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Tocotrienol-Rich Vitamin E (Tocovid) Improved Nerve Conduction Velocity in Type 2 Diabetes Mellitus Patients in a Phase II Double-Blind, Randomized Controlled Clinical Trial.
Chuar, PF, Ng, YT, Phang, SCW, Koay, YY, Ho, JI, Ho, LS, Botross Henien, NP, Ahmad, B, Abdul Kadir, K
Nutrients. 2021;(11)
Abstract
Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes that affects approximately half of the diabetic population. Up to 53% of DPN patients experience neuropathic pain, which leads to a reduction in the quality of life and work productivity. Tocotrienols have been shown to possess antioxidant, anti-inflammatory, and neuroprotective properties in preclinical and clinical studies. This study aimed to investigate the effects of tocotrienol-rich vitamin E (Tocovid SuprabioTM) on nerve conduction parameters and serum biomarkers among patients with type 2 diabetes mellitus (T2DM). A total of 88 patients were randomized to receive 200 mg of Tocovid twice daily, or a matching placebo for 12 months. Fasting blood samples were collected for measurements of HbA1c, renal profile, lipid profile, and biomarkers. A nerve conduction study (NCS) was performed on all patients at baseline and subsequently at 2, 6, 12 months. Patients were reassessed after 6 months of washout. After 12 months of supplementation, patients in the Tocovid group exhibited highly significant improvements in conduction velocity (CV) of both median and sural sensory nerves as compared to those in the placebo group. The between-intervention-group differences (treatment effects) in CV were 1.60 m/s (95% CI: 0.70, 2.40) for the median nerve and 2.10 m/s (95% CI: 1.50, 2.90) for the sural nerve. A significant difference in peak velocity (PV) was also observed in the sural nerve (2.10 m/s; 95% CI: 1.00, 3.20) after 12 months. Significant improvements in CV were only observed up to 6 months in the tibial motor nerve, 1.30 m/s (95% CI: 0.60, 2.20). There were no significant changes in serum biomarkers, transforming growth factor beta-1 (TGFβ-1), or vascular endothelial growth factor A (VEGF-A). After 6 months of washout, there were no significant differences from baseline between groups in nerve conduction parameters of all three nerves. Tocovid at 400 mg/day significantly improve tibial motor nerve CV up to 6 months, but median and sural sensory nerve CV in up to 12 months of supplementation. All improvements diminished after 6 months of washout.
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Does the use of the largest possible metal head increase the wear of vitamin E-doped cross-linked polyethylene? Two-year results from a randomized controlled trial.
Tsikandylakis, G, Mortensen, KRL, Gromov, K, Mohaddes, M, Malchau, H, Troelsen, A
The bone & joint journal. 2021;(7):1206-1214
Abstract
AIMS: We aimed to investigate if the use of the largest possible cobalt-chromium head articulating with polyethylene acetabular inserts would increase the in vivo wear rate in total hip arthroplasty. METHODS In a single-blinded randomized controlled trial, 96 patients (43 females), at a median age of 63 years (interquartile range (IQR) 57 to 69), were allocated to receive either the largest possible modular femoral head (36 mm to 44 mm) in the thinnest possible insert or a standard 32 mm head. All patients received a vitamin E-doped cross-linked polyethylene insert and a cobalt-chromium head. The primary outcome was proximal head penetration measured with radiostereometric analysis (RSA) at two years. Secondary outcomes were volumetric wear, periacetabular radiolucencies, and patient-reported outcomes. RESULTS At two years, 44 patients in each group were available for RSA assessment. The median total two-year proximal head penetration was -0.02 mm (IQR -0.09 to 0.07; p = 0.548) for the largest possible head and -0.01 mm (IQR -0.07 to 0.10; p = 0.525) for 32 mm heads. Their difference was not statistically significant (p = 0.323). Neither group demonstrated a bedding-in period. The median steady-state volumetric wear rates were 6.1 mm3/year (IQR -59 to 57) and 3.5 mm3/year (-21 to 34) respectively, and did not differ between the groups (p = 0.848). There were no statistically significant differences in periacetabular radiolucencies or patient-reported outcomes. CONCLUSION The use of the largest possible metal head did not increase vitamin E-doped cross-linked polyethylene wear compared with 32 mm heads at two years. Linear wear was negligible and volumetric wear rates were very low in both head size groups. There was a tendency towards higher values of volumetric wear in large heads that warrants longer-term evaluation before any definite conclusions about the association between head size and wear can be drawn. Cite this article: Bone Joint J 2021;103-B(7):1206-1214.
