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Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.
Paganoni, S, Hendrix, S, Dickson, SP, Knowlton, N, Macklin, EA, Berry, JD, Elliott, MA, Maiser, S, Karam, C, Caress, JB, et al
Muscle & nerve. 2021;(1):31-39
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Abstract
An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.
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Efficacy and safety of cerebrolysin in neurorecovery after moderate-severe traumatic brain injury: results from the CAPTAIN II trial.
Muresanu, DF, Florian, S, Hömberg, V, Matula, C, von Steinbüchel, N, Vos, PE, von Wild, K, Birle, C, Muresanu, I, Slavoaca, D, et al
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2020;(5):1171-1181
Abstract
INTRODUCTION The objective of this trial was to evaluate the efficacy and safety of Cerebrolysin in treating patients after moderate to severe traumatic brain injury (TBI) as an adjunct to standard care protocols. The trial was designed to investigate the clinical effects of Cerebrolysin in the acute (neuroprotective) stage and during early and long-term recovery as part of a neurorestorative strategy. MATERIALS AND METHODS The study was a phase IIIb/IV single-center, prospective, randomized, double-blind, placebo-controlled clinical trial. Eligible patients with a Glasgow Coma Score (GCS) between 7 and 12 received study medication (50 ml of Cerebrolysin or physiological saline solution per day for 10 days, followed by two additional treatment cycles with 10 ml per day for 10 days) in addition to standard care. We tested ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses using a multivariate, directional test, to reflect the global status of patients after TBI. RESULTS The study enrolled 142 patients, of which 139 underwent formal analysis (mean age = 47.4, mean admission GCS = 10.4, and mean Baseline Prognostic Risk Score = 2.6). The primary endpoint, a multidimensional ensemble of 13 outcome scales, indicated a "small-to-medium"-sized effect in favor of Cerebrolysin, statistically significant at day 90 (MWcombined = 0.59, 95% CI 0.52 to 0.66, P = 0.0119). Safety and tolerability observations were comparable between treatment groups. CONCLUSION Our trial confirms previous beneficial effects of the multimodal, biological agent Cerebrolysin for overall outcome after moderate to severe TBI, as measured by a multidimensional approach. Study findings must be appraised and aggregated in conjunction with existing literature, as to improve the overall level of insight regarding therapeutic options for TBI patients. The widely used pharmacologic intervention may benefit from a large-scale observational study to map its use and to establish comparative effectiveness in real-world clinical settings.
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Effects of edaravone on postoperative cognitive function in elderly patients undergoing hip joint replacement surgery: A randomized controlled trial.
Zhang, NN, Sun, L, Chen, WT, Yang, YL, Wu, YM
International journal of surgery (London, England). 2020;:13-18
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Abstract
BACKGROUND Postoperative cognitive dysfunction (POCD) is a complication of central nervous system in patients after surgery. Edaravone as a brain-protective agent may have protective effect on postoperative cognitive function. The study was designed to explore the effects of edaravone on postoperative cognitive function in elderly patients undergoing hip joint replacement surgery and potential mechanism. PATIENTS AND METHODS Patients undergoing hip joint replacement surgery were randomly allocated into 2 groups: the edaravone group (group E) and the control group (group C). Group E received intravenous edaravone at a dose of 0.5 mg/kg after induction of anesthesia, while group C received normal saline. The cognitive function was evaluated with the Mini-Mental State Examination (MMSE) 1day before surgery,3 days and the 7 days after surgery. Patients' plasma samples were collected to detect the levels of S100β protein (S100β), interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), superoxide dismutase (SOD) and malondialdehyde (MDA) before the induction of anesthesia, at the end of surgery and on postoperative day 3. RESULTS The MMSE scores in group E were higher than those of group C 3 days after surgery (25.98 ± 1.99 vs 24.86 ± 1.86, p = 0.003). There were remarkable rises (p < 0.05) in plasma IL-6, S100βand MMP-9 levels at the end of surgery and on postoperative day 3 in the two groups, however, edaravone pretreatment could reduce these levels to a certain extent compared with group C (p < 0.05).In group E, the SOD concentration was higher at the end of surgery (16.03 ± 2.46U/ml vs. 13.65 ± 2.53U/ml, p = 0.0001), while the MDA level was lower on postoperative day 3 than those in group C (7.01 ± 2.37 nmol/ml vs. 11.34 ± 3.18 nmol/ml, p = 0.0001). CONCLUSION The results indicated that preoperative intervention with edaravone may improve the postoperative cognitive function in elderly patients undergoing hip joint replacement surgery.
