7 months postpartum) with a history of preeclampsia participated in a double-blind placebo-controlled crossover study. Following 6 weeks of placebo and losartan treatment (50 mg/day), participants wore a 24-hour blood pressure monitor and completed 1 study visit in which 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusions of acetylcholine (ACh, 10 -7 -10 2 mM) or ACh + 15 mM N G nitro L-arginine methyl ester (L-NAME; NO synthase inhibitor) to assess endothelium- and NO-dependent dilation, respectively. Red blood cell flux was measured over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=Doppler flux/mean arterial pressure) and normalized to maximum (%max; 28 mM SNP + 43°C). Systemic losartan treatment augmented endothelium-dependent (losartan: 96±4 vs placebo: 70±14%max; P &lt;0.001) and NO-dependent (losartan: 35±14 vs placebo: 23±8%; P &lt;0.001) dilation. There was no effect of treatment on 24-hour systolic blood pressure (losartan: 117±4 vs placebo: 117±8 mmHg), diastolic blood pressure (losartan: 72±5 vs placebo: 71±5 mmHg) or mean arterial pressure (losartan: 92±4 vs placebo: 92±6 mmHg; all P&gt;0.05 ). Losartan treatment increased endothelium-dependent vasodilation via NO-mediated pathways in the absence of changes in blood pressure in women with a history of preeclampsia. These data suggest that systemic AT 1 R inhibition may be a viable therapeutic approach to treat persistent microvascular dysfunction in otherwise healthy women who have had preeclampsia.

The effects of palatinose on attention and cerebral blood flow in healthy adults: A randomized double-blind placebo-controlled crossover study

ObjectiveThe primary energy source for the brain is glucose, and a continuous supply is required for the brain to work longer. This study aimed to verify the effects of palatinose on attention and cerebral blood flow in healthy adults. MethodsThis randomized, double-blind, placebo-controlled crossover study included 64 healthy Japanese adults. Participants performed the Digit Vigilance Task (DVT) 60 min pre-ingestion (14:00) and 0 (15:00), 60 (16:00), 120 (17:00), and 180 (18:00) min after ingestion of 10 g of either palatinose or glucose. Cerebral blood flow was measured using a wearable 2CH functional near-infrared spectrometer (fNIRS) during each DVT. The participants underwent the Uchida-Kraepelin (UK) test between each DVT to control for fatigue. ResultsDVT reaction times with palatinose intake were significantly shorter than those with glucose intake at 16:00, 17:00, and 18:00 (p = 0.0015, p < 0.001, and p < 0.001, respectively). The change in cerebral blood flow as a function of total hemoglobin level was significantly higher in the palatinose group than in the glucose group (p = 0.018). Regarding the post-UK mood questionnaire, “physically fatigued” and “annoyed” were significantly lower in the palatinose intake group compared to the glucose intake group at 17:00 (p = 0.0445 and p = 0.0318, respectively). Furthermore, “physically fatigued” was significantly lower, and “seriously” was higher in the palatinose intake compared to the glucose intake group at 18:00 (p = 0.00652 and p < 0.001, respectively). ConclusionThese findings suggest that 10 g of palatinose has favorable effects on attention and cerebral blood flow.Trial registration: UMIN000046182.

Use of autologous adipose-derived mesenchymal stem cells for ovarian rejuvenation in poor responder IVF patients: a phase 1 randomized placebo-controlled double-blind crossover study

Background: Despite the application of various methods to augment ovarian responsiveness, the management of poor ovarian responders remains challenging and pregnancy rates following in vitro fertilization are poor. Advances in adult stem cell research and their clinical application has prompted interest in their use in assisted reproduction. We report the first double-blind, randomized, placebo-controlled clinical study using autologous human stromal vascular fraction (SVF) containing adipose-derived stem cells (ADSCs) for ovarian rejuvenation. Materials and methods: Thirty patients were recruited. Twenty-one had lower-than-expected reserves for their age and 9 had premature ovarian insufficiency. Patients were randomized into a placebo group (10) and an intervention group (20). SVF was obtained from adipose tissue following abdominal liposuction; the ADSC component was characterized using flow cytometry. Three equal insertions, adjusted based on ovarian volume, were performed at monthly intervals via an ultrasound-guided transvaginal needle puncture. The SVF was not cultured before transplantation. Those in the placebo group were then crossed over to the intervention group and received a single SVF (maximally concentrated) insertion (crossover group). Results: The median viable SVF cell number inserted per patient over 3 months, and the percentage of mesenchymal stem cells (MSC) thereof, was 1.6×106 and 13.2%, respectively. Resulting anti-Mullerian hormone (AMH) changes were variable over the treatment course with a notable placebo effect. Patients with premature ovarian insufficiency showed no change in AMH, both to intervention and placebo. Despite this, a temporary return of menses was noted in a third of patients while on treatment. Patients with low reserves for age showed an increase in AMH, although not statistically significant when compared to placebo. In the crossover group, insertions were limited to one intervention comprising all cells; here a significantly higher median of 3.4×106 SVF cells were injected containing an average of 16.9% MSCs. No significant change in AMH was noted. To date 12 patients have undergone ovarian stimulation and in vitro fertilization after stem cell therapy; of these 9 have had embryo transfers with a resulting pregnancy rate of 33%. There were also 2 spontaneous pregnancies. Conclusion: Although the application of SVF-derived ADSCs for ovarian rejuvenation remains experimental, the current study provides further support for the safety of this approach and presents encouraging results as to its efficacy in assisted reproduction.