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The Effects of Tocotrienol-Rich Vitamin E (Tocovid) on Diabetic Neuropathy: A Phase II Randomized Controlled Trial.
Ng, YT, Phang, SCW, Tan, GCJ, Ng, EY, Botross Henien, NP, M Palanisamy, UD, Ahmad, B, Abdul Kadir, K
Nutrients. 2020;(5)
Abstract
Chronic hyperglycemia increases oxidative stress, activates inflammatory pathways and reduces nerve growth factor (NGF) among diabetic patients, which contribute to development of diabetic peripheral neuropathy (DPN). Tocotrienol-Rich Vitamin E (Tocovid) possesses potent antioxidant and anti-inflammatory properties which are postulated to target these pathogeneses in order to ameliorate DPN. This study aims to evaluate the effects of Tocovid on nerve conduction parameters and serum biomarkers among diabetic patients. This multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial was conducted on 80 eligible participants. The intervention group (n = 39) was randomly allocated to receive 200 mg of Tocovid twice a day, and the control group (n = 41) received placebo twice a day. At the end of eight weeks, the nerve conduction parameters, as assessed by nerve conduction study, as well as serum biomarkers (NGF, malondialdehyde, vascular cell adhesion molecule 1, tumor necrosis factor receptor 1 and thromboxane B2) were compared between the two groups. Compared to placebo, Tocovid significantly improves the nerve conduction velocities of all nerves (+1.25 m/s, interquartile range [IQR] 3.35, p < 0.001, median nerve; +1.60 m/s, IQR 1.80, p < 0.001, sural nerve; +0.75 m/s, IQR 2.25, p < 0.001, tibial nerve). Meanwhile, the levels of serum NGF were significantly higher in the Tocovid group as compared to placebo at eight weeks post-intervention. Participants receiving Tocovid illustrated highly significant improvement in terms of nerve conduction velocities for all nerves tested after eight weeks of supplementation. In addition, Tocovid supplementation elevated the levels of serum NGF, in which its increase is postulated to reflect enhanced neuronal functions. This novel finding suggests that Tocovid could be a disease-modifying agent targeting serum NGF to improve nerve conduction velocities.
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Adverse Maternal and Neonatal Outcomes in Indicated Compared with Spontaneous Preterm Birth in Healthy Nulliparas: A Secondary Analysis of a Randomized Trial.
Tita, AT, Doherty, L, Roberts, JM, Myatt, L, Leveno, KJ, Varner, MW, Wapner, RJ, Thorp, JM, Mercer, BM, Peaceman, A, et al
American journal of perinatology. 2018;(7):624-631
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Abstract
OBJECTIVE To compare the risks of adverse maternal and neonatal outcomes associated with spontaneous (SPTB) versus indicated preterm births (IPTB). METHODS A secondary analysis of a multicenter trial of vitamin C and E supplementation in healthy low-risk nulliparous women. Outcomes were compared between women with SPTB (due to spontaneous membrane rupture or labor) and those with IPTB (due to medical or obstetric complications). A primary maternal composite outcome included: death, pulmonary edema, blood transfusion, adult respiratory distress syndrome (RDS), cerebrovascular accident, acute tubular necrosis, disseminated intravascular coagulopathy, or liver rupture. A neonatal composite outcome included: neonatal death, RDS, grades III or IV intraventricular hemorrhage (IVH), sepsis, necrotizing enterocolitis (NEC), or retinopathy of prematurity. RESULTS Of 9,867 women, 10.4% (N = 1,038) were PTBs; 32.7% (n = 340) IPTBs and 67.3% (n = 698) SPTBs. Compared with SPTB, the composite maternal outcome was more frequent in IPTB-4.4% versus 0.9% (adjusted odds ratio [aOR], 4.0; 95% confidence interval [CI], 1.4-11.8), as were blood transfusion and prolonged hospital stay (3.2 and 3.7 times, respectively). The frequency of composite neonatal outcome was higher in IPTBs (aOR, 1.8; 95% CI, 1.1-3.0), as were RDS (1.7 times), small for gestational age (SGA) < 5th percentile (7.9 times), and neonatal intensive care unit (NICU) admission (1.8 times). CONCLUSION Adverse maternal and neonatal outcomes were significantly more likely with IPTB than with SPTB.
