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Long-Term Outcomes of Radical Radiation Therapy with Hypoxia Modification with Biomarker Discovery for Stratification: 10-Year Update of the BCON (Bladder Carbogen Nicotinamide) Phase 3 Randomized Trial (ISRCTN45938399).
Song, YP, Mistry, H, Irlam, J, Valentine, H, Yang, L, Lane, B, West, C, Choudhury, A, Hoskin, PJ
International journal of radiation oncology, biology, physics. 2021;(5):1407-1415
Abstract
PURPOSE Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes. METHODS AND MATERIALS Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis. RESULTS We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08). CONCLUSIONS Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification.
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Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial.
Ix, JH, Isakova, T, Larive, B, Raphael, KL, Raj, DS, Cheung, AK, Sprague, SM, Fried, LF, Gassman, JJ, Middleton, JP, et al
Journal of the American Society of Nephrology : JASN. 2019;(6):1096-1108
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Abstract
BACKGROUND Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.
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Efficacy and safety of nicotinamide in haemodialysis patients: the NICOREN study.
Lenglet, A, Liabeuf, S, El Esper, N, Brisset, S, Mansour, J, Lemaire-Hurtel, AS, Mary, A, Brazier, M, Kamel, S, Mentaverri, R, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(5):870-879
Abstract
BACKGROUND Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. METHODS The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N -methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. RESULTS After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 ± 0.4 to 1.8 ± 0.5 and 2.3 ± 0.5 to 1.7 ± 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). CONCLUSIONS Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.
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Oral nicotinamide reduces transepidermal water loss: a randomized controlled trial.
Chen, AC, Martin, AJ, Dalziell, RA, Halliday, GM, Damian, DL
The British journal of dermatology. 2016;(6):1363-1365
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[Performance evaluation of integrated cytoprotective therapy of different duration in patients with cerebral infarction].
Chichanovskaia, LV, Tsukurova, LA, Kovalenko, AL, Nazarov, MV, Lukin, DI, Rumiantseva, SA, Silina, EV, Stupin, VA, Nedorostkova, TIu, Kabaeva, EN, et al
Eksperimental'naia i klinicheskaia farmakologiia. 2015;(1):21-6
Abstract
The paper reviews the preliminary results of a multicenter randomized clinical research. The aim of the study was to determine the optimal duration of different types of energy-correction therapy. 99 case report forms of patients with cerebral infarction were reviewed with their prior envelope randomization into three groups. Patients in the first group (experimental group), consisting of 32 patients, as part of combined therapy received ascorbic acid (5% solution twice a day in a recommended dosage of 20 ml/day for 20 days); the second group (37 patients) received 10 ml of cytoflavin intravenously by drop infusion twice a day for 10 days; the third group received cytoflavin for 20 days (from day 1 to day 10 - 20 ml a day, from day 11 to day 20 - 10 ml a day). The average NIH scale score on admission was 14.9 ± 2.6. Prescription of cytoflavin came with average 1.7 - 1.8 time regression (p < 0.05) of the volumes of cerebral ischemia in the of cases of the 10- and 20-day courses of treatment, while there were no significant morphologic changes in the ascorbic acid group. These results correlated with the best dynamics and outcomes of the neurological and performance status of patients receiving cytoflavin. Despite the lack of significant general differences in the clinical and morphological data of the second and third groups, the patients with underlying grave medical condition in the 20-day cytoflavin group (with NIH score of 14-20 points on admission) tended to have improved neurologic status parameters in comparison with the experimental group and the 10-day cytoflavin group. These results attest to the advantages of personalized antioxidant energy-correction therapy.
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[Current approaches to cerebroprotective treatment of premature newborns in reanimation and intensive care departments].
Rogatkin, SO, Volodin, NN, Degtiareva, MG, Grebennikova, OV, Marganiia, MSh, Serova, ND
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2011;(1):27-32
Abstract
This work was conducted in the frames of a multicenter clinical trial. The aim was to study efficacy of cytoflavin (infusion solution) in the prevention and treatment of posthypoxic CNS lesions in premature newborns. The study included 120 premature newborns (gestation period 28-36 weeks) who was born in severe distress and needed the intensive therapy after primary reanimation measures. Cytoflavin was prescribed in the first 2-4 h after the delivery to 61 newborns. The control group included 59 newborns who did not receive the drug. To assess treatment efficacy, the determination of some plasma neurospecific proteins (GFAP, NSE, MBP) was carried out along with standard clinical/instrumental and laboratory monitoring. The results revealed the marked cerebroprotective effect of cytoflavin. The significantly higher rate of normalization of KOC, pO2, PCO2 and elimination of lactate acidosis that led to the reduction of severity and frequency of ischemic and hemorrhagic CNS lesions as well as lower levels of plasma neurospecific proteins were seen in the main group compared to the control one.
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[The complex energy correction of chronic brain ischemia].