A grape seed and bilberry extract reduces blood pressure in individuals at risk of developing type 2 diabetes: the PRECISE study, a double-blind placebo-controlled cross-over intervention study.

Type 2 Diabetes Mellitus (T2DM) is a major risk factor for the development of cardiometabolic diseases. T2DM prevention is largely based on weight-loss and whole diet changes, but intervention with dietary plant bioactives may also improve metabolic health. To assess whether supplementation with bilberry and grape seed extract for 12 weeks improves cardiometabolic outcomes in individuals at risk of developing T2DM, and to determine whether individual treatment response is associated with differences in gut microbiota composition and levels of phenolic metabolites in blood and feces. In the randomized, double-blind, placebo-controlled, cross-over PRECISE intervention study, 14 participants, aged ≥45 years, with a BMI >28 kg/m2, and having an increased risk of T2DM, received a supplement containing 250 mg of bilberry plus 300 mg of grape seed extract, or 550 mg of a control extract, per day, for 12 weeks each. Blood samples were obtained for the assessment of HbA1c, fasting glucose, oral glucose tolerance tests, insulin, glucagon levels, total, LDL and HDL cholesterol, and phenolic acids. We also assessed advanced glycation end products in the skin, ambulatory 24 hours blood pressure, 7-day dietary intake by weighed food diaries, fecal levels of phenolic metabolites using LC-MS/MS and gut microbiota composition using 16S rRNA gene sequencing analysis. The combined bilberry and grape seed extract did not affect glucose and cholesterol outcomes, but it decreased systolic and diastolic ambulatory blood pressure by 4.7 (p < 0.001) and 2.3 (p = 0.0009) mmHg, respectively. Eight out of fourteen participants were identified as blood pressure 'responders'. These responders had higher levels of phenylpropionic and phenyllactic acids in their fecal samples, and a higher proportional abundance of Fusicatenibacter-related bacteria (p < 0.01) in their baseline stool samples. Long-term supplementation with bilberry and grape seed extract can improve systolic and diastolic blood pressure in individuals at risk of T2DM. Individual responsiveness was correlated with the presence of certain fecal bacterial strains, and an ability to metabolize (epi)catechin into smaller phenolic metabolites.Clinical trial registry number: Research Registry (number 4084).

(162) Safety and Feasibility of Platelet-Rich Plasma Injections for Peyronie’s Disease: A Randomized Double-blind Placebo-controlled Cross-over Study

Abstract Introduction Peyronie’s Disease (PD) is prevalent in approximately 7.1% of the general population. Current treatment approaches include medical therapy and surgical intervention, and intervention only occurs once the disease process has entered the chronic, stable phase. The only FDA-approved medical therapy involves use of intralesional collagenase clostridium histolyticum injection and surgical interventions include tunica albuginea plication, plaque excision without grafting, or placement of penile prothesis. Autologous platelet rich plasma (PRP) may prove to be a viable treatment for this patient population due to its ability to facilitate tissue repair and wound healing via various growth factors. Objective We hypothesized that PRP can be safely utilized in patients with PD, with minimal adverse events. Methods We reviewed data for an initial series of men recruited into an ongoing randomized double-blind placebo-controlled cross-over study at the University of Miami from April 2021 to June 2022. Patients received a total of two injections of PRP or placebo directly into the dominant plaque, separated by two weeks. Patients were observed immediately post-injection and assessed with Visual Analogue Pain Scale, and at follow-up for complications and tolerability. Patients are followed three- and six-months post-injection, of which then the patient crosses over into the other treatment / placebo arm. The patient undergoes goniometer measurement with an artificial erection, IIEF-15 and PDQ questionnaire assessment prior to crossover and at the end of the study. ClinicalTrials.gov Identifier: NCT04512287. Results We report data from 24 men who completed two injections for Arm 1 (PRP or placebo) and 15 men who completed two injections (PRP or placebo) after cross-over. No post-procedural minor adverse events were seen in any of the men. None of the participants reported adverse effects such as penile bruising, swelling, edema, allergy, penile fracture, or mild pain at injection site. Six men completed 6-month follow-up and no complications were reported. No worsening curvature was observed in men completing pre/post evaluations. Conclusions PRP appears to be a safe and feasible treatment modality in patients with PD from our limited data accumulated thus far in our ongoing randomized placebo-controlled trial with PRP for PD. We expect to report efficacy data as soon as it becomes available. Our study is the first study in the USA accruing men with PRP for PD in a clinical trial and believe that safety and efficacy data accumulated from our study will be important for patient counseling. Disclosure No

