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Effects of a Dulaglutide plus Calorie-Restricted Diet versus a Calorie-Restricted Diet on Visceral Fat and Metabolic Profiles in Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial.
Zhang, Y, Qu, Z, Lu, T, Shao, X, Cai, M, Dilimulati, D, Gao, X, Mao, W, Hu, F, Su, L, et al
Nutrients. 2023;15(3)
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Polycystic ovary syndrome (PCOS) is a unification of reproductive endocrine and metabolic disorders. Lifestyle and weight management, particularly dietary intake aimed at weight loss, are initial treatment strategies for PCOS. A calorie-restricted diet (CRD) seems to be the optimal dietary pattern for weight management in the PCOS population. The aim of this study was to evaluate modifications in fat distribution, the androgenic state, and metabolic profiles in the overweight and obese PCOS-affected population, who obtained modest and equivalent weight loss induced by a CRD regimen with or without Dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA). This study was a randomised controlled trial which enrolled 68 females diagnosed with PCOS. Participants were randomly assigned to receive to one of the two groups: a GLP-1 RA combined with CRD or CRD alone. Results showed that participants in the GLP-1 RA + CRD group took a shorter time to achieve a 7% weight loss goal than those in the CRD group. Furthermore, both interventions had similar positive effects in improving menstrual frequency and reducing levels of blood pressure, insulin, aminotransferases, lipids, total fat mass, total lean mass, and abdominal subcutaneous adipose tissue mass after equivalent weight loss. Authors conclude that their findings support the importance of dietary intervention as a first-line treatment in women with PCOS, and that GLP-1 RA therapy offers an effective and generally tolerable adjunct therapy to aid in achieving weight targets based on dietary therapy in overweight and obese women with PCOS.
Abstract
The effects of dulaglutide and a calorie-restricted diet (CRD) on visceral adipose tissue (VAT) and metabolic profiles in polycystic ovary syndrome (PCOS) have not been extensively investigated. In this study, we investigated whether dulaglutide combined with CRD could further reduce VAT and promote clinical benefits as compared with a CRD regimen alone in overweight or obese PCOS-affected women. Between May 2021 and May 2022, this single-center, randomized, controlled, open-label clinical trial was conducted. Overall, 243 participants with PCOS were screened, of which 68 overweight or obese individuals were randomly randomized to undergo dulaglutide combined with CRD treatment (n = 35) or CRD treatment alone (n = 33). The duration of intervention was set as the time taken to achieve a 7% weight loss goal from baseline body weight, which was restricted to 6 months. The primary endpoint was the difference in the change in VAT area reduction between the groups. The secondary endpoints contained changes in menstrual frequency, metabolic profiles, hormonal parameters, liver fat, and body composition. As compared with the CRD group, the dulaglutide + CRD group had a considerably shorter median time to achieve 7% weight loss. There was no significant between-group difference in area change of VAT reduction (-0.97 cm2, 95% confidence interval from -14.36 to 12.42, p = 0.884). As compared with CRD alone, dulaglutide + CRD had significant advantages in reducing glycated hemoglobin A1c and postprandial plasma glucose levels. The results of the analyses showed different changes in menstruation frequency, additional metabolic profiles, hormonal markers, liver fat, and body composition between the two groups did not differ significantly. Nausea, vomiting, constipation, and loss of appetite were the main adverse events of dulaglutide. These results emphasize the value of dietary intervention as the first line of treatment for PCOS-affected women, while glucagon-like peptide 1 receptor agonist therapy provides an efficient and typically well tolerated adjuvant therapy to aid in reaching weight targets based on dietary therapy in the population of overweight/obese PCOS-affected women.
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Treatment of obesity and metabolic-associated fatty liver disease with a diet or orlistat: A randomized controlled trial.