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Evaluation of in vivo wear of vitamin E-diffused highly crosslinked polyethylene at five years: a multicentre radiostereometric analysis study.
Galea, VP, Connelly, JW, Shareghi, B, Kärrholm, J, Sköldenberg, O, Salemyr, M, Laursen, MB, Muratoglu, O, Bragdon, C, Malchau, H
The bone & joint journal. 2018;(12):1592-1599
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AIMS: The primary aim of this study was to compare the wear properties of vitamin E-diffused, highly crosslinked polyethylene (VEPE) and one formulation of moderately crosslinked and mechanically annealed ultra-high molecular weight polyethylene (ModXLPE) in patients five years after primary total hip arthroplasty (THA). The secondary aim was to assess the clinical results of patients treated with VEPE by evaluating patient-reported outcome measures (PROMs), radiological evidence of fixation, and the incidence of mechanical failure. PATIENTS AND METHODS A total of 208 patients (221 THAs) from four international centres were recruited into a prospective study involving radiostereometric analysis (RSA) and the assessment of clinical outcomes. A total of 193 hips (87%) were reviewed at the five-year follow-up. Of these, 136 (70%) received VEPE (vs ModXLPE) liners and 68 (35%) received ceramic (vs metal) femoral heads. PROMs and radiographs were collected preoperatively and at one, two, and five years postoperatively. In addition, RSA images were collected to measure PE wear postoperatively and at one, two, and five years after surgery. RESULTS We observed similar bedding in one year postoperatively and wear two years postoperatively between the two types of liner. However, there was significantly more penetration of the femoral head in the ModXLPE cohort compared with the VEPE cohort five years postoperatively (p < 0.001). The only variables independently predictive of increased wear were ModXLPE (vs VEPE) liner type (β = 0.22, p = 0.010) and metal (vs ceramic) femoral head (β = 0.21, p = 0.013). There was no association between increased wear and the development of radiolucency (p = 0.866) or PROMs. No patient had evidence of osteolysis. CONCLUSION Five years postoperatively, patients with VEPE (vs ModXLPE) and ceramic (vs metal) femoral heads had decreased wear. The rates of wear for both liners were very low and have not led to any osteolysis or implant failure due to aseptic loosening.
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Effect of Maternal Smoking on Plasma and Urinary Measures of Vitamin E Isoforms in the First Month after Extreme Preterm Birth.
Stone, C, Qiu, Y, Kurland, IJ, Slaughter, JC, Moore, P, Cook-Mills, J, Hartert, T, Aschner, JL
The Journal of pediatrics. 2018;:280-285.e3
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We examined the effect of maternal smoking on plasma and urinary levels of vitamin E isoforms in preterm infants. Maternal smoking during pregnancy decreased infant plasma alpha- and gamma-tocopherol concentrations at 1 week and 4 weeks, with 45% of infants of smokers deficient in alpha-tocopherol at 1 month after birth.
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Haptoglobin Genotype and Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis in China: A Multicenter, Randomized, Placebo-Controlled Trial Design.