The effect of acute oral pyridoxine supplementation on peripheral chemoreflex sensitivity in human hypertension

ATP has been identified as an important signalling molecule in the carotid body. Animal models of hypertension have uncovered that ATP transmission via purinergic (P2) receptors increases carotid body tonicity and sensitivity, which drives sympathetic outflow and elevates blood pressure. A naturally occurring metabolite of pyridoxine (Vitamin B6), namely pyridoxal-5-phosphate, is a non-selective P2X receptor antagonist. In this study we tested the hypothesis that oral administration of pyridoxine reduces peripheral chemoreflex sensitivity and blood pressure in human hypertension. 14 treated hypertensive patients (4 men, 71±5 yr, 27±6 kg·m -2 , 156±19/83±8 mmHg) completed a double-blind placebo-controlled crossover study with either oral pyridoxine (600 mg) or placebo. Two-hours later, minute ventilation (V̇ E ), end-tidal partial pressures of oxygen and carbon dioxide (P ET O 2 and P ET CO 2 ), mean arterial pressure (MAP), and heart rate (HR) were recorded during an isocapnic hypoxic rebreathing protocol (target P ET O 2 45mmHg). Cardiorespiratory responses were taken as the change from baseline to peak rebreathing (final 15s). Arterial oxygen saturation (S a O 2 ) was calculated from P ET O 2 using the Severinghaus equation, and peripheral chemoreflex sensitivity taken as ΔV̇ E divided by ΔS a O 2 . Baseline V̇ E (13.02±3.26 vs. 12.68±4.13 L·min -1 , P=0.616), MAP (109±11 vs. 104±10 mmHg, P=0.058), and HR (63±11 vs. 62±8 BPM, P=0.463), were not different between pyridoxine and placebo conditions, respectively. The ΔV̇ E response to isocapnic hypoxia tended to be blunted with pyridoxine compared to placebo (6.88±3.94 vs. 9.87±7.69 L·min -1 ; P=0.188), but this did not reach statistical significance. Similarly, peripheral chemoreflex sensitivity was not different with pyridoxine compared to placebo (-0.46±0.31 vs. -0.64±0.49 L·min -1 ·% -1 , P=0.148). However, individuals with a higher peripheral chemoreflex sensitivity in the placebo condition, displayed a more marked reduction in peripheral chemoreflex sensitivity following pyridoxine (R 2 =0.63, P=0.005). While HR and MAP increased during isocapnic hypoxia (both P&lt;0.001), the magnitude of this response did not differ with pyridoxine or placebo administration. In this preliminary study, oral pyridoxine lowered neither blood pressure nor peripheral chemoreflex sensitivity in human hypertension. However, oral pyridoxine did lower peripheral chemoreflex sensitivity in those hypertension patients in whom baseline peripheral chemoreflex sensitivity (i.e., placebo condition) was highest. It is possible that oral pyridoxine supplementation may be beneficial for those hypertensive patients who exhibit overactivation of their peripheral chemoreflex. Health Research Council of New Zealand (Ref# 19/687), the University of Auckland Faculty Research Development Fund, and the New Zealand Lottery Grants Board (R-LHR-2021-153114). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The interplay between bicarbonate kinetics and gastrointestinal upset on ergogenic potential after sodium bicarbonate intake: a randomized double-blind placebo-controlled trial

