Targeting AKR1B10 by drug repurposing with epalrestat overcomes chemoresistance in non-small cell lung cancer patient-derived tumor organoids.

PURPOSE: Systemic treatments given to non-small cell lung cancer (NSCLC) patients are often ineffective due to drug resistance. In the present study, we investigated patient-derived tumor organoids (PDTOs) and matched tumor tissues from surgically treated NSCLC patients to identify drug repurposing targets to overcome resistance towards standard-of-care platinum-based doublet chemotherapy. EXPERIMENTAL DESIGN: PDTOs were established from ten prospectively enrolled non-metastatic NSCLC patients from resected tumors. PDTOs were compared with matched tumor tissues by histopathology/immunohistochemistry, whole exome and transcriptome sequencing. PDTO growths and drug responses were determined by measuring 3D tumoroid volumes, cell viability, and proliferation/apoptosis. Differential gene expression analysis identified drug-repurposing targets. Validations were performed with internal/external NSCLC patient data sets. NSCLC cell lines were used for aldo-keto reductase 1B10 (AKR1B10) knockdown studies and xenograft models to determine the intratumoral bioavailability of epalrestat. RESULTS: PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant towards carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels. CONCLUSIONS: PDTOs are efficient preclinical models recapitulating the tumor characteristics and are suitable for drug testing. AKR1B10 can be targeted by repurposing epalrestat to overcome chemoresistance in NSCLC. Epalrestat has the potential to advance to clinical trials in drug-resistant NSCLC patients due to favorable toxicity, pharmacological profile, and bioavailability.

Increased social media utilization and content creation by cardiothoracic surgery programs during the coronavirus disease 2019 pandemic.

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has changed the landscape of professional activities, emphasizing virtual meetings and social media (SoMe) presence. Whether cardiothoracic programs increased their SoMe presence is unknown. We examined SoMe use and content creation by cardiothoracic surgery programs during the COVID-19 pandemic. Methods: We searched the Accreditation Council for Graduate Medical Education to identify all cardiothoracic surgery residency programs (n = 122), including independent (n = 74), integrated (n = 33), and congenital (n = 15) training programs at 78 US cardiothoracic surgery teaching institutions. We then manually searched Google, Facebook, Instagram, LinkedIn, and Twitter to identify the associated residency and departmental accounts. The timeline for our search was between 10/2021 and 4/2022. March 2020 was used as the starting point for the COVID-19 pandemic. We also contacted the account managers to identify account content creators. The data are descriptively reported and analyzed. Results: Of 137 SoMe accounts from 78 US cardiothoracic surgery teaching institutions, 72 of 137 (52.6%) were on Twitter, 34 of 137 (24.8%) on Facebook, and 31 of 137 (22.6%) on Instagram. Most accounts were departmental accounts (105/137 = 76.6%) versus 32 of 137 (23.4%) training program accounts. Most training program-specific SoMe accounts across all platforms were created after the COVID-19 pandemic, whereas departmental accounts were pre-existing (P < .001). The most pronounced SoMe growth was on Instagram at the training program level, with 91.7% of Instagram accounts created after the pandemic. Trainees are the content creators for 94.4% of residency accounts and 33.3% of departmental accounts. Facebook's presence was stagnant. Congenital training programs did not have a specific SoMe presence. Conclusions: SoMe presence by cardiothoracic surgery training programs and departments has increased during the pandemic. Twitter is the most common platform, with a recent increased trend on Instagram. Trainees largely create content. SoMe education and training pathways may be needed for involved trainees to maximize their benefits.

Safety and efficacy of adipose-derived mesenchymal stem cells for knee osteoarthritis: A systematic review and m-analysis.

