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Brain Sciences Jun 2024Porcine Liver Decomposition Product (PLDP) was obtained by treating pig liver homogenate with protease and filling it into capsules. We have already confirmed from three...
Porcine Liver Decomposition Product (PLDP) was obtained by treating pig liver homogenate with protease and filling it into capsules. We have already confirmed from three clinical trials that PLDP enhances visual memory and delays memory recall, and we believe that its activity is due to various phospholipids, including phosphatidylcholine (PC). In this study, we clinically evaluated PLDP for depressive symptoms caused by a decline in cognitive function. This clinical trial was conducted using the Revised Hasegawa Dementia Scale (HDS-R). The HDS-R (maximum score is 30 points) is a test similar to the Mini-Mental State Examination (MMSE), which is commonly used in Japan. Dementia is suspected if the score falls below 20 on the HDS-R. Additionally, in a previous clinical trial, there was no change in scores in the placebo group after three doses of the HDS-R. In order to clearly confirm the effectiveness of PLDP, this study was conducted under stricter conditions (HDS-R points of 15 to 23) than previous clinical trials (all participants had scores of 20 or higher). Therefore, from ethical considerations, a clinical trial was conducted using the scores before PLDP administration as a control. In this study, PLDP was administered orally at 4 capsules per day, and the HDS-R was confirmed 2 and 4 weeks after administration. A significant increase in HDS-R scores was observed at 2 and 4 weeks after PLDP administration. Additionally, regarding each item of the HDS-R, PLDP significantly increased 2 and 4 weeks after oral administration for the question items assessing delayed recall, and the question item assessing verbal fluency tasks was recognized. From the above results, we confirmed the reproducibility of the effect of PLDP in improving the delayed recall of verbal memories. Furthermore, increasing scores on verbal fluency tasks suggest that PLDP may enhance frontal lobe function and prevent or improve depressive symptoms. The effects observed in this study may differ from the mechanisms of action of existing antidepressants, and we believe that this may lead to the discovery of new antidepressants.
PubMed: 38928586
DOI: 10.3390/brainsci14060586 -
Biomedicines Jun 2024Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on...
Vitamin D3 (Calcitriol) Monotherapy Decreases Tumor Growth, Increases Survival, and Correlates with Low Neutrophil-to-Lymphocyte Ratio in a Murine HPV-16-Related Cancer Model.
Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on HPV-16-related cancer has been sparsely explored. In this study, we aimed to determine whether monotherapy or combination therapy with cisplatin (CP) reduces tumor growth and affects survival and systemic inflammation. Treatments were administered to C57BL/6 mice with HPV-16-related tumors (TC-1 cells) as follows: (1) placebo (100 µL vehicle, olive oil, orally administered daily); (2) VitD3 (3.75 µg/kg calcitriol orally administered daily); (3) CP (5 mg/kg intraperitoneally, every 7 days); and (4) VitD3+CP. Tumor growth was monitored for 25 days, survival for 60 days, and the neutrophil-to-lymphocyte ratio (NLR) was evaluated on days 1 (baseline), 7, and 14. VitD3+CP showed greater success in reducing tumor volume compared to CP monotherapy ( = 0.041), while no differences were observed between CP and VitD3 monotherapy ( = 0.671). Furthermore, VitD3+CP prolonged survival compared to CP ( = 0.036) and VitD3 ( = 0.007). Additionally, at day 14 the VitD3 and VitD3+CP groups showed significantly lower NLR values than the CP group ( < 0.05, for both comparisons). Vitamin D3 could be a promising adjuvant in the treatment of cervical cancer or solid tumors and deserves further investigation.
PubMed: 38927564
DOI: 10.3390/biomedicines12061357 -
Biomolecules Jun 2024Exogenous supplementation with ketone beverages has been shown to reduce plasma glucose levels during acute nutritional ketosis. It remains to be investigated whether... (Randomized Controlled Trial)
Randomized Controlled Trial
Exogenous supplementation with ketone beverages has been shown to reduce plasma glucose levels during acute nutritional ketosis. It remains to be investigated whether growth differentiation factor 15 (GDF-15)-an anorexigenic hormone-is involved in this process. The aim was to investigate the effect of a ketone ester beverage delivering β-hydroxybutyrate (KEβHB) on plasma levels of GDF-15, as well as assess the influence of eating behaviour on it. The study was a randomised controlled trial (registered at clinicaltrials.gov as NCT03889210). Individuals were given a KEβHB beverage or placebo in a cross-over fashion. Blood samples were collected at baseline, 30, 60, 90, 120, and 150 min after ingestion. Eating behaviour was assessed using the three-factor eating questionnaire. GDF-15 levels were not significantly different ( = 0.503) after the KEβHB beverage compared with the placebo. This finding remained consistent across the cognitive restraint, emotional eating, and uncontrolled eating domains. Changes in the anorexigenic hormone GDF-15, irrespective of eating behaviour, do not appear to play a major role in the glucose-lowering effect of exogenous ketones.
