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Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study.
Meador, KJ, Pennell, PB, May, RC, Brown, CA, Baker, G, Bromley, R, Loring, DW, Cohen, MJ, ,
Neurology. 2020;(7):e729-e740
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Abstract
OBJECTIVE Emerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. METHODS The NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age). RESULTS Periconceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function-Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age. CONCLUSIONS Use of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development. CLINICALTRIALSGOV IDENTIFIER NCT00021866.
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Predictive Factors for Efficacy of AST-120 Treatment in Diabetic Nephropathy: a Prospective Single-Arm, Open-Label, Multi-Center Study.
Hwang, YC, Kim, SW, Hur, KY, Cha, BS, Kim, IJ, Park, TS, Baik, SH, Yoon, KH, Lee, KW, Lee, IK, et al
Journal of Korean medical science. 2019;(15):e117
Abstract
BACKGROUND Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 μol/L to 1.91 ± 0.72 μol/L; P = 0.002) but not in the non-responder group. CONCLUSION The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.
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Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics.
Mayer, GJ, Wanner, C, Weir, MR, Inzucchi, SE, Koitka-Weber, A, Hantel, S, von Eynatten, M, Zinman, B, Cherney, DZI
Kidney international. 2019;(2):489-504
Abstract
In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events.
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Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease.
Gritter, M, Vogt, L, Yeung, SMH, Wouda, RD, Ramakers, CRB, de Borst, MH, Rotmans, JI, Hoorn, EJ
Nephron. 2018;(1):48-57
Abstract
BACKGROUND/AIMS: Dietary potassium (K+) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K+ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the "K+ in CKD" study. METHODS The K+ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15-44 mL/min/1.73 m2), and an average eGFR decline > 2 mL/min/1.73 m2/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K+ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K+ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K+ concentrations. CONCLUSION The K+ in CKD study will demonstrate if K+ sup-plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects.
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The Oral β-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies.
Kokai-Kun, JF, Roberts, T, Coughlin, O, Sicard, E, Rufiange, M, Fedorak, R, Carter, C, Adams, MH, Longstreth, J, Whalen, H, et al
Antimicrobial agents and chemotherapy. 2017;(3)
Abstract
SYN-004 (ribaxamase) is a β-lactamase designed to be orally administered concurrently with intravenous β-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess β-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of β-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).
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Fenofibrate and extended-release niacin improve the endothelial protective effects of HDL in patients with metabolic syndrome.
Gomaraschi, M, Ossoli, A, Adorni, MP, Damonte, E, Niesor, E, Veglia, F, Franceschini, G, Benghozi, R, Calabresi, L
Vascular pharmacology. 2015;:80-86
Abstract
BACKGROUND Fibrates and niacin are at present the most effective therapies to increase plasma levels of high density lipoprotein-cholesterol (HDL-C); to date, limited data are available on their effects on HDL protective functions. METHODS AND RESULTS Within a multicenter, randomized, open-label, cross-over study, 37 patients with metabolic syndrome received 6weeks' treatment with fenofibrate or extended-release niacin (ER niacin), with a 4weeks' wash-out period. HDL ability to preserve endothelial cell homeostasis was assessed by incubating cultured endothelial cells with HDL isolated from patients at baseline and after each treatment. HDL isolated from patients at baseline were as effective as control HDL in inhibiting vascular cell adhesion molecule-1 (VCAM-1) expression, but less efficient in promoting endothelial cell nitric oxide (NO) release. Both fenofibrate and ER niacin increased HDL ability to inhibit TNFα-induced VCAM-1 expression (+7% and +11%, respectively). Fenofibrate and ER niacin also improved the impaired HDL ability to induce the expression of endothelial nitric oxide synthase and NO production (+10% and +8%, respectively). Interestingly, HDL isolated after treatment showed an ability to promote endothelial NO release similar to HDL isolated from controls. No differences were observed between the two drugs. With both drugs, HDL function was improved irrespective of baseline HDL-C levels. CONCLUSION Treatment with fenofibrate or ER niacin in patients with metabolic syndrome not only increased HDL-C levels but also improved the endothelial protective effects of HDL.
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The China Stroke Secondary Prevention Trial (CSSPT) protocol: a double-blinded, randomized, controlled trial of combined folic acid and B vitamins for secondary prevention of stroke.
Liu, X, Shi, M, Xia, F, Han, J, Liu, Z, Wang, B, Yang, F, Li, L, Wu, S, Wang, L, et al
International journal of stroke : official journal of the International Stroke Society. 2015;(2):264-8
Abstract
RATIONALE Epidemiological studies suggest that elevated homocysteine is linked to stroke and heart disease. However, the results of lowering homocysteine levels in reducing the risk of stroke recurrence are controversial. AIMS The study aims to evaluate whether homocysteine-lowering therapy with folic acid and vitamins B6 and B12 reduces recurrent stroke events and other combined incidence of recurrent vascular events and vascular death in ischemic stroke patients of low folate regions. DESIGN This is a multicenter, randomized, double-blinded, placebo-controlled trial. Patients (n = 8000, α = 0.05, β = 0.10) within one-month of ischemic stroke (large-artery atherosclerosis or small-vessel occlusion) or hypertensive intracerebral haemorrhage with plasma homocysteine level ≥ 15 μmol/l will be enrolled. Eligible patients will be randomized by a web-based, random allocation system to receive multivitamins (folic acid 0.8 mg, vitamin B6 10 mg, and vitamin B12 500 μg) or matching placebo daily with a median follow-up of three-years. STUDY OUTCOMES Patients will be evaluated at six monthly intervals. The primary outcome event is the composite event 'stroke, myocardial infarction, or death from any vascular cause', whichever occurs first. Secondary outcome measures include nonvascular death, transient ischemic attack, depression, dementia, unstable angina, revascularization procedures of the coronary, and cerebral and peripheral circulations. DISCUSSION This is the first multicenter randomized trial of secondary prevention for ischemic stroke in a Chinese population with a higher homocysteine level but without folate food fortification.
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Efficacy and safety of a 14-day administration of tolvaptan in the treatment of patients with ascites in hepatic oedema.
Sakaida, I, Yamashita, S, Kobayashi, T, Komatsu, M, Sakai, T, Komorizono, Y, Okada, M, Okita, K, ,
The Journal of international medical research. 2013;(3):835-47
Abstract
OBJECTIVE To investigate the efficacy and safety of 14 days' orally administered tolvaptan as adjunctive treatment for hepatic oedema in Japanese liver cirrhosis patients with insufficient response to conventional diuretics, with the option to increase dose in those who did not respond initially. METHODS This multicentre, single-arm, phase 3 study allocated patients with liver cirrhosis and persistent ascites to 7-day treatment with 7.5 mg/day tolvaptan followed by an additional 7 days' treatment. Responders at day 7 (achieving ≥ 1 kg body-weight reduction) continued on 7.5 mg/day tolvaptan; nonresponders (<1 kg body-weight reduction) received 15 mg/day tolvaptan. Conventional diuretic treatment continued throughout. The primary endpoint was change in body weight from baseline, as a marker of ascites volume. RESULTS A total of 51 patients received 7.5 mg/day tolvaptan for 7 days, which caused a significant reduction in mean body weight (55% response rate). During the second 7-day treatment period, 30 patients received 7.5 mg/day tolvaptan and 13 patients received tolvaptan 15 mg/day: response rates were 43% and 23%, respectively. Two serious adverse events were observed. Serum sodium was within normal range. CONCLUSIONS Tolvaptan therapy for 14 days (with possible dose increase as necessary), in combination with conventional diuretics, effectively reduced body weight in patients with hepatic oedema.