Zang, S, Chen, J, Song, Y, Bai, L, Chen, J, Chi, X, He, F, Sheng, H, Wang, J, Xie, S, et al
Advances in therapy. 2018;(2):218-231
Abstract
INTRODUCTION Vitamin E is one of the most promising agents for nonalcoholic steatohepatitis (NASH) treatment, and its drug responsiveness may be closely associated with haptoglobin (Hp) genotype. However, its efficacy and safety remain unknown in China. This clinical trial of vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis (VENS) is conducted to evaluate (a) the efficacy and safety of treatment with vitamin E softgel (300 mg/day) determined from standardized histologic scoring of liver biopsies, (b) whether treatment with vitamin E improves biochemical parameters, cytokines, anthropometric parameters, controlled attenuation parameter (CAP), and transient elastography (TE) values determined by Fibroscan and health-related quality of life (SF-36), (c) whether the efficacy of vitamin E treatment is associated with the Hp genotype in nondiabetic adults with NASH. METHODS VENS is a multicenter, randomized, double-masked, placebo parallel controlled trial to evaluate the efficacy and safety of treatment with vitamin E softgel in nondiabetic adults with NASH versus treatment with placebo in China. Liver biopsies are read by a pathological evaluation committee independently according to the NASH Clinical Research Network (CRN) scoring system. The NAFLD activity score (NAS) represents the sum of scores for steatosis, lobular inflammation, and hepatocyte ballooning. The definition of histologic improvement requires all three of the following criteria to be met: (a) either improvement in NAS by at least 2 points or post-treatment NAS score no higher than 3, (b) at least 1-point improvement in the score for ballooning, and (c) no worsening of fibrosis stages. We plan to recruit 120 biopsy-proven NASH patients from13 centers in China. Participants will be randomly assigned to groups treated with either with vitamin E (100 mg, tid) or placebo for 96 weeks then followed by 24 weeks of post-treatment observation. Biochemical parameters, cytokines, anthropometric parameters, CAP and TE values, Hp genotype, and several questionnaires will be collected as per the schedule. This protocol was approved by the Ethics Committee of Hangzhou Normal University Affiliated Hospital to ensure patients safety, and R&G Pharmastudies Co., Ltd. was established for monitoring the accumulated interim data to review efficacy and quality of data collection and overall study management. RESULTS As a preliminary study, a mobile phone application (app) for lifestyle modification and database recording ( http://laiyivens.365hy.com ) was exploited for every participant. The percentage of NAFLD patients with Hp 2-2 allele is much higher than that of Western patients (65.71% vs 36%, respectively), which suggests that the Chinese benefit more from vitamin E treatment. CONCLUSION VENS is the first randomized controlled trial (RCT) to evaluate the efficacy of Vitamin E in treating nondiabetic NASH patients in China. TRIAL REGISTRATION This study registered at https://clinicaltrials.gov (registration number: NCT02962297). FUNDING Zhejiang Medicine Co., Ltd.
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3-year follow-up of a long-term registry-based multicentre study on vitamin E diffused polyethylene in total hip replacement.
Sillesen, NH, Greene, ME, Nebergall, AK, Huddleston, JI, Emerson, R, Gebuhr, P, Troelsen, A, Malchau, H
Hip international : the journal of clinical and experimental research on hip pathology and therapy. 2016;(1):97-103
Abstract
PURPOSE Preclinical studies of vitamin E diffused highly cross-linked polyethylene (E-XLPE) has shown enhanced mechanical properties with less wear. The purpose of our study was to document the early clinical outcome of E-XLPE to ensure, for the safety of patients, that there are no unforeseen early adverse events from using this new biomaterial. METHODS The enrolled patients (n = 977) have received either a porous titanium coated or porous plasma sprayed acetabular shell with either a E-XLPE liner or a medium cross-linked (AXL) liner. At each follow-up 5 patient-reported outcome measures (PROMs) were completed: Harris Hip Score, Case Mix Indicator, UCLA Activity Score, SF-36, and EQ-5D. Radiographs were measured for cup and stem position, as well as femoral head penetration into the liner (wear). Postoperative complications and revisions were collected. RESULTS At 3 years follow-up, there were 13 revisions due to: 4 periprosthetic fractures; 1 sepsis; 6 instabilities; and 2 implant mismatches at surgery. Wear of the hip implant, calculated by software analysis of pelvis x-rays, from the postoperative interval to 3 years showed a liner penetration rate of 0.027 mm/year for AXL and 0.005 mm/year for E-XLPE with no significant difference between the 2 (p = 0.24). Improvement was seen in all PROMs from the preoperative interval to 3 years after surgery (p<0.0001). CONCLUSIONS Early follow-up of the E-XLPE and AXL liners show low penetration. PROMs indicate improvement after total hip arthroplasty in functionality and quality of life across the centers. We have not observed any early in vivo adverse effects from diffusing the liners with vitamin E. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00545285.
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Vitamin E-Coated and Heparin-Coated Dialyzer Membranes for Heparin-Free Hemodialysis: A Multicenter, Randomized, Crossover Trial.
