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Physiological Reports Jun 2024Methylphenidate (MPH) has been previously shown to increase resting energy expenditure (REE) in individuals of normal weight; however, the effects on individuals living... (Randomized Controlled Trial)
Randomized Controlled Trial
Methylphenidate (MPH) has been previously shown to increase resting energy expenditure (REE) in individuals of normal weight; however, the effects on individuals living with obesity are currently unknown. Ten individuals living with obesity were randomly assigned to undergo 60 days of MPH administration with a daily dose of 0.5 mg/kg body weight or a placebo control. REE was measured before and after the 60-day intervention. There was a trend toward significance for group × time interaction on REE (p = 0.082) with a large effect size (η = 0.331), with MPH administration increasing REE compared to a decrease in placebo control. Preliminary findings from this pilot study show that MPH has the potential to counter the adaptive thermogenic process commonly seen in weight loss. This is a unique finding among pharmacotherapies, as no approved obesity drugs measurably impact REE.
Topics: Humans; Methylphenidate; Male; Female; Obesity; Pilot Projects; Energy Metabolism; Adult; Double-Blind Method; Middle Aged; Central Nervous System Stimulants
PubMed: 38924673
DOI: 10.14814/phy2.16085 -
Diabetes, Obesity & Metabolism Jun 2024To explore differences in imeglimin response among type 2 diabetes (T2D) patient clusters using data-driven cluster analysis.
Differences in imeglimin response in subgroups of patients with type 2 diabetes stratified by data-driven cluster analysis: A post-hoc analysis of imeglimin clinical trial data.
AIM
To explore differences in imeglimin response among type 2 diabetes (T2D) patient clusters using data-driven cluster analysis.
METHODS
Data-driven cluster analysis (non-hierarchical k-means clustering) was performed on randomized, double-blind, imeglimin monotherapy and adjunctive (to insulin) therapy trials based on four baseline variables: (1) disease duration; (2) body mass index (BMI); (3) HbA1c; and (4a) homeostatic model assessment of β-cell function (HOMA-β) (monotherapy trials) or (4b) insulin total daily dose (adjunctive trial).
RESULTS
Four clusters were identified with distinct clinical characteristics in both monotherapy (1-4) and adjunctive therapy (I-IV) trials; clusters 1 and I had lower values across all four indices versus the overall population, clusters 2 and II had a longer diabetes duration, cluster 3 had higher baseline BMI and HOMA-β, and cluster III had higher baseline BMI and insulin total daily dose, while clusters 4 and IV had higher baseline HbA1c. Between-group differences in HbA1c change (95% confidence interval) and effect size (ES) at week 24 varied considerably by cluster (cluster 1: -0.82 [-1.00, -0.63], ES = 1.47; cluster 2: -0.64 [-0.89, -0.39], ES = 1.18; cluster 3: -0.86 [-1.38, -0.33], ES = 0.84; cluster 4: -1.27 [-1.73, -0.82], ES = 1.44). For imeglimin adjunctive therapy, HbA1c improvements were significant versus placebo at week 16, excluding cluster III (cluster I: -0.63 [-0.95, -0.31], ES = 0.88; cluster II: -0.66 [-1.02, -0.30], ES = 1.13; cluster III: -0.31 [-0.73, 0.11], ES = 0.46; cluster IV: -0.82 [-1.29, -0.35], ES = 0.99).
CONCLUSIONS
Differences in imeglimin response were observed among T2D patient clusters. Patient stratification may help with selection of those most probable to respond to imeglimin.
PubMed: 38924336
DOI: 10.1111/dom.15716 -
Cannabis and Cannabinoid Research Jun 2024Cannabis is one of the world's most commonly used substances; however, many questions remain unanswered as to how cannabis impacts the body. Recently, there has been a...
Acute Cannabis Administration Transiently Reduces Mitochondrial DNA in Young Adults: Findings from a Secondary Analysis of a Double-Blind, Placebo-Controlled, Randomized Clinical Trial.