OBJECTIVE: This research aimed to study the safety and efficacy of adipose-derived mesenchymal stem cells (ADMSCs) for knee osteoarthritis (OA). METHODS: We used six databases to search for records and then screened them for eligibility. In both randomized and non-randomized studies, the risk of bias was assessed. The data were then retrieved and used in single-arm and double-arm analyses using Comprehensive Meta-Analysis (CMA) Version 3.0 and RevMan Version 5.3, respectively. RESULTS: Based on the study's inclusion criteria, we included 15 studies with a total of 463 patients. According to our single-arm analyses, there was a significant improvement in quality of life (QOL) among the three dose subgroups (high, medium, and low doses), as measured by SF-36 scores after a year of follow-up [low dose: mean (M)=-23.99; 95% confidence interval (CI) [-31.49 to -16.49]; P<0.001; medium dose: M=-15.96; 95% CI [-23.5 to-8.42]; P<0.001; high dose: M=-19.31; 95% CI [-28.02 to -10.59], P<0.001] and the knee injury and osteoarthritis outcome score (KOOS) QOL sub-score after six months following ADMSCs injection in the low-dose group (M=24.9; 95% CI [4.3 to 45.6]; P<0.05). Moreover, after three months of follow-up, we detected significant pain reduction as measured by the numeric pain rating scale (NPRS), with no significant difference between the low and medium doses (low dose: M=-3.12; 95% CI [-5.09 to -1.14]; P<0.01; medium dose; M=-2.17; 95% CI [-3.13 to -1.21]; P<0.001). However, after a year, the results were no longer significant. Despite finding no significant difference between them after 6 and 12 months post-treatment in the Visual Analogue scale (VAS) scale and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, double-arm analyses revealed significant pain reduction in the ADMSCs group over the control after 12 months as estimated by the WOMAC pain sub-score (mean difference (MD)=-1.85, 95% CI [-3.55, -0.15], P<0.05). After six months, the low dosage group's knee functions and activity levels improved significantly, as determined by the WOMAC physical function and stiffness subscales (M=-23.79; 95% CI [-38.43 to -9.16]; P=0.001; M=-10.25; 95% CI [-17.31 to -2.59]; P<0.01, respectively), as well as the KOOS scores after a year (P<0.01 for all KOOS subscales). In the ADMSCs injections group, there were no serious adverse effects [event rate (ER)=0.11; 95% CI [0.03-0.3]; P=0.001]. CONCLUSION: In the present single-arm meta-analysis, ADMSCs were associated with significant reduction in pain and improvement in QOL and knee functions in patients with knee OA. However, double arm analyses did not confirm these positive findings, which may be returned to the small sample size of included patients. Therefore, to introduce ADMSCs into clinical practice and establish guidelines for their use, more randomized controlled clinical trials with large sample sizes and long-term follow-ups are needed.

Totally robotic enucleation of a mid-esophageal leiomyoma.

Enucleation of an esophageal leiomyoma is the treatment of choice in symptomatic patients. Several open or minimally invasive approaches have been shown to be safe and effective. Robotic approaches allow for delicate and precise dissection with improved three-dimensional visualization. The robotic operative technique for enucleation has not been well described. In this context, we present the case of a 53-year-old obese man struggling with dysphagia and odynophagia due to a mid-esophageal leiomyoma. In the case presentation, we review the preoperative workup with high-quality images, robotic port placement, equipment needed, intraoperative conduct, and postoperative course. We provide a step-by-step video tutorial encompassing the preoperative workup, operative steps, tips and tricks, and postoperative course using a totally robotic enucleation of a 7-cm mid-esophageal leiomyoma. This case presentation can serve as a comprehensive teaching case for trainees and a high-quality example of the conduct of the operation for practicing surgeons, including some tips and tricks for optimal results. We also highlight that an assistant port is not required.

Lithium carbonate as add-on therapy to radioiodine in the treatment on hyperthyroidism: a systematic review and meta-analysis.

BACKGROUND: The main purpose is to investigate the effect of LiCO3 as an add-on therapy with radioactive iodine in increasing the cure and decreasing the T4 level compared to radioactive iodine alone. The primary outcome is the cure rate as defined by the number of hyperthyroid patients who became euthyroid or hypothyroid. The secondary outcome is the T4 level. METHODS: Four databases were searched (PubMed, Scopus, Web of Science, and Cochrane central library). The inclusion criteria were randomized and non-randomized clinical trials of hyperthyroidism patients receiving LiCO3 with radioiodine compared with hyperthyroidism patients receiving radioactive iodine alone. Included studies were appraised with the risk of bias version 2 tool, according to the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. RESULTS: Nine studies were eligible for inclusion in the study, six randomized control trials and three non-randomized control trials. There were 477 patients in the intervention group and 451 patients in the control group. The cure rate was not significantly different between the two groups, while it was significantly increased with 5000 to 6500 mg optimized cumulative dose of LiCO3 compared with the control group, P = 0.0001. The T4 level showed no significant difference between the two groups, P = 0.13. CONCLUSIONS: LiCO3 adjunct to radioactive iodine did not show significant differences compared with radioactive iodine alone in terms of cure rate or decreasing T4 level. However, the dose of 5000 to 6000 mg of LiCO3 may increase the cure rate.