Suslina, ZA, Rumiantseva, SA, Tanashian, MM, Skoromets, AA, Klocheva, EG, Fedin, AI, Kovalenko, AL, Silina, EV, Sholomov, II
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2011;(3):25-30
Abstract
Considerable disturbance of all quality of life domains that worsens social adaptation and daily living and results in an asthenic-neurotic syndrome, along with neurologic and mnestic-intellectual disturbances, was revealed in patients with chronic brain ischemia (stages I, II, III). Based on the results of the double blind placebo-controlled trial, the high clinical efficacy of cytoflavin in patients with chronic brain ischemia has been shown. The treatment with cytoflavin decreases the severity of subjective symptoms and complaints thus increasing the working ability of patients, improves balance and gait, decreases the severity of asthenic and neurotic syndromes, improves cognitive and memory functions (information storage, reasoning and attention), positively effects on quality of sleep and all aspects of quality of life, in particular, on physical activity, self-rating of health and viability as well as social activity, mental health and emotional lability.
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[Possibilities of treatment of multiple sclerosis exacerbations without corticosteroids: a role of metabolic and antioxidant therapy].
Bisaga, GN, Odinak, MM, Boĭko, AN, Mel'nik, IuB, Popova, NF
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2011;(2):44-8
Abstract
A multicenter randomized post-registration control-comparative trial included 94 patients with relapsing-remitting and secondary-progressive multiple sclerosis (MS) in the acute phase. Patients were stratified into 2 groups: patients of group 1 (n=53) received cytoflavin and basic treatment (trental and group B vitamins) and patients of group 2 (n=41) received only basic treatment. Based on the results of the 5-day treatment, each of these groups was stratified into 2 subgroups: patients of subgroup 1A (n=22) who demonstrated a positive effect continued to receive cytoflavin and basic treatment; subgroup 1B (n=31) received corticosteroids (metipred) as an add-on in the pulse- treatment regime; group 2A (n=14) continued to receive basic treatment due to the positive effect; group 2B (n=27) received corticosteroids as an add-on in the pulse-treatment regime. The treatment including cytoflavin, trental, group B vitamins and corticosteroids, was well-tolerated. The positive effect was due to the decrease in the need for corticosteroids: 41.5% of patients treated with cytoflavin and only 34% of patients receiving basic treatment did not need corticosteroids. The significant reduction of neurologic symptoms assessed with the EDSS was seen in patients treated with cytoflavin compared to the group which did not receive this drug. The clinical effect was observed in all patients. There was a decrease in lipid peroxidation levels and in the content of antibodies to basic myelin protein and the improvement of cognitive function.
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[Efficacy of cytoflavin in patients in the acute ischemic stroke].
Odinak, MM, Skvortsova, VI, Vozniuk, IA, Rumiantseva, SA, Stakhovskaia, LV, Klocheva, EG, Novikova, LB, Ianishevskiĭ, SN, Golokhvastov, SIu, Tsygan, NV
Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2010;(12):29-36
Abstract
We present the results of a multicenter study on efficacy of cytoflavin in the treatment of patients with acute ischemic stroke. Seventy patients (41 of the main group and 29 of the control group) were enrolled in the study. All patients received basic therapy aimed at improving systemic hemodynamics, rheological blood properties and at the prevention of stroke complications. Patients of the main group were treated with cytoflavin as follows: days 1-10 - 20 ml (in 400 ml of the 0,9% NaCl solution) twice a day intravenously in drops; days 11-35 - 850 mg twice a day. We assessed the dynamics of restoration of lost functions (NIHSS, the Rankin scale, the Barthel index) and volumes of ischemic lesion (MRI T1-, T2-, diffusion-weighted images). Results of the study on patients of the control group were supplemented with literature data about 306 patients studied using clinical scales and 40 patients studied with MRI. We revealed a trend towards an effect of cytoflavin on the preservation of brain matter in the acute phase of stroke. Cytoflavin reduced the neurological deficit and improved activities of daily living in patients that may be explained by the less brain damage.
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[Cytoflavine effect on exudative-destructive manifestations of lung tuberculosis in children and teenagers].
Volchegorskiĭ, IA, Novoselov, PN, Denisenko, IA
Eksperimental'naia i klinicheskaia farmakologiia. 2009;(4):20-4
Abstract
A prospective, placebo-controlled ordinary-"blind"-randomized investigation of the cytoflavine effect on roentgenological manifestations of exudative-destructive processes in pulmonary tissues in cases of tuberculosis in children and teenagers has been performed in comparison to changes in the the functional state of neutrophilic granulocytes and Micobacterium tuberculosis incidence in sputum during a standard four-months course of antituberculosis therapy. It is estasblished that the administration of cytoflavine at the beginning of antituberculosis complex therapy (10 mL per 24 hours, for 5 days) results in rapid suppression of exudative-destructive disease manifestations and quick cavity repair in tuberculosis-affected areas, at an increase in the probability of outcome with "small post-tuberculosis changes". The rapid suppression of exudative-destructive processes in patients having received cytoflavine was caused by its optimizing influence on phagocytic blood capacity and did not depend on the development of abacillarity in patients.