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Effects of Butyphthalide Combined with Idebenone on Inflammatory Cytokines and Vascular Endothelial Functions of Patients with Vascular Dementia.
Qi, FX, Hu, Y, Kang, LJ, Li, P, Gao, TC, Zhang, X
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2020;(1):23-27
Abstract
OBJECTIVE To determinate the clinical effect of butyphthalide combined with idebenone in the treatment of vascular dementia (VD) and the influence on inflammatory cytokines and vascular endothelial functions. STUDY DESIGN Clinical comparative study. PLACE AND DURATION OF STUDY Department of Neurology, Baoding First Central Hospital, from June 2017 to June 2018. METHODOLOGY Eighty-eight VD patients were divided into observation group (44 cases) and control group (44 cases) at random. Idebenone was given to the control group, and butyphthalide combined with idebenone was given to the observation group for 12 weeks. C-reactive protein (CRP), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected before and after the treatment to evaluate the level of serum inflammatory factors. Peripheral blood endothelial microparticles (EMPs), endothelin (ET-1), and vascular endothelial growth factor (VEGF) were detected to evaluate vascular endothelial functions. Mini-mental state examination (MMSE), clinical dementia scale (CDR), and ability of daily life (ADL), were used to evaluate cognitive function, dementia degree, and self-care ability in daily life. The occurrences of adverse reactions were recorded. RESULTS Before the treatment, the comparison differences in the indexes of both groups had no statistical significance (p>0.05). After the treatment, the scores of CD62E+, VEGF, and MMSE of observation group rose obviously, compared with those before the treatment, and were significantly higher than those of control group (p <0.05). After the treatment, the scores of IL-6, CRP, TNF-α, IL-1β, CD31+, CDl44+, ET-1, CDR and ADL of observation group significantly lowered, compared with those before the treatment, and were significantly lower than those of control group (p <0.05). The differences in the adverse reactions of both groups had no statistical significance (p >0.05). CONCLUSION Butyphthalide combined with idebenone can effectively reduce serum inflammatory factor level of VD patients, regulate vascular endothelial functions, relieve dementia degree, and improve cognitive function and daily activity ability.
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Coenzyme Q10 supplementation in acute ischemic stroke: Is it beneficial in short-term administration?
Ramezani, M, Sahraei, Z, Simani, L, Heydari, K, Shahidi, F
Nutritional neuroscience. 2020;(8):640-645
Abstract
Backgrounds and aims: Clinical studies demonstrated that the efficacy of Coenzyme Q10 (CoQ10) as an adjuvant therapeutic agent in several neurological diseases such as Parkinson disease (PD), Huntington disease (HD), and migraine. The purpose of this study is to investigate oxidative stress effects, antioxidant enzymes activity, neuroinflammatory markers levels, and neurological outcome in acute ischemic stroke (AIS) patients following administration of CoQ10 (300 mg/day). Methods: Patients with AIS (n = 60) were randomly assigned to a placebo group (wheat starch, n = 30) or CoQ10-supplemented group (300 mg/day, n = 30). The intervention was administered for 4 weeks. Serum CoQ10 concentration, malondialdehyde (MDA), superoxide dismutase (SOD) activity, glial fibrillary acidic protein (GFAP) levels as primary outcomes and National Institute of Health Stroke Scale (NIHSS), Modified Ranking Scale (MRS), and Mini-Mental State Examination (MMSE) as secondary outcome were measured at the both beginning and end of the study. Results: Forty-four subjects with AIS completed the intervention study. A significant increase in CoQ10 level was observed in the supplement-treated group compared with placebo group (mean difference = 26.05 ± 26.63 ng/ml, 14.12 ± 14.69 ng/ml, respectively; P = 0.01), moreover CoQ10 supplementation improved NIHSS and MMSE scores significantly (P = 0.05, P = 0.03 respectively). but there were no statistically significant differences in MRS score, MDA, SOD, and GFAP levels between the two groups. Conclusions: CoQ10 probably due to low dose and short duration of supplementation, no favorable effects on MDA level, SOD activity and GFAP level.