High dose vs. low dose oxytocin for labor augmentation: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To compare the safety and efficacy between high dose and low dose oxytocin administration for labor augmentation. METHODS: We searched for the available studies during March 2020 in PubMed, Cochrane Library, Scopus, and ISI Web of science. All randomized clinical trials (RCTs) that assessed safety and efficacy of high dose vs. low dose oxytocin for labor augmentation were considered. The extracted data were entered into RevMan software. Dichotomous and continuous data were pooled as odds ratio (OR) and mean difference (MD) respectively, with the corresponding 95% confidence intervals (CI). Our main outcomes were cesarean delivery rate, spontaneous vaginal delivery rate, uterine hyperstimulation and tachysystole, and labor duration from oxytocin infusion. RESULTS: Eight RCTs with 3,154 patients were included. High dose oxytocin did not reduce cesarean delivery rate compared to low dose oxytocin (OR=0.76, 95% CI [0.52, 1.10], p=0.15). After solving the reported heterogeneity, high dose oxytocin did not increase the rate of spontaneous vaginal deliveries vs. low dose oxytocin (OR=1.06, 95% CI [0.84, 1.32], p=0.64). Low dose oxytocin was linked to a significant decline in uterine hyperstimulation and tachysystole (p>0.001). A reduction in labor duration was found in high dose oxytocin group over low oxytocin regimen (MD=-1.02 h, 95% CI [-1.77, -0.27], p=0.008). CONCLUSIONS: We found no advantages for high dose oxytocin over low dose oxytocin in labor augmentation except in reducing labor duration. Low dose oxytocin is safer as it decreases the incidence of uterine hyperstimulation and tachysystole. More trials are needed to confirm our findings.

Effect of chlormadinone acetate versus drospirenone-containing oral contraceptives on the endocrinal features of women with polycystic ovary syndrome: Systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a serious endocrinal disorder in women of reproductive age. Hormonal treatment with oral contraceptives, containing estrogen (ethinyl-estradiol, EE) with progestogen (drospirenone, DRSP) or (chlormadinone acetate, CMA), has improved symptoms and biomarkers of PCOS. OBJECTIVE: The aim of the present meta-analysis is to compare the effects of EE/DRSP versus EE/CMA on the endocrinal features of women with PCOS. DATA SOURCES: Several electronic databases were searched for combinations of the following relevant MeSH terms were used: (ethinyl-estradiol OR EE) AND (drospirenone OR DRSP) AND (chlormadinone acetate OR CMA) AND (polycystic ovary syndrome). METHODS: Records were screened for eligible studies and data were extracted to an online data extraction form. Outcomes of Ferryman-Gallwey score (FGS), body mass index, dehydroepiandrosterone sulfate (DHEAS), free androgen index, sex hormone-binding globulin, delta-4-androstenedione (A) and total testosterone levels (T) were pooled as weighted mean difference (WMD) and 95% confidence interval (CI) in a fixed effect meta-analysis model. RESULTS: Three RCTs (EE/DRSP: n = 98 and EE/CMA: n = 87) were pooled in the analysis. The overall effect favoured EE/DRSP over EE/CMA in reducing (A) levels after three months (WMD -0.63; 95% CI [-0.94, -0.32], P < 0.001), FGS after six months (WMD -0.44; 95% CI [-0.99, -0.19], P = 0.0006), and total (T) after three months (WMD -0.12; 95% CI [-0.23, -0.01], P = 0.03). CONCLUSIONS: EE/DRSP showed a more potent effect than EE/CMA in the reduction of FGS after six months, (A) levels and (T) levels after three months in patients with PCOS.

Adipose-derived stem cells: Effectiveness and advances in delivery in diabetic wound healing.