This double-blind placebo-controlled cross-over study utilized comprehensive monitoring of blood bicarbonate (HCO3¯) kinetics and evaluation of gastrointestinal (GI) upset to determine their impact on an ergogenic potential of sodium bicarbonate (SB) co-ingested with carbohydrate (CHO). Nineteen CrossFit athletes performed 6 bouts of 15 s Wingate Anaerobic Test (WAnT) 90 min post-ingestion of 0.4 g·kg−1 body mass (BM) of SB (SB + CHO treatment) or PLA (PLA + CHO treatment) with 15 g CHO. Blood HCO3¯ concentration was evaluated at baseline, 30-, 60-, 75- and 90 min post-ingestion, in between WAnT bouts, and 3 and 45 min post-exercise, while GI upset at 120 min after protocol started. Control (no supplementation; CTRL) procedures were also performed. An effective elevation of extra-cellular buffering capacity was observed 60–90 min post-ingestion of SB + CHO. At mean peak blood HCO3¯, or at start of exercise an increase > 6 mmol·L−1 in HCO3¯ was noted in 84% and 52.6% participants, respectively. SB + CHO did not prevent performance decrements in WAnT bouts. There were no significant relationships between changes in blood HCO3¯ and WAnTs’ performance. Total GI was significantly higher in SB + CHO compared to CTRL, and stomach problems in SB + CHO compared to CTRL and PLA + CHO. There were inverse associations between peak- (p = 0.031; r = − 0.495), average- (p = 0.002; r = − 0.674) and minimum power (p = 0.008; r = − 0.585) and total GI upset, as well as average power and severe GI distress (p = 0.042; r = − 0.471) at SB + CHO. The implemented dose of SB + CHO was effective in improving buffering capacity, but did not prevent decrements in WAnTs’ performance. GI side effects were crucial in affecting the ergogenic potential of SB and thus must be insightfully monitored in future studies.

Oral ketone esters acutely improve myocardial contractility in post-hospitalized COVID-19 patients: A randomized placebo-controlled double-blind crossover study.

COVID-19 is associated with subclinical myocardial injury. Exogenous ketone esters acutely improve left myocardial function in healthy participants and patients with heart failure, but the effects have not been investigated in participants previously hospitalized for COVID-19. This is a randomized placebo-controlled double-blind crossover study comparing a single oral ketone ester dose of 395 mg/kg with placebo. Fasting participants were randomized to either placebo in the morning and oral ketone ester in the afternoon or vice versa. Echocardiography was performed immediately after intake of the corresponding treatment. Primary outcome was left ventricular ejection fraction (LVEF). Secondary outcomes were absolute global longitudinal strain (GLS), cardiac output and blood oxygen saturation. Linear mixed effects models were used to assess differences. We included 12 participants previously hospitalized for COVID-19 with a mean (±SD) age of 60 ± 10 years. The mean time from hospitalization was 18 ± 5 months. Oral ketone esters did not increase LVEF between placebo and oral ketone ester [mean difference: -0.7% (95% CI -4.0 to 2.6%), p = 0.66], but increased GLS [1.9% (95% CI: 0.1 to 3.6%), p = 0.04] and cardiac output [1.2 L/min (95% CI: -0.1 to 2.4 L/min), p = 0.07], although non-significant. The differences in GLS remained significant after adjustment for change in heart rate (p = 0.01). There was no difference in blood oxygen saturation. Oral ketone esters increased blood ketones over time (peak level 3.1 ± 4.9 mmol/L, p < 0.01). Ketone esters increased blood insulin, c-peptide, and creatinine, and decreased glucose and FFA (all p ≤ 0.01) but did not affect glucagon, pro-BNP, or troponin I levels (all p > 0.05). In patients previously hospitalized with COVID-19, a single oral dose of ketone ester had no effect on LVEF, cardiac output or blood oxygen saturation, but increased GLS acutely. https://clinicaltrials.gov/, identifier NCT04377035.

Hemodynamic effect of pimobendan following intramuscular and intravenous administration in healthy dogs: A pilot study.

BackgroundPimobendan is widely used for the treatment of dogs with heart failure via the oral route. A new injectable form of pimobendan is now available and its potential usefulness via intravenous route has been recently demonstrated in dogs. However, the cardiovascular effects of intramuscular (IM) administration of injectable pimobendan have not been investigated yet.HypothesisIM administration of pimobendan may have the same hemodynamic effect as the IV route.MethodsSix healthy Beagle dogs underwent a placebo-controlled double-blind crossover study. The early cardiovascular effects after a single dose of IM and IV injections of pimobendan (0.2 ml/kg; Pimo IM and Pimo IV, respectively) were compared to the same volume of IM placebo (Saline IM) in anesthetized dogs. Clinical [heart rate (HR) and blood pressure (BP)] and echocardiographic hemodynamic parameters [left ventricular (LV) inflow waveforms of diastolic early wave (eV), atrial systolic wave (aV), diastolic early mitral ring velocity (e′), peak velocity (pV), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR)] were monitored with 15 min intervals for 120 min.ResultsDiastolic BP decreased significantly at 30 min in Pimo IM compared to Saline IM. Mean eV and CO values significantly increased from 75 min, e′ from 60 min, pV from 75 min, and SV from 15 to 120 min, whereas SVR significantly decreased at 30–60 min in Pimo IM compared to those of Saline IM (P < 0.05). Compared with the Pimo IV, eV and pV were significantly lower at 30–60 min (P < 0.05) while SV was significantly higher at 90–105 min in Pimo IM (P < 0.05). Other hemodynamic parameters (BP, HR, SVR, CO, e′, and E/e′) did not significantly change between Pimo IM and IV.ConclusionsThe hemodynamic effect of pimobendan following IM and IV injection was described. Our results suggested that IM administration of pimobendan is equally comparable and possibly interchangeable with IV administration. This warrant further studies to investigate the clinical effectiveness of IM pimobendan in treating dogs with congestive heart failure or in heart failure cases unable to receive IV or oral administration.