Topics: Humans; Growth Differentiation Factor 15; Male; Ketosis; Adult; 3-Hydroxybutyric Acid; Female; Cross-Over Studies; Young Adult; Beverages; Blood Glucose; Feeding Behavior
PubMed: 38927068
DOI: 10.3390/biom14060665 -
Aesthetic Plastic Surgery Jun 2024Skin rejuvenation has always been of great concern. Although salicylic acid (SA) has multiple properties, it is mainly used in dermatology as a superficial peeling...
BACKGROUND
Skin rejuvenation has always been of great concern. Although salicylic acid (SA) has multiple properties, it is mainly used in dermatology as a superficial peeling agent that can improve photodamaged epidermis. However, the effect of SA on the photoaging dermis is unclear.
PURPOSE
To evaluate the efficacy and safety of supramolecular SA alone for treating photoaged skin, and the effect of SSA on photoaged dermis.
METHODS
This is a double-blind, randomized, placebo-controlled trial. 36 patients with photodamaged hands were enrolled. One hand was randomly selected as SSA treated side. 30% SSA biweekly and 2% SSA daily was applied for 4 months; an additional follow-up was performed 2 weeks after the last treatment. Skin photoaging score (SPS), global aesthetic improvement scale (GAIS), viscoelasticity, ultrasound parameters, color and transepidermal water loss (TEWL) were assessed.
RESULTS
SSA treatment induced a significant increase in collagen density and skin elasticity, accompanied by an increase in dermal thickness and a decrease in melanin index and TEWL. As result, the GAIS and the SPS were improved significantly after SSA treatment. No adverse events were observed after SSA treatments, and 98% of the subjects were satisfied or very satisfied with the treatment.
CONCLUSION
SSA can increase collagen density and skin elasticity to alleviate skin photoaging effectively and safely.
LEVEL OF EVIDENCE I
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
PubMed: 38926250
DOI: 10.1007/s00266-024-04180-1 -
Psychoneuroendocrinology Jun 2024Hormonal changes in ovarian hormones like estradiol (E2) during the menstrual cycle affect emotional processes, including emotion recognition, memory, and regulation. So...
Hormonal changes in ovarian hormones like estradiol (E2) during the menstrual cycle affect emotional processes, including emotion recognition, memory, and regulation. So far, the neural underpinnings of the effect of E2 on emotional experience have been investigated using task-based functional magnetic resonance imaging (fMRI) and functional connectivity. In the present study, we examined whether the intrinsic network dynamics at rest (i.e., directed effective connectivity) related to emotion regulation are (1) modulated by E2 levels and (2) linked to behavioral emotion regulation ability. Hence, 29 naturally cycling women participated in two resting-state fMRI scans in their early follicular phase after being administered a placebo or an E2 valerate, respectively. Emotion regulation ability was assessed using a standard emotion regulation task in which participants were asked to down-regulate their emotions in response to negative images. The regions of two functionally predefined neural networks related to emotional down-regulation and reactivity were used to investigate effective connectivity at rest using spectral dynamic causal modelling. We found that E2, compared to placebo, resulted in changes in effective connectivity in both networks. In the regulation network, prefrontal regions showed distinct connectivity in the E2 compared to the placebo condition, while mixed results evolved in the emotional reactivity network. Stepwise regressions revealed that in the E2 condition a connection from the parietal to the prefrontal cortex predicted regulation ability. Our results demonstrate that E2 levels influence effective connectivity in networks underlying emotion regulation and emotional reactivity. Thus, E2 and its potential modification via hormonal administration may play a supporting role in the treatment of mental disorders that show a dysregulation of emotions.
PubMed: 38924828
DOI: 10.1016/j.psyneuen.2024.107103 -
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