With the increasing global prevalence of diabetes mellitus, a significant rise in the number of patients suffering from non-healing wounds is expected. However, available treatments, such as revascularization surgery and foot care education are often insufficient to ensure satisfactory wound healing. One therapeutic strategy that has been identified as particularly promising utilizes adipose-derived stem cells (ADSCs). Through a comprehensive literature search of published and ongoing studies, we aimed to provide an overview of the experimental basis, the scientific background, and advances in the delivery of ADSCs for treating non-healing diabetic wounds. ADSCs have the capacity to differentiate into multiple cell lineages and are considered an alternative to bone marrow-derived mesenchymal stem cells. They can be easily extracted from the adipose tissue and are capable of in-vitro expansion. The reviewed experimental studies showed that ADSCs can enhance diabetic wound healing through increasing epithelialization and granulation tissue formation, anti-inflammatory and anti-apoptotic effects, and release of angiogenic cytokines. Moreover, few small clinical trials showed that ADSCs treatment in patients with diabetic ulcers caused enhanced ulcer evolution, lower pain scores, and improved claudication walking distances with no reported complications. In conclusion, ADSCs have a promising potential in the regenerative therapy of chronic diabetic wounds. However, larger studies should confirm their efficacy and long-term safety in diabetic patients.

Denosumab versus bisphosphonates in patients with advanced cancers-related bone metastasis: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Bone metastasis is reported to be associated with poor quality of life, and increased risk of hospitalization. We aim to synthesize evidence from published randomized controlled trials (RCTs) which compared the efficacy of denosumab versus bisphosphonates in patients with advanced cancers. METHODS: We searched for all published RCTs in the following electronic databases: PubMed, Scopus, Web of Science, and Cochrane Central. Retrieved records were screened for eligibility. Time-to-event data were pooled as hazard ratio (HR) using the generic inverse-variance method and dichotomous data were pooled as relative risk (RR) in a random-effect model. We used Review Manager 5.3 for windows. RESULTS: Six unique RCTs with a total of 7722 patients were included. Overall effect estimates favored denosumab group in comparison to intravenous (IV) bisphosphonates in the following terms: time to first skeletal-related events (HR 0.92, 95% CI [0.86, 0.98], p = 0.01), time to subsequent skeletal-related event (RR 0.92, 95% CI [0.86, 0.99], p = 0.03), and radiation to bone (RR 0.81, 95% CI [0.71, 0.92], p = 0.02). Denosumab group was associated with increased risk of grade 3 or 4 hypocalcaemia (RR 1.99, 95% CI [1.11, 3.54], p = 0.02) and reduced risk of renal impairment or toxicity (RR 0.75, 95% CI [0.61, 0.91], p = 0.003) in comparison to IV bisphosphonates group. Pooled studies were homogenous. CONCLUSION: Denosumab showed a favorable significant impact on delaying the time to first skeletal-related event and reducing the incidence of radiation to the bone event in comparison to bisphosphonates, with similar efficacy regarding overall survival and time to disease progression. Further large-scale and long-term studies are needed to clarify the long-term efficacy and safety of both regimens.

Safety and efficacy of sofosbuvir plus velpatasvir with or without ribavirin for chronic hepatitis C virus infection: A systematic review and meta-analysis.

Velpatasvir is a newly FDA-approved inhibitor of hepatitis C virus (HCV) NS5A protein. We performed this systematic review and meta-analysis to investigate the safety and efficacy of velpatasvir plus sofosbuvir in the treatment of chronic HCV infection. A computerized literature search of PubMed, SCOPUS, EMBASE, EBSCO, Web of science, and Cochrane CENTRAL was conducted using relevant keywords. Data from eligible studies were pooled in a fixed effect meta-analysis model, using OpenMeta[Analyst] software. Pooled data from six randomized trials (n=1427 patients) showed that velpatasvir plus sofosbuvir achieved sustained virological response (SVR12) rates of 98.2% in genotype-1, 99.4% in genotype-2, 94.7% in genotype-3, 99.6% in genotype-4, 97.1% in genotype-5, and 98.8% in genotype-6 patients. The addition of ribavirin did not significantly increase the SVR12 (RR=0.95, 95%CI [0.88, 1.02]) or decrease relapse rates (RR=2.52, 95% CI [0.49, 12.87]) in HCV genotype-1 patients. However, adding ribavirin significantly increased SVR12 (RR=89.5, 95% CI [80.4, 99.5]) in genotype-3 patients. In conclusion, the 12-week regimen of sofosbuvir plus velpatasvir was highly effective in HCV patients, including those with cirrhosis and former treatment experience. Except for genotype-3, adding ribavirin was not associated with significant improvements in SVR12 rates. Further studies should investigate the effect of adding ribavirin to this regimen, especially in HCV genotype-3 patients.

Efficacy and safety of atazanavir/ritonavir-based antiretroviral therapy for HIV-1 infected subjects: a systematic review and meta-analysis.