Feng, X, Lin, Y, Zhuo, S, Dong, Z, Shao, C, Ye, J, Zhong, B
The American journal of clinical nutrition. 2023;117(4):691-700
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Metabolic-associated fatty liver disease (MAFLD) is characterised by excessive lipid accumulation in hepatocytes. Weight management by the treatment to target strategy through lifestyle intervention remains the primary approach for MAFLD treatment. The aim of this study was to compare the efficacy of a conventional energy-restricted diet (the control group), orlistat, and an experimental diet in the Asian population with obesity and MAFLD. This study was a prospective, open-label, monocentric randomised controlled study. Participants (n = 118) were randomly assigned to the control (n = 39), orlistat (n = 40), or experimental diet (n = 39) groups at a 1:1:1 allocation. Results showed that: - orlistat and the experimental diet were superior to lifestyle intervention in ameliorating liver steatosis [fatty liver]. - the experimental diet had an advantage over lifestyle intervention when patients adhered to the diet. - orlistat was superior to the experimental diet and lifestyle modifications in decreasing liver fat content. Authors conclude that more multicentre, large-scale, prospective studies are needed to verify the long-term efficacy and safety of the experimental diet and orlistat treatment in subjects with MAFLD.
Abstract
BACKGROUND Losing weight by lifestyle interventions is the first-line treatment for metabolic-associated fatty liver disease (MAFLD) but is limited by low compliance. OBJECTIVES This study aimed to compare the effects of orlistat or an experimental high-protein/lower-carbohydrate diet with a control diet in Asian patients with obesity and MAFLD. METHODS A total of 118 Asian patients with obesity and MAFLD confirmed with MRI-based proton density fat fraction with Dixon sequence were enrolled and allocated to the control group, the orlistat group, or the experimental diet group for 24 wk. The primary endpoint was the relative change in liver fat content (LFC) assessed by MRI-based proton density fat fraction. RESULTS A total of 118 subjects with obesity and MAFLD were randomly assigned to the control group (n = 39), the orlistat group (n = 40), or the experimental diet group (n = 39). All 3 groups demonstrated improvement in liver steatosis at wk 24. The absolute decrease in LFC in the orlistat group was 9.1% and 5.4% in the experimental diet group, both significantly higher than that in the control group (P < 0.05). The relative reduction in LFC was 30.2% in the experimental diet group, which was significantly higher than the 12.2% observed in the control group (P = 0.01). CONCLUSIONS Orlistat and the experimental diet group reduced liver steatosis compared to the control group. This trial was registered at Chinese Clinical Trial Registry (ChiCTR-1900027172). http://www.chictr.org.cn.
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Effect of an Immune-Boosting, Antioxidant and Anti-Inflammatory Food Supplement in Hospitalized COVID-19 Patients: A Prospective Randomized Pilot Study.
Reino-Gelardo, S, Palop-Cervera, M, Aparisi-Valero, N, Espinosa-San Miguel, I, Lozano-Rodríguez, N, Llop-Furquet, G, Sanchis-Artero, L, Cortés-Castell, E, Rizo-Baeza, M, Cortés-Rizo, X
Nutrients. 2023;15(7)
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Coronavirus Disease 2019 (COVID-19), has spread worldwide, reaching pandemic proportions. The symptoms caused by COVID-19 disease are nonspecific and may range from asymptomatic to severe pneumonia and death. The aim of this study was to evaluate the potential effect of a food supplement (probiotics, prebiotics, vitamin D, zinc and selenium) in patients admitted with COVID-19. This study was a prospective, randomised, non-blinded clinical trial. A total of 162 patients were enrolled at Sagunto Hospital, 42.0% of whom were women. Participants were assigned to one of the two groups: probiotic or control group. Results showed that higher mortality was found in men, older patients and those with severe radiological involvement. Furthermore, administration of the food supplement product Gasteel Plus®, as an adjuvant to the treatment established in the hospital for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pneumonia, reduced the duration of digestive symptoms and hospital stay in patients with mild–moderate pulmonary involvement. Authors conclude that their findings demonstrate the importance of considering the use of the food supplement under review in the prevention and treatment of SARS-CoV-2, including severe cases, which showed no side effects.