Cannabis is one of the world's most commonly used substances; however, many questions remain unanswered as to how cannabis impacts the body. Recently, there has been a resurgence of research into the effects of plant-derived cannabinoids on mitochondrial health. In particular, a number of studies implicate mitochondrial-Δ9-tetrahydrocannabinol (Δ9-THC) interactions with altered memory, metabolism, and catalepsy in mice. Although the research in this field is expanding rapidly, there is little known about the effects of cannabis on mitochondria health in human subjects either in acute or chronic term use. Blood samples were obtained from a double-blind, placebo-controlled, parallel-group randomized clinical trial in which adults who regularly use cannabis (1-4 days/week) aged 19-25 years were randomized 2:1 to receive either an active (12.5% Δ9-THC) cigarette or placebo (<0.01% Δ9-THC) cigarette containing 750 mg of cannabis before driving simulator testing. DNA was extracted from whole blood using commercial spin columns, followed by measurement of mt-ND1, mt-ND4, and β2M using quantitative polymerase chain reaction. One-way repeated measures analysis of variance (ANOVA) followed by Dunnett's multiple comparisons test was used to observe changes in mitochondrial DNA (mtDNA) copy number over time. A two-tailed Pearsons R test was used to assess correlations between mtDNA copy number and cannabinoid levels (Δ9-THC and metabolites) in blood. We found that exposure to active cannabis containing Δ9-THC, as opposed to placebo, was associated with an acute reduction in mitochondrial DNA copy number in whole blood at 15 min and 1 h after smoking. The observed decrease in mtDNA copy number negatively correlated with blood concentrations of 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), the two primary metabolites of Δ9-THC, but not Δ9-THC itself. Further, the negative correlation between 11-OH THC and THC-COOH concentrations and mtDNA copy number was found in only a subgroup of participants who use cannabis infrequently, suggesting a tolerance effect. These results illuminate mitochondrial alterations attributed to Δ9-THC consumption, which may be mediated by metabolites. These results appear to suggest stronger effects in individuals who consume cannabis less frequently, suggesting some form of tolerance to the effects of Δ9-THC and its metabolites on mtDNA content in whole blood. Mitochondria; mtDNA; cannabis; THC; THC metabolites; blood; THC-COOH; 11-OH-THC.
PubMed: 38923954
DOI: 10.1089/can.2023.0282 -
European Journal of Pain (London,... Jun 2024Placebo analgesic research demonstrates pain reduction after using a placebo analgesic. Recent studies have documented that sometimes possessing a placebo analgesic...
BACKGROUND
Placebo analgesic research demonstrates pain reduction after using a placebo analgesic. Recent studies have documented that sometimes possessing a placebo analgesic induces placebo analgesia. These prior studies used a 'cream' as the stimulus and proposed that the effect is driven by an expectancy of obtaining benefits from the owned analgesic. This paper examines three pivotal components of placebo analgesia: placebo form, ownership and expectancy induced by verbal suggestion. We investigate analgesic expectancy between cream versus oil form of placebo stimulus and systematically isolate the effects of ownership, verbal suggestion and their interaction, comparing with the effect of use, to decipher the dynamics of placebo analgesia.
METHODS
Study 1 (N = 46) evaluated analgesic expectancy between cream and oil. Study 2 (N = 119) exposed participants to a placebo analgesic oil and randomized them into PU (possess and use), PA (possess and anticipate), P (possess-only) or A (anticipate-only) conditions. Pain outcomes were assessed using a cold pressor test. Comparing PA and P conditions assessed the verbal suggestion effect, comparing PA and A conditions evaluated the possession effect, while comparing PU and PA conditions shed light on the use effect.
RESULTS
In Study 1, participants showed comparable analgesic expectancy for cream and oil. In Study 2, both PA and PU groups performed equally well, reporting higher pain threshold, F(3, 115) = 5.14, p = 0.002, = 0.12; and a greater probability of persistent hand submersion than P and A groups, X(3) = 8.06, p = 0.045.
CONCLUSION
The findings highlight the significance of integrating possession with expectancy to induce placebo analgesia, which has clinical implications.
SIGNIFICANCE
This study delves into the intricate dynamics of placebo analgesia, shedding light on the significant influence of ownership and verbal suggestion. Through a meticulous exploration of the relationship between ownership and expectancy induced by verbal suggestion, we propose novel avenues for enhancing placebo responses. This research has implications for clinical practice and pain management strategies, potentially revolutionizing approaches to pain relief and therapeutic outcomes. Our findings contribute to a paradigm shift in understanding placebo analgesia, emphasizing the pivotal interaction between ownership and verbal suggestion.
PubMed: 38923640
DOI: 10.1002/ejp.2303 -
ACR Open Rheumatology Jun 2024Using the modified Rodnan skin score (mRSS) as a surrogate for disease activity, a phase 2a study in patients with systemic sclerosis (SSc) measured efficacy of the...
OBJECTIVE
Using the modified Rodnan skin score (mRSS) as a surrogate for disease activity, a phase 2a study in patients with systemic sclerosis (SSc) measured efficacy of the autotaxin inhibitor ziritaxestat. Mathematical modeling of mRSS was used to predict disease progression, examine candidate trial designs, and predict the probability of successfully discriminating treatment effect.