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Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage.
Woo, PYM, Ho, JWK, Ko, NMW, Li, RPT, Jian, L, Chu, ACH, Kwan, MCL, Chan, Y, Wong, AKS, Wong, HT, et al
BMC neurology. 2020;(1):401
Abstract
ASBTRACT BACKGROUND There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. METHODS This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). RESULTS No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59). CONCLUSIONS Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. CLINICAL TRIAL REGISTRATION Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.
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A randomized controlled trial on the use of magnesium sulfate and melatonin in neonatal hypoxic ischemic encephalopathy.
El Farargy, MS, Soliman, NA
Journal of neonatal-perinatal medicine. 2019;(4):379-384
Abstract
BACKGROUND Birth asphyxia is a leading case of neonatal morbidity and mortality especially in developing countries. Hypoxic-ischemic encephalopathy (HIE) attributed to asphyxia can be ameliorated with several remedies, although full recovery is currently not feasible. The aim of this trial on infants with HIE who are receiving melatonin therapy, is to assess the added effect of magnesium sulfate (MgSO4) on the expression of S100-B, a marker of brain injury. METHODS This study is a randomized controlled trial on neonates with moderate HIE (Sarnat grade II). Infants were randomized into 2 groups; group1 who received MgSO4 and melatonin; and group 2 who received melatonin only. Serum concentrations of S100-B were measured at baseline, and at days 2 and 6 of therapy. RESULTS The study included 60 neonates of them 30 infants in group 1 and 30 infants in group 2. S100-B did not differ between groups 1 and 2 at enrollment (median = 13.5 vs 13.2, p = 0.381). However, group 1 had lower concentrations of S100-B at 2 days (median = 8 vs 12, p = 0.001) and at 6 days (median = 3 vs 10.5, p < 0.001), respectively. Compared to baseline, S100-B decreased in in group 2 at day 6 (13.2 vs 10.5, p = 0.011) but did not decrease at day 2 (13.2 vs 12, p = 0.478). CONCLUSIONS MgSO4 may have an added effect for the reduction in brain injury in infants with HIE who are receiving melatonin.
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Outcomes of Perilla Seed Oil as an Additional Neuroprotective Therapy in Patients with Mild to Moderate Dementia: A Randomized Control Trial.
Kamalashiran, C, Sriyakul, K, Pattaraarchachai, J, Muengtaweepongsa, S
Current Alzheimer research. 2019;(2):146-155
Abstract
BACKGROUND Dementia is a common medical disorder in the elderly. Oxidative stress plays a major role in the process of cognitive decline in dementia. Perilla seed oil demonstrates its neuroprotective effects via anti-oxidative mechanisms against dementia. We investigate neuroprotective effects of perilla seed oil as an additional treatment in patients with mild to moderate dementia. METHOD A double-blind, randomized-control trial (perilla seed oil versus placebo) in patients with mild to moderate dementia was conducted. Perilla seed oil or placebo was added on with standard treatment for six months. Cognitive function was compared at nine months after enrollment. RESULT 182 patients, with 94 in the experimental group and 88 in the placebo group, were able to complete the study. Cognitive function is not significantly different compared between groups. However, the total cholesterol and LDL cholesterol were significantly lower in the experimental group. Perilla seed oil had no adverse effect to kidney, liver, blood components or glucose metabolism. CONCLUSION Perilla seed oil as additional neuroprotective therapy in patients with mild to moderate dementia does not improve cognitive function. Perilla seed oil significantly reduced total cholesterol and LDL cholesterol. A clinical trial is needed to prove the benefit of cholesterol-lowering effects with perilla seed oil in human.