Abstract
BACKGROUND COVID-19 disease is a serious global health problem. Few treatments have been shown to reduce mortality and accelerate time to recovery. The aim of this study was to evaluate the potential effect of a food supplement (probiotics, prebiotics, vitamin D, zinc and selenium) in patients admitted with COVID-19. METHODS A prospective randomized non-blinded clinical trial was conducted in a sample of 162 hospitalized patients diagnosed with COVID-19 recruited over eight months. All patients received standard treatment, but the intervention group (n = 67) was given one food supplement stick daily during their admission. After collecting the study variables, a statistical analysis was performed comparing the intervention and control groups and a multivariate analysis controlling for variables that could act as confounding factors. RESULTS ROC curve analysis with an area under the curve (AUC) value of 0.840 (p < 0.001; 95%CI: 0.741-0.939) of the food supplement administration vs. recovery indicated good predictive ability. Moreover, the intervention group had a shorter duration of digestive symptoms compared with the control group: 2.6 ± 1.3 vs. 4.3 ± 2.2 days (p = 0.001); patients with non-severe disease on chest X-ray had shorter hospital stays: 8.1 ± 3.9 vs. 11.6 ± 7.4 days (p = 0.007). CONCLUSIONS In this trial, the administration of a food supplement (Gasteel Plus®) was shown to be a protective factor in the group of patients with severe COVID-19 and allowed early recovery from digestive symptoms and a shorter hospital stay in patients with a normal-mild-moderate chest X-ray at admission (ClinicalTrials.gov number, NCT04666116).
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Clinical Trial: Probiotics in Metformin Intolerant Patients with Type 2 Diabetes (ProGasMet).
Nabrdalik, K, Drożdż, K, Kwiendacz, H, Skonieczna-Żydecka, K, Łoniewski, I, Kaczmarczyk, M, Wijata, AM, Nalepa, J, Holleman, F, Nieuwdorp, M, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2023;168:115650
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Metformin has been the number one drug of choice for the management of type 2 diabetes, however there is a proportion of individuals who suffer from stomach issues and discontinue therapy. This may be due to the possibility that metformin impacts gut microbiota composition. This randomised control trial of 82 individuals with metformin intolerance aimed to determine the effect of a multi-strain probiotic in conjunction with metformin administration. The results showed that whilst on probiotics, there was a significant improvement in symptoms, with reduced incidence and severity of nausea, reduced frequency and severity of stomach pain and bloating and self-assessed improvement of tolerability of metformin. Nausea was also decreased, but only when the probiotic was allowed time to act. It was concluded that probiotic supplementation improves gastrointestinal side effects associated with metformin intolerance. This study could be used by healthcare professionals to understand that individuals who are on metformin may experience gastrointestinal side effects, which may be relieved with a multi-strain probiotic.
Abstract
BACKGROUND For decades, metformin has been the drug of first choice in the management of type 2 diabetes. However, approximately 2-13% of patients do not tolerate metformin due to gastrointestinal (GI) side effects. Since metformin influences the gut microbiota, we hypothesized that a multi-strain probiotics supplementation would mitigate the gastrointestinal symptoms associated with metformin usage. METHODS AND ANALYSIS This randomized, double-blind, placebo-controlled, single-center, cross-over trial (ProGasMet study) assessed the efficacy of a multi-strain probiotic in 37 patients with metformin intolerance. Patients were randomly allocated (1:1) to receive probiotic (PRO-PLA) or placebo (PLA-PRO) at baseline and, after 12 weeks (period 1), they crossed-over to the other treatment arm (period 2). The primary outcome was the reduction of GI adverse events of metformin. RESULTS 37 out of 82 eligible patients were enrolled in the final analysis of whom 35 completed the 32 weeks study period and 2 patients resigned at visit 5. Regardless of the treatment arm allocation, while on probiotic supplementation, there was a significant reduction of incidence (for the probiotic period in PRO-PLA/PLA-PRO: P = 0.017/P = 0.054), quantity and severity of nausea (P = 0.016/P = 0.024), frequency (P = 0.009/P = 0.015) and severity (P = 0.019/P = 0.005) of abdominal bloating/pain as well as significant improvement in self-assessed tolerability of metformin (P < 0.01/P = 0.005). Moreover, there was significant reduction of incidence of diarrhea while on probiotic supplementation in PRO-PLA treatment arm (P = 0.036). CONCLUSION A multi-strain probiotic diminishes the incidence of gastrointestinal adverse effects in patients with type 2 diabetes and metformin intolerance.