Atazanavir (ATZ) is a well-tolerated protease inhibitor that can be boosted with ritonavir (r) to treat infection with resistant strains of human immunodeficiency virus 1 (HIV-1). The aim of this meta-analysis was to compare the efficacy, safety, and metabolic effects of ATZ/r regimen versus commonly used antiretroviral drugs such as lopinavir (LPV) and darunavir (DRV) in HIV-1-infected patients. We searched PubMed, Scopus, Embase and Cochrane CENTRAL, using relevant keywords. Data were extracted from eligible randomized trials and pooled as risk ratios (RR) or standardized mean differences (SMD) in a meta-analysis model using RevMan software. Nine randomized controlled trials (RCTs) (3292 patients) were eligible for the final analysis. After 96 weeks of treatment, the pooled effect estimate did not favor either ATZ/r or LPV/r in terms of virological failure rate (RR 1.11, 95% CI [0.74, 1.66]). However, ATZ/r was marginally superior to LPV/r in terms of increasing the proportion of patients with HIV RNA <50 copies/ml (RR 1.09, 95% CI [1.01, 1.17]). The pooled effect estimate did not favor ATZ/r over DRV/r regarding the change in plasma levels of total cholesterol, triglycerides, or high-density lipoprotein at 24, 48, and 96 weeks. Moreover, no significant difference was found between the two regimens (ATZ/r and DRV/r) in terms of change in visceral (SMD -0.06, 95%CI [-0.33, 0.21]) or subcutaneous adipose tissue (SMD 0.12, 95% CI [-0.15, 0.39]). The ATZ/r regimen was generally as effective and well-tolerated as the LPV/r regimen for the treatment of HIV-1 patients. Compared to the DRV/r regimen, ATZ/r has no favorable effect on the plasma lipid profile or adipose tissue distribution.

Safety and efficacy of ocrelizumab in rheumatoid arthritis patients with an inadequate response to methotrexate or tumor necrosis factor inhibitors: a systematic review and meta-analysis.

We conducted this systematic reviews and meta-analysis to investigate the safety and efficacy of ocrelizumab in patients with active rheumatoid arthritis (RA) who exhibited resistance or intolerance to methotrexate or biological therapy. We performed a web-based literature search of PubMed, Google Scholar, EBSCO, Scopus, Embase, and Web of science for studies that compared ocrelizumab plus methotrexate versus methotrexate plus placebo in RA patients. Data were extracted from eligible studies and pooled as risk ratios (RR), using RevMan software. Pooling data from four RCTs (2230 patients) showed that ocrelizumab plus methotrexate were superior to methotrexate plus placebo at 24 weeks in terms of improvement on the American college of rheumatology (ACR20, ACR50, and ACR70) criteria (p < 0.00001), disease activity score 28-ESR (RR = 3.77, 95% CI [2.47, 5.74], p < 0.00001), and Sharp/van der Heijde radiological score (RR = 1.63, 95% CI [1.43, 1.85], p < 0.00001). These effects were consistent among all ocrelizumab doses. The rates of serious adverse events were comparable between the ocrelizumab and placebo containing groups (RR = 1, 95% CI [0.78, 1.28], p = 0.98). However, infusion related reactions were significantly higher in ocrelizumab group (RR = 2.13, 95% CI [1.69, 2.68], p < 0.00001), compared to placebo group. The combination of ocrelizumab plus methotrexate was superior to methotrexate plus placebo on all clinical and radiographic improvement scales. The incidence of adverse events, including serious adverse events, was comparable between both groups. Future trials should investigate the efficacy of ocrelizumab alone and develop strategies to alleviate its related infusion reactions.