Evaluation of shoseiryuto for seasonal allergic rhinitis, using an environmental challenge chamber

BackgroundComplementary and alternative medicine, including Japanese traditional medicine (JTM), has been used for various allergic diseases, but the evidence is limited. Shoseiryuto (Xiao-Qing-Long-Tang), one of the representative JTM drugs, is frequently used to treat allergic rhinitis (AR). However, its efficacy for seasonal AR has not been fully established. Using an Environmental challenge chamber (ECC), we evaluated the therapeutic effects of shoseiryuto on AR induced by Japanese cedar pollen (JCP). MethodsA placebo-controlled double-blind crossover study with shoseiryuto was conducted using the ECC. The shoseiryuto or placebo was orally administered from 2 weeks before the exposure test. The pollen exposure test was conducted for 3 h, and the pollen concentration was set at 8000 pollen/m3. The primary endpoint of the study was the total nasal symptom score (TNSS) during pollen exposure. A physician certified by the Japanese Society of Oriental Medicine as a specialist checked each participant's “pattern”, a comprehensive expression of signs obtained from individual patients' subjective symptoms and other personal findings. Blood samples collected just before the first pollen exposure were stimulated with cedar antigens and used for immunological studies. ResultsThe results of the 46 participants were analyzed, and no significant side effects were detected. There was no significant difference in TNSS during pollen exposure for 3 h in the ECC between the shoseiryuto and placebo groups. However, some symptoms were improved in the shoseiryuto group after leaving the ECC. There was no significant correlation between the “fluid retention pattern” and TNSS. In immunological studies, shoseiryuto did not inhibit Th2-type cytokine production and mRNA expression. ConclusionsOral administration of shoseiryuto from 2 weeks before pollen exposure did not prevent or inhibit immediate symptoms of AR induced by JCP in the ECC. Further study is needed to reevaluate the shoseiryuto specific “pattern” in JTM.

Chronic Uptake of A Probiotic Nutritional Supplement (AB001) Inhibits Absorption of Ethylalcohol in the Intestine Tract - Results from a Randomized Double-blind Crossover Study.

Background:Regular alcohol consumption, e.g. by social drinking, is a potential source of consecutive health problems in many countries worldwide. A probiotic nutritional supplement (AB001) has been developed to reduce alcohol absorption from the intestine tract and to mitigate potential health care risks.Methods:This randomized placebo-controlled double-blind crossover study was conducted with 24 healthy subjects (13 male, 11 female, age: 25.4 ± 7.7 years, BMI: 23.6 ± 2.5 kg/m²). The subjects were randomized to take 2 capsules/day of AB001 or placebo for 1 week prior to an alcohol exposure experiment. On the experimental day, they ingested a light breakfast and drank a moderate glass of spirit (0.3 g/kg body weight). Breath alcohol tests and blood draws for determination of blood alcohol levels were performed for up to 6 hours. After crossover, the experiment was repeated in the following week. Areas under the curves were calculated to determine alcohol absorption rates.Results:A significant reduction of blood alcohol levels by 70.3% (P < 0.005 vs. placebo) was seen with AB001, (breath test: −30.7%; P < 0.005 vs. placebo). No difference was seen in a cognitive function test performed 60 minutes after alcohol ingestion (22.4 ± 7.7 seconds vs. 22.7 ± 5.6 seconds, n.s.). There were no adverse events or serious adverse events reported in this studyConclusions:One week of supplementation with AB001 resulted in a substantially reduced absorption of alcohol into the body. Regular uptake of AB001 may help to prevent liver and other organ damage, and may reduce the negative medical and economical impact of social drinking on the individual and the society.