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A randomized controlled trial of an oral probiotic to reduce antepartum group B Streptococcus colonization and gastrointestinal symptoms.
Hanson, L, VandeVusse, L, Forgie, M, Malloy, E, Singh, M, Scherer, M, Kleber, D, Dixon, J, Hryckowian, AJ, Safdar, N
American journal of obstetrics & gynecology MFM. 2023;5(1):100748
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Streptococcus agalactiae (or group B Streptococcus [GBS]) is an encapsulated, gram-positive, beta-haemolytic anaerobe that asymptomatically colonizes the genitourinary tract. Vertical transmission of GBS during normal vaginal birth can lead to neonatal colonization and risk for early-onset GBS disease. The aim of this study was to present the findings of a phase II, double-blind, randomised, placebo-controlled trial of an antenatal probiotic intervention to reduce GBS colonization. A secondary aim was to determine if the probiotic intervention reduces gastrointestinal (GI) symptoms of pregnancy. Participants (n=107) were randomly assigned to one of the two groups: probiotic intervention (n=55) or placebo group (n=54). Results show that: - there weren’t any significant differences between the groups in demographic characteristics, perinatal or neonatal outcomes, or intrapartum antibiotic prophylaxis doses. - there wasn’t any significant difference between groups in the presence of the probiotic bacteria on the rectal swabs, whereas the vaginal swabs showed a trend toward greater presence in probiotic group participants. - more probiotic participants took antenatal antibiotics (5/39) compared with controls (1/44). Authors conclude that probiotic bacteria colonisation of the genitourinary tract occurred more in the intervention group than in the control group and significantly reduced GI symptoms of pregnancy.
Abstract
BACKGROUND Probiotics have been suggested as a strategy to reduce antenatal group B Streptococcus colonization. Although probiotics are known to improve gastrointestinal symptoms, this has not been studied during pregnancy. OBJECTIVE This study aimed to evaluate the efficacy of a probiotic to reduce: (1) standard-of-care antenatal group B Streptococcus colonization and colony counts and (2) gastrointestinal symptoms of pregnancy. STUDY DESIGN In a double-blind fashion, 109 healthy adult pregnant people were randomized to Florajen3 probiotic or placebo capsules once daily from 28 weeks' gestation until labor onset. Baseline vaginal and rectal study swabs for group B Streptococcus colony-forming units and microbiome analysis were collected at 28 and 36 weeks' gestation. Standard-of-care vaginal to rectal group B Streptococcus swabs were collected from all participants at 36 weeks' gestation and determined the need for intrapartum antibiotic prophylaxis. Data collection included solicitation of adverse events, demographic information, Antepartum Gastrointestinal Symptom Assessment score, yogurt ingestion, sexual activity, and vaginal cleaning practices. RESULTS A total of 83 participants completed the study to 36 weeks' gestation with no adverse events. Standard-of-care group B Streptococcus colonization was 20.4% in the control group and 15.4% in probiotic group participants (-5%; P=.73). The relative risk for positive standard-of-care vaginal-rectal group B Streptococcus colonization was 1.33 (95% confidence interval, 0.5-3.40) times higher in the control group than in the probiotic group (P=.55). There were no differences in median vaginal (P=.16) or rectal (P=.20) group B streptococcus colony-forming units at baseline or at 36 weeks (vaginal P>.999; rectal P=.56). Antepartum Gastrointestinal Symptom Assessment scores were similar at baseline (P=.19), but significantly decreased in probiotic group participants at 36 weeks (P=.02). No covariates significantly altered group B Streptococcus colonization. Significantly more Florajen3 bacteria components were recovered from the vaginal-rectal samples of probiotic group participants (32%; P=.04) compared with controls. CONCLUSION The findings of this study provided insufficient evidence for the clinical application of the Florajen3 probiotic intervention to reduce standard-of-care vaginal-rectal group B Streptococcus colonization. The prevalence of group B Streptococcus was lower than expected in the study population, and intervention adherence was poor. Probiotic bacteria colonization of the genitourinary tract occurred more in intervention group participants than in controls and significantly reduced gastrointestinal symptoms of pregnancy.