Safety and Efficacy of Brodalumab for Moderate-to-Severe Plaque Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Psoriasis is an inflammatory skin disease that affects 2-3% of the worldwide population. The interleukin-17 cytokine family has been proven to play a central role in the pathogenesis of psoriasis. Brodalumab is a novel biologic agent that targets interleukin-17 molecules and their receptors. We aimed to evaluate the safety and efficacy of brodalumab as a therapeutic agent for moderate-to-severe psoriasis in a meta-analysis framework. METHODS: A computer literature search of PubMed, OVID, Cochrane Central, EMBASE, EBSCO, Scopus, and Web of Science was conducted using relevant keywords. Data were extracted from eligible trials and analyzed using RevMan (Version 5.3 for windows) and OpenMeta [Analyst] software. RESULTS: Six clinical trials (n = 4118 patients) were pooled in the final analysis. The pooled effect size favored brodalumab over placebo in terms of the Psoriasis Area and Severity Index (PASI) 75 [risk ratio (RR) = 12.61, 95% confidence interval (CI) 9.74-16.34], PASI 90 (RR = 28.72, 95% CI 18.34-44.98), and PASI 100 (RR = 61.23, 95% CI 25.48-147.17). Analysis of secondary outcomes showed that brodalumab was superior to placebo in terms of static physician's global assessment (RR = 32.53, 95% CI 13.80-76.69) and psoriasis symptoms inventory scores (RR = 14.70, 95% CI 8.38-25.78). Meta-regression analysis found a significant linear association between the brodalumab dose and the effect size on PASI and psoriasis symptoms inventory scores. The rate of overall adverse events was slightly higher in the brodalumab group (RR = 1.13, 95% CI 1.06-1.22); however, none of the individual adverse events were significantly higher in the brodalumab group, compared to the placebo group. CONCLUSION: Brodalumab showed an acceptable safety profile and a robust efficacy in the treatment of moderate-to-severe plaque psoriasis. However, the current evidence is insufficient to confirm maintenance of these results in the long term; therefore, larger studies with longer follow-up periods are required.

Meta-Analysis of Creatine for Neuroprotection Against Parkinson's Disease.

BACKGROUND: Creatine is an antioxidant agent that showed neuroprotective effects in animal models of Parkinson's disease (PD). Creatine was selected by the National Institute of Neurological Disorders and Stroke as a possible disease modifying agent for Parkinson's disease. Therefore, many clinical trials evaluated the efficacy of creatine for patients with PD. The aim of this systematic review and meta-analysis is to synthesize evidence from published randomized controlled trials (RCTs) about the efficacy of Creatine for patients with PD. METHODS: We followed PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for PubMed, EBSCO, web of science and Ovid Midline was carried out. We included RCTs comparing creatine with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, and UPDRS III were pooled as mean difference (MD) between two groups from baseline to the endpoint. Statistical heterogeneity was assessed by visual inspection of the forest plot and measured by chi-square and I square tests. RESULTS: Three RCTs (n=1935) were included in this study. The overall effect did not favor either of the two groups in terms of: UPDRS total score (MD 1.07, 95% CI [3.38 to 1.25], UPDRS III (MD 0.62, 95% CI [2.27 to 1.02]), UPDRS II (MD 0.03, 95% CI [0.81 to 0.86], or UPDRS I (MD 0.03, 95% CI [0.33 to 0.28]). CONCLUSION: Current evidence does not support the use of creatine for neuroprotection against PD. Future well-designed, randomized controlled trials are needed.

Meta-analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypotension.

PURPOSE: Droxidopa has been approved for the treatment of neurogenic orthostatic hypotension (NOH) under the US Food and Drug Administration accelerated approval program, which warrants confirmatory evidence on long-term efficacy of droxidopa. Hereby, we synthesize evidence from published randomized controlled trials (RCTs) about the safety and efficacy of droxidopa for patients with neurogenic orthostatic hypotension. METHODS: A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager version 5.3 for Windows. Subgroup analysis and sensitivity analysis were conducted to investigate long-term durability of droxidopa against placebo. RESULTS: Four RCTs with a total of 485 patients (droxidopa, n = 246; placebo, n = 239) were eligible for the final analysis. The mean difference (MD) of change in the main outcomes from baseline to endpoint favored droxidopa than placebo [Orthostatic Hypotension Questionnaire (OHQ) MD -0.61, P = 0.004; dizziness/lightheadedness score MD -0.83, P = 0.008; and standing systolic blood pressure (SBP) MD 4.09, P = 0.03]. The efficacy of droxidopa decreased gradually after 2 weeks, and its statistical significance was lost after 8 weeks (OHQ score MD -0.18, P = 0.61; dizziness/lightheadedness score MD -0.71, P = 0.11; and standing SBP MD 2.96, P = 0.29). None of the adverse events were significantly higher in the case of droxidopa compared to placebo. CONCLUSION: Droxidopa is a safe and effective drug for the short-term management of NOH symptoms. However, current evidence is insufficient to confirm the efficacy of droxidopa for long-term use. Therefore, further studies with increased sample size are needed.