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Indoxyl Sulfate Elimination in Renal Replacement Therapy: Influence of Citrate- versus Acetate-Buffering Component during Bicarbonate Dialysis.
Hyšpler, R, Tichá, A, Šafránek, R, Moučka, P, Nývltová, Z, Štochlová, K, Dusilová-Sulková, S, Zadák, Z
Disease markers. 2018;:3985861
Abstract
Indoxyl sulfate has been identified as a major factor in the dysregulation of several genes. It is classified as a poorly dialyzable uremic toxin and thus a leading cause in the poor survival rate of dialysis patients. A monocentric, prospective, open cohort study was performed in 43 male patients undergoing chronic renal replacement therapy in a single hemodialysis center. The aim of the study was to determine the influence of acetate- versus citrate-buffered dialysis fluids in hemodialysis (HD) and postdilution hemodiafiltration (HDF) settings on the elimination of indoxyl sulfate. Also, additional factors potentially influencing the serum concentration of indoxyl sulfate were evaluated. For this purpose, the predialysis and postdialysis concentration ratio of indoxyl sulfate and total protein was determined. The difference was of 1.15 (0.61; 2.10), 0.89 (0.53; 1.66), 0.32 (0.07; 0.63), and 0.44 (0.27; 0.77) μmol/g in acetate HD and HDF and citrate HD and HDF, respectively. Acetate HD and HDF were superior when concerning IS elimination when compared to citrate HD and HDF. Moreover, residual diuresis was determined as the only predictor of lower indoxyl sulfate concentration, suggesting that it should be preserved as long as possible. This trial is registered with EU PAS Register of Studies EUPAS23714.
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The dynamics of the metabolism of acetate and bicarbonate associated with use of hemodialysates in the ABChD trial: a phase IV, prospective, single center, single blind, randomized, cross-over, two week investigation.
Smith, WB, Gibson, S, Newman, GE, Hendon, KS, Askelson, M, Zhao, J, Hantash, J, Flanagan, B, Larkin, JW, Usvyat, LA, et al
BMC nephrology. 2017;(1):273
Abstract
BACKGROUND In the United States, hemodialysis (HD) is generally performed via a bicarbonate dialysate. It is not known if small amounts of acid used in dialysate to buffer the bicarbonate can meaningfully contribute to overall buffering administered during HD. We aimed to investigate the metabolism of acetate with use of two different acid buffer concentrates and determine if it effects blood bicarbonate concentrations in HD patients. METHODS The Acid-Base Composition with use of hemoDialysates (ABChD) trial was a Phase IV, prospective, single blind, randomized, cross-over, 2 week investigation of peridialytic dynamics of acetate and bicarbonate associated with use of acid buffer concentrates. Eleven prevalent HD patients participated from November 2014 to February 2015. Patients received two HD treatments, with NaturaLyte® and GranuFlo® acid concentrates containing 4 and 8 mEq/L of acetate, respectively. Dialysate order was chosen in a random fashion. The endpoint was to characterize the dynamics of acetate received and metabolized during hemodialysis, and how it effects overall bicarbonate concentrations in the blood and dialysate. Acetate and bicarbonate concentrations were assessed before, at 8 time points during, and 6 time points after the completion of HD. RESULTS Data from 20 HD treatments for 11 patients (10 NaturaLyte® and 10 GranuFlo®) was analyzed. Cumulative trajectories of arterialized acetate were unique between NaturaLyte® and GranuFlo® (p = 0.003), yet individual time points demonstrated overlap without remarkable differences. Arterialized and venous blood bicarbonate concentrations were similar at HD initiation, but by 240 min into dialysis, mean arterialized bicarbonate concentrations were 30.2 (SD ± 4.16) mEq/L in GranuFlo® and 28.8 (SD ± 4.26) mEq/L in NaturaLyte®. Regardless of acid buffer concentrate, arterial blood bicarbonate was primarily dictated by the prescribed bicarbonate level. Subjects tolerated HD with both acid buffer concentrates without experiencing any related adverse events. CONCLUSIONS A small fraction of acetate was delivered to HD patients with use of NaturaLyte® and GranuFlo® acid buffers; the majority of acetate received was observed to be rapidly metabolized and cleared from the circulation. Blood bicarbonate concentrations appear to be determined mainly by the prescribed concentration of bicarbonate. TRIAL REGISTRATION This trial was registered on ClinicalTrials.gov on 11 Dec 2014 ( NCT02334267 ).
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Montelukast for Children with Obstructive Sleep Apnea: Results of a Double-Blind, Randomized, Placebo-Controlled Trial.