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Testosterone does not affect lower urinary tract symptoms while improving markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial.
Rastrelli, G, Cipriani, S, Lotti, F, Cellai, I, Comeglio, P, Filippi, S, Boddi, V, Della Camera, PA, Santi, R, Boni, L, et al
Journal of endocrinological investigation. 2022;45(7):1413-1425
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Benign prostatic hyperplasia (BPH) — also called benign prostate enlargement — is frequent in aging populations, with a 40 – 50% prevalence in men aged 50–60 years and up to 90% in men older than 80 years. The aim of this study was to verify whether testosterone therapy (TTh) in men with BPH, metabolic syndrome (MetS) and low testosterone is able to improve lower urinary tract symptoms (LUTS) and intraprostatic inflammation. This study is a double blind, randomised 24-week clinical trial in men with low testosterone and MetS and a candidate for prostate surgery for BPH. Patients (n=144) were centrally randomised 1:1 to one of the two groups; TTh or placebo. Results show that TTh administered for 24 weeks is a safe option and it improves prostatic inflammatory features thus ameliorating one of the pathogenic components of BPH. However, there were no differences in improvements of the urinary symptoms between both groups (TTh and placebo). Authors conclude that decreased inflammation is not accompanied by a consistent improvement in urinary symptoms, and that their findings show the safety of TTh in subjects with BPH of surgical significance.
Abstract
PURPOSE Benign Prostatic Hyperplasia (BPH) is a result of prostate inflammation, frequently occurring in metabolic syndrome (MetS). Low testosterone is common in MetS. A randomized clinical trial was designed to evaluate if 24 weeks of testosterone therapy (TTh) in BPH men with MetS and low testosterone improve urinary symptoms and prostate inflammation. METHODS One-hundred-twenty men with MetS waitlisted for BPH surgery were enrolled. They were categorized into normal testosterone (TT ≥ 12 nmol/L and cFT ≥ 225 pmol/L; n = 48) and testosterone deficient (TD) (TT < 12 nmol/L and/or cFT < 225 pmol/L; n = 72) then randomized to testosterone gel 2% (5 g/daily) or placebo for 24 weeks. At baseline and follow-up, questionnaires for urinary symptoms and trans-rectal ultrasound were performed. Prostate tissue was collected for molecular and histopathological analyses. RESULTS No differences in the improvement of urinary symptoms were found between TTh and placebo (OR [95% CI] 0.96 [0.39; 2.37]). In TD + TTh, increase in prostate but not adenoma volume was observed (2.64 mL [0.07; 5.20] and 1.82 mL [- 0.46; 0.41], respectively). Ultrasound markers of inflammation were improved. In a subset of 61 men, a hyper-expression of several pro-inflammatory genes was found in TD + placebo when compared with normal testosterone. TTh was able to counteract this effect. For 80 men, the inflammatory infiltrate was higher in TD + placebo than in normal testosterone (0.8 points [0.2; 1.4]) and TD + TTh men (0.9 points [0.2; 1.5]). CONCLUSIONS Twenty-four weeks of TTh in TD men with BPH and MetS improves ultrasound, molecular and histological proxies of prostate inflammation. This does not result in symptom improvement.
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Combination therapy with tamsulosin and traditional herbal medicine for lower urinary tract symptoms due to benign prostatic hyperplasia: A double-blinded, randomized, pilot clinical trial.