METHODS
Patients with SSc receiving 600 mg of ziritaxestat or placebo for 24 weeks were included, in addition to data up to week 52 of the open-label extension (OLE). Longitudinal mRSS data were described using a disease progression model; drug effect was a binary variable. Parameters used to predict the OLE mRSS outcome were estimated using data from the 24-week double-blind phase and validated with observed data. Three trial designs were simulated to identify which had the highest probability of detecting a treatment effect. Power to detect a treatment effect was quantified using the simulations.
RESULTS
Maximum decreases from baseline in mRSS were 50.4% (ziritaxestat) and 34.7% (placebo). Study designs based on 300 patients randomized 2:1 or 1:1 to 600 mg of ziritaxestat or placebo had similar probabilities of detecting a significant treatment effect. Power to detect a treatment effect was >80% for all simulations.
CONCLUSION
Disease progression and drug effect could be predicted beyond the range of observed data. This modeling and simulation approach may inform future trial design, including study duration, and predict the probability of success.
PubMed: 38923416
DOI: 10.1002/acr2.11678 -
Journal of Cardiovascular Pharmacology May 2024In vitro investigations have established metformin's capacity to downregulate PCSK9 expression, suggesting a potential beneficial effect on atherogenic lipoprotein...
In vitro investigations have established metformin's capacity to downregulate PCSK9 expression, suggesting a potential beneficial effect on atherogenic lipoprotein particles when combined with metformin therapy. Our objective was to assess whether metformin could mitigate statin-induced adverse effects on PCSK9, thereby improving lipid profiles in patients with coronary artery disease (CAD) but without diabetes. Employing an open-label, placebo-controlled, randomized trial, we randomized patients with CAD but without diabetes into CLA (Cholesterol-Lowering Agents alone: atorvastatin+/-ezetimibe, n=38) and Met+CLA groups (metformin plus CLA, n=33) at a 1:1 ratio. The primary endpoint was the therapeutic impact of one-month metformin combination treatment on LDL-C and PCSK9 levels. Baseline LDL-C and PCSK9 levels were 76.18 mg·dL-1 and 80.54 ng·mL-1, respectively. After one month, metformin significantly reduced LDL-C (-20.81%, P<0.001), enabling 72% of patients to attain guideline-recommended LDL-C goals. Noteworthy reductions in PCSK9 levels (-15.03%, P<0.001) were observed. Moreover, Met+CLA markedly reduced LDL particle number more than CLA alone (-10.65% vs 1.45%, P=0.009), primarily due to diminished small-dense LDL particle count. Mechanistically, our study demonstrated metformin's inhibition of statin-induced PCSK9 expression in human hepatocellular cells. In summary, a one-month metformin combination regimen reduced LDL-C levels in patients with CAD but without diabetes by inhibiting PCSK9 expression.
PubMed: 38922587
DOI: 10.1097/FJC.0000000000001592 -
Revista Gaucha de Enfermagem 2024To analyze the effectiveness of Bach flower therapy compared to placebo in reducing perceived stress levels in primary health care nursing professionals. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To analyze the effectiveness of Bach flower therapy compared to placebo in reducing perceived stress levels in primary health care nursing professionals.
METHOD
Pragmatic, parallel randomized clinical trial conducted with 87 primary care nursing professionals with self-identified stress, from October 2021 to June 2022, in the cities of Osasco and São Paulo, Brazil. The intervention group (n=43) received the collective flower formula, and the placebo group (n=44) received only the diluent. Data analysis was performed using the linear mixed model, and effect size was measured by partial Eta squared, significance level 5%.
RESULTS
Data analysis showed a significant reduction in perceived stress levels within groups (p=0.038). However, there was no significant difference between the study groups (p=0.750). Participants in the intervention group reported a greater perception of changes than participants in the placebo group, but without statistical significance (p=0,089).
CONCLUSION
The floral formula was not more effective than the placebo formula in reducing perceived stress. There was a significant stress reduction among nursing professionals in both study groups, although with a small effect size.
Topics: Humans; Female; Male; Adult; Flowers; Primary Care Nursing; Middle Aged; Occupational Stress; Phytotherapy; Stress, Psychological; Brazil
PubMed: 38922232
DOI: 10.1590/1983-1447.2024.20230132.en -
Journal of Cardiovascular Development... Jun 2024To assess the acute effect of empagliflozin versus dapagliflozin administration on flow-mediated vasodilation in patients with type 2 diabetes mellitus.