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Effect of topiramate on eating behaviours in Prader-Willi syndrome: TOPRADER double-blind randomised placebo-controlled study.
Consoli, A, Çabal Berthoumieu, S, Raffin, M, Thuilleaux, D, Poitou, C, Coupaye, M, Pinto, G, Lebbah, S, Zahr, N, Tauber, M, et al
Translational psychiatry. 2019;(1):274
Abstract
Prader-Willi Syndrome (PWS) is a rare genetic syndrome leading to severe behavioural disorders and mild cognitive impairment. The objective of this double-blind randomised placebo-controlled trial was to study the efficacy and tolerance of topiramate on behavioural disorders in patients with PWS. Participants (aged 12-45 years) had genetically confirmed PWS and severe irritability/impulsivity, eating disorders and/or obesity, and skin picking. Thirty-two participants received a placebo (PBO), and 30 participants received topiramate (TOP) (50-200 mg/day) for 8 weeks. The primary outcome was the rate of responders using the Clinical Global Impression-Improvement (CGI-I) scale. The secondary outcome measures included the Aberrant Behaviour Checklist, the Dykens Hyperphagia Questionnaire (DHK), the Self-Injurious Behaviour Scale (SIBS) and the body mass index (BMI). We found no significant difference in the primary outcome (the CGI-I): 9 (30%) patients were very much or much improved in the TOP group compared to 7 (22.6%) patients in the PBO group. However, the DHK behaviour and severity scores improved significantly more over time in patients treated with topiramate versus those receiving a placebo, with a significant dose-effect relationship. DHK scores were also significantly associated with genetic subtypes and hospitalisation status. The effects of topiramate on eating behaviours remained significant after adjusting for genetic subtype and hospitalisation. Topiramate had therefore a significant effect on eating disorders, with a dose-effect relationship. Given the burden of eating disorders in PWS, we believe that topiramate may become the first psychotropic option within the global care of obesity in individuals with PWS.
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Neuroprotective role of dexmedetomidine in epilepsy surgery: A preliminary study.
Bindra, A, Kaushal, A, Prabhakar, H, Chaturvedi, A, Chandra, PS, Tripathi, M, Subbiah, V, Sathianathan, S, Banerjee, J, Prakash, C
Neurology India. 2019;(1):163-168
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Abstract
PURPOSE Long standing temporal lobe epilepsy (TLE) causes cerebral insult and results in elevated brain injury biomarkers, S100b and neuron specific enolase (NSE). Surgery for TLE, has the potential to cause additional cerebral insult. Dexmedetomidine is postulated to have neuroprotective effects. The aim of this study was to assess the effect of intraoperative dexmedetomidine on S100b and NSE during TLE surgery. MATERIALS AND METHODS 19 consenting adult patients with TLE undergoing anteromedial temporal lobectomy were enrolled and divided into two groups. Patients in Group D (n = 9) received dexmedetomidine whereas patients in Group C (n = 10) received saline as placebo in addition to the standard anaesthesia technique. Blood samples of these patients were drawn, before induction of anaesthesia, at the end of surgery, as well at 24 hours and 48 hours postoperatively, and analysed for serum S100b and NSE. RESULTS The demographic and clinical profile was comparable in both the groups. The baseline S100b in group C and group D was 66.7 ± 26.5 pg/ml and 34.3 ± 21.7 pg/ml (P = 0.013) respectively. After adjustment for the baseline, the overall value of S100b was 71.0 ± 39.8 pg/ml and 40.5 ± 22.5 pg/ml (P = 0.002) in the control and study group, respectively. The values of S100b (79.3 ± 53.6 pg/ml) [P = 0.017] were highest at 24 hours postoperatively. The mean value of NSE in the control and study group was 32.8 ± 43.4 ng/ml (log 3.0 ± 0.1) and 13.51 ± 9.12 ng/ml (log 2.42 ± 0.60), respectively. The value of NSE in both the groups was comparable at different time points. CONCLUSIONS Lower perioperative values of S100b were observed in patients who received intraoperative dexmedetomidine. Dexmedetomidine may play a role in cerebroprotection during epilepsy surgery.