Lee, CL, Shin, HK, Lee, JY, Kwon, O, Seo, CS, Kim, AR, Seo, BN, Yang, SW, Song, KH, Lim, JS, et al
International journal of urology : official journal of the Japanese Urological Association. 2022;29(6):503-509
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Benign prostatic hyperplasia (BPH) is a common diagnosis of progressive enlargement of the prostate in older men and the prevalence increases with an aging population. BPH is one of the leading causes of lower urinary tract symptoms (LUTS), causing significant morbidity and decreasing the quality of life of older men. The aim of this study was to describe the efficacy and safety of combination therapy with tamsulosin, and two traditional herbal medicines - Hachimijiogan (HJG) and Ryutanshakanto (RST) in patients with LUTS due to BHP. This study is a double-blind randomised controlled trial. Participants (n= 44) were randomly assigned to one of the three groups: control (tamsulosin and placebo), RST (tamsulosin and RST) or HJG (tamsulosin and HJG) group. Results show that: - in all three groups, prostate volume increased after treatment compared to that before treatment. The HJG and RST combination do not exhibit inferior efficacy to alpha‐blocker monotherapy. - patients in all three groups showed significant improvement in international prostate symptom score (IPSS) and quality of life index without significant differences among the groups. - there weren’t significant differences in the laboratory tests results among the groups before and after treatment. Authors conclude that HJG and RST in conjunction to tamsulosin can be safe supplements for patients with adverse events on taking other medications or high operation risk.
Abstract
OBJECTIVES To evaluate the efficacy and safety of tamsulosin and Hachimijiogan or Ryutanshakanto in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. METHODS A prospective, randomized, double-blind method was used to determine the efficacy and safety of the combination or placebo at baseline and 4, 8, and 12 weeks of study. The International Prostate Symptom Score, quality of life index, complete voiding diary, and National Institutes of Health-Chronic Prostatitis Symptom Index were studied. Uroflowmetery and postvoid residual urine volume were measured and compared. Laboratory tests including prostate-specific antigen were performed. RESULTS In all groups, International Prostate Symptom Score and quality of life showed improvement, but no significant differences were shown among the groups. Prostate volume increased after treatment, and uroflowmetric parameters showed improvements after treatment without significance among the three groups. The total score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant improvement in all groups, without significant differences among the groups. Only the pain sub-score of the National Institutes of Health-Chronic Prostatitis Symptom Index showed a significant decrease in the tamsulosin with Ryutanshakanto group compared to the control group. A total of 11 adverse reactions occurred, but they were mild and not related to the study drugs. CONCLUSION Ryutanshakanto can provide pain relief in patients with chronic prostatitis and chronic pelvic pain syndrome. If more research is conducted, Hachimijiogan and Ryutanshakanto may be applied as add-on treatments in patients with storage symptoms with alpha-blocker monotherapy.
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The effect of Melatonin on Improving the benign Prostatic Hyperplasia Urinary Symptoms, a Randomized Clinical Trial.
Fotovat, A, Samadzadeh, B, Ayati, M, Nowroozi, MR, Momeni, SA, Yavari, S, Nasseri, A, Sharifi, L
Urology journal. 2022;19(5):406-411
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Benign prostatic hyperplasia (BPH) is a common issue in men older than 40. BPH is accompanied by irritating and obstructive symptoms that sometimes lead to surgery due to lack of recovery. Tamsulosin is an alpha-receptor blocker that is considered a standard treatment for patients. The aim of this study was to investigate the effect of melatonin [a hormone secreted by the pineal gland at night that regulates the sleep-wake cycle] along with standard treatment on improving the BPH urinary symptoms as well as patients’ quality of life due to their urinary problems. This study is a single centre, parallel group randomised, double-blind clinical trial with balanced randomisation. Patients (n = 108) were randomly allocated to one of the two groups. Results show the combination of melatonin and tamsulosin was significantly effective in treating the symptoms of frequency and nocturia in patients with BPH. Authors conclude that their findings can be used to pave the way to improving the symptoms of patients with BPH.
Abstract
PURPOSE to investigate the effect of melatonin along with tamsulosin in improving BPH urinary symptoms. MATERIALS AND METHODS A total of 108 men with BPH symptoms, age of ≥ 50 years, and International Prostate Symptom Score (IPSS) ≥ 8 entered into the parallel group randomized, double-blind clinical trial with balanced randomization. The treatment group received of 3mg melatonin plus 0.4mg tamsulosin and the control group received placebo plus 0.4mg tamsulosin. Patients and physicians were concealed by sealed and opaque envelopes. Symptoms were assessed at baseline and 1 month after treatment. Finally all scores at the initial and end of the study were compared and analyzed using SPSS software. RESULTS This study showed that adding melatonin to the classic treatment of BPH patients with tamsulosin could significantly reduce the likelihood of nocturia by 2.39 times (95% CI: 1.07-5.32, OR = 2.39, p = 0.033) and could also reduce the frequency of urination by 2.59 times (95% CI: 1.15-5.84, OR = 2.59, p = 0.021). There was no statistically significant difference between the two groups in IPSS, intermittency, incomplete emptying, straining, urgency, and weak stream. CONCLUSION Melatonin plus tamsulosin treatment is associated with a significant improvement of nocturia and frequency in patients with benign proststic hyperplasia. However, it is necessary to do more studies.
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Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.
O'Donoghue, ML, Rosenson, RS, Gencer, B, López, JAG, Lepor, NE, Baum, SJ, Stout, E, Gaudet, D, Knusel, B, Kuder, JF, et al
The New England journal of medicine. 2022;387(20):1855-1864
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Numerous epidemiologic studies over the past three decades have shown an association between higher circulating lipoprotein(a) concentrations and an increased risk of atherosclerotic cardiovascular disease. The aim of this study was to evaluate the efficacy and safety of repeated administration of a small interfering RNA designed to lower the body's production of apolipoprotein(a). This study is a multicentre, randomised, double-blind, placebo-controlled, dose-finding trial. Patients were randomly assigned in a 1:1:1:1:1 ratio to receive one of four doses of small interfering RNA (n= 281) (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. Results show that treatment with small interfering RNA markedly reduced the concentration of lipoprotein(a) in a dose-dependent manner and appeared to be safe. At higher doses, the treatment reduced the lipoprotein(a) concentration by more than 95%, as compared with placebo, with nearly all patients who received the treatment with small interfering RNA having a lipoprotein(a) concentration of less than 125 nmol per litre. Authors conclude that further large-scale interventions are needed to confirm a causal role for lipoprotein(a) in atherosclerotic cardiovascular disease.
Abstract
BACKGROUND Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
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Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial.
Sesso, HD, Manson, JE, Aragaki, AK, Rist, PM, Johnson, LG, Friedenberg, G, Copeland, T, Clar, A, Mora, S, Moorthy, MV, et al
The American journal of clinical nutrition. 2022;115(6):1490-1500
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Cocoa is made from the bean of the cacao tree and has a long history of potential health benefits based upon its flavanol and procyanidin content. Cocoa extract also contains methylxanthines [alkaloids] such as theobromine and caffeine, which may enhance the vascular and central nervous system effects of cocoa flavanols. The aim of this study was to evaluate the flavanol-rich cocoa extract containing all potential bioactive components of the cocoa bean on clinical cardiovascular outcomes. This study is a randomised, double-blind, placebo-controlled, 2 × 2 factorial trial testing a cocoa extract supplement and a multivitamin supplement (COSMOS). This study focuses on the cocoa extract component of the trial. A total of 21,442 participants underwent randomisation to one of the four groups. Results show that after a median of 3.6 years of treatment there was no statistically significant effect on the primary outcome of total cardiovascular events. However, cocoa flavanol supplementation significantly reduced cardiovascular disease death by 27%, whereas other individual cardiovascular outcomes had no significant reductions in risk. Authors conclude that longer-term follow-up of the trial cohort and ongoing ancillary mechanistic studies in COSMOS may further elucidate the relation between cocoa extract supplementation and clinical cardiovascular events.
Abstract
BACKGROUND Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested. OBJECTIVES We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults. METHODS We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina. RESULTS During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns. CONCLUSIONS Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.