AIM
To assess the acute effect of empagliflozin versus dapagliflozin administration on flow-mediated vasodilation in patients with type 2 diabetes mellitus.
DESIGN
A double-blind clinical trial, at the Experimental and Clinical Therapeutics Institute, University Health Sciences Center, at the Universidad de Guadalajara, in inpatients with T2D according to the 2023 ADA criteria.
METHODS
Thirty patients (15 males and 15 females), aged between 35 and 65 years, were included in this study, according to the 2023 ADA criteria. The eligible patients were randomly assigned to three groups: empagliflozin 25 mg once daily, dapagliflozin 10 mg once daily, or placebo once daily. Anthropometric parameters were taken using validated techniques. FMD was measured using a high-resolution semiautomatic ultrasound UNEX-EF 38G (UNEX Co., Ltd., Nagoya, Japan). Arterial tension was determined with the OMRON electronic digital sphygmomanometer (HEM 907 XL, Kyoto, Japan).
RESULTS
The group of patients who received empagliflozin had a significantly lower baseline flow-mediated dilation (FMD) compared to the group receiving dapagliflozin ( = 0.017); at the end of this study, the empagliflozin group achieved a comparable FMD to the dapagliflozin group ( = 0.88).
CONCLUSION
After the treatment period, the empagliflozin and dapagliflozin groups achieved similar FMD, suggesting a class effect.
PubMed: 38921682
DOI: 10.3390/jcdd11060182 -
Journal of Cardiovascular Development... Jun 2024Trimethyl--oxide (TMAO) has been linked to peripheral artery disease (PAD). Taurisolo is a natural, balanced phytocomplex containing resveratrol, quercetin, catechins,...
Trimethyl--oxide (TMAO) has been linked to peripheral artery disease (PAD). Taurisolo is a natural, balanced phytocomplex containing resveratrol, quercetin, catechins, procianidins, gallic acid, and caffeic acid. Numerous studies have shown that Taurisolo reduces the damage of TMAO and exerts a protective effect on endothelial cells (ECs). The aim of this randomized, double-blind, single-center study was to evaluate the effects of Taurisolo on claudication in patients with PAD (Rutheford grade I, category II, Fontaine Classification: Stage IIA, American Medical Association Whole Person Impairment Classification: Class 0-WPI 0%) in two parallel groups of 31 patients. The primary outcomes were an increase in the pain-free walking distance and the ankle/brachial pressure index at the beginning and at the end of the treatment with Taurisolo. The secondary endpoint was the serum TMAO changes. The claudication distance improved by 14.1% in the Taurisolo group and by 2.0% in the placebo group, while the maximal distance increased by 15.8% and 0.6% only, respectively (both < 0.05). The TMAO plasma levels decreased from 3.97 ± 2.13 micromole/L to 0.87 ± 0.48 ( < 0.0001) in the treated group. All these changes were highly significant both in univariate mixed models as well as in the adjusted model. Ultimately, Taurisolo might be an effective intervention to ameliorate intermittent claudication.
PubMed: 38921674
DOI: 10.3390/jcdd11060174 -
Journal of Functional Morphology and... May 2024Hypoxia increases inspiratory muscle work and consequently contributes to a reduction in exercise performance. We evaluate the effects of inspiratory muscle warm-up...
Hypoxia increases inspiratory muscle work and consequently contributes to a reduction in exercise performance. We evaluate the effects of inspiratory muscle warm-up (IMW) on a 10 km cycling time trial in normoxia (NOR) and hypoxia (HYP). Eight cyclists performed four time trial sessions, two in HYP (FiO: 0.145) and two in NOR (FiO: 0.209), of which one was with IMW (set at 40% of maximal inspiratory pressure-MIP) and the other was with the placebo effect (PLA: set at 15% MIP). Time trials were unchanged by IMW (NOR: 893.8 ± 31.5 vs. NOR: 925.5 ± 51.0 s; HYP: 976.8 ± 34.2 vs. HYP: 1008.3 ± 56.0 s; > 0.05), while ventilation was higher in HYP (107.7 ± 18.3) than HYP (100.1 ± 18.9 L.min; ≤ 0.05), and SpO was lower (HYP: 73 ± 6 vs. HYP: 76 ± 6%; ≤ 0.05). A post-exercise-induced reduction in inspiratory strength was correlated with exercise elapsed time during IMW sessions (HYP: r = -0.79; ≤ 0.05; NOR: r = -0.70; ≤ 0.05). IMW did not improve the 10 km time trial performance under normoxia and hypoxia.
PubMed: 38921633
DOI: 10.3390/jfmk9020097