Islam, MS, Hassan, ZA, Chalmin, F, Vido, S, Berrada, M, Verhelst, D, Donnadieu, P, Moranne, O, Esnault, VL
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016;(5):752-762
Abstract
BACKGROUND Hemodialysis requires effective anticoagulation to avoid blood circuit clotting. In patients at high risk for bleeding, several alternative methods have been developed. STUDY DESIGN Multicenter, prospective, randomized, crossover study evaluating the noninferiority of vitamin E-coated compared with heparin-coated dialyzers in a 4-hour heparin-free hemodialysis strategy. SETTINGS & PARTICIPANTS 32 adult long-term hemodialysis patients from 2 French hemodialysis units with well-functioning fistulas or double-lumen catheters. INTERVENTION Patients were randomly allocated to a first period using either vitamin E- or heparin-coated dialyzers. After a washout period of 2 hemodialysis sessions, each patient was switched to the alternative dialyzer for a second period. Each study period started with 2 hemodialysis sessions with reduced heparin dose (50% and 25% of usual heparin dose, respectively, for sessions 1 and 2) followed by 2 heparin-free sessions. OUTCOMES The primary end point was the percentage of successful study periods, defined as no circuit-clotting event leading to premature interruption of any of the 4 dialysis sessions. Secondary end points included total number and cumulative duration of hemodialysis sessions without clotting, number of saline solution flushes, dialysis circuit bubble trap status and dialyzer membrane status by visual inspection, and dialysis adequacy. RESULTS The percentage of success with vitamin E-coated dialyzers (25/32 study periods [78%]) was not inferior to that with heparin-coated dialyzers (26/32 study periods [81%]). Visual inspection showed equal numbers of clean dialysis circuit bubble traps (vitamin E-coated, 34/121; heparin-coated, 32/120), whereas clean fiber bundles were more frequently noted with the vitamin E-coated compared with heparin-coated dialyzers (25/121 vs 2/120; P=0.002). LIMITATIONS Results may not extrapolate to critically ill patients. Differences in dialyzer transparency may account for visual inspection scores. CONCLUSIONS The success rate of 4-hour heparin-free hemodialysis sessions is lower than that previously claimed in uncontrolled studies. Vitamin E-coated and heparin-coated dialyzers exposed patients to similar and unacceptable high failure rates. Further studies are required to improve heparin-free hemodialysis.
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Vitamins (A, C and E) and oxidative status of hemodialysis patients treated with HFR and HFR-Supra.
Palleschi, S, Ghezzi, PM, Palladino, G, Rossi, B, Ganadu, M, Casu, D, Cossu, M, Mattana, G, Pinna, AM, Contu, B, et al
BMC nephrology. 2016;(1):120
Abstract
BACKGROUND Hemodiafiltration with on-line endogenous reinfusion (HFR) is an extracorporeal dialytic method that combines diffusion, convection and adsorption. HFR-Supra (HFR-S) is a second-generation system with increased convective permeability and adsorption capability. Previous studies suggested that HFR reduces oxidative stress compared to standard haemodialysis. The principal aim of the present study was to compare antioxidant vitamins behavior and oxidative status of hemodialysis patients treated with HFR and HFR-S. METHODS The study was designed as a multicenter, randomized, crossover trial. Forty-one patients were recruited from 19 dialysis centers and after a 4-month washout stabilization period in on-line hemodiafiltration (ol-HDF), each patient was randomized to a sequence of treatments (HFR-S followed by HFR or viceversa) with each treatment applied over 6 months. Plasma levels of Advanced Oxidation Protein Products, Total Antioxidant Status, vitamins C, A and E and their ligands (Retinol Binding Protein and total lipids) were measured at baseline and at the end of each treatment period. RESULTS Results show that the higher convective permeability of HFR-S with respect to HFR did not produce additional beneficial effects on the patients' oxidative status, a slight decrease of both Vitamin A and Retinol Binding Protein being the only difference registered in the long-term. However, as compared to ol-HDF, both the re-infusive techniques allowed to reduce the intradialytic loss of Vitamin C and, in the long-term, improve the patients' oxidative status and increase Retinol Binding Protein plasma values. No significant differences were found between the Vitamin C concentration of pre- and post cartridge UF neither in HFR-S nor in HFR showing that the sorbent resin does not adsorb Vitamin C. CONCLUSION HFR-S and HFR are almost equivalent in term of impact on antioxidant vitamins and oxidative status of hemodialysis patients. Nonetheless, as compared to ol-HDF, both treatments produced a sensible sparing of Vitamin C and may represent a new approach for reducing oxidative stress and related complications in dialysis patients. Long-term effects of re-infusive treatments on patients' cardiovascular morbidity and mortality need to be evaluated. TRIAL REGISTRATION ClinicalTrials.gov Identifier NCT01492491 , retrospectively registered in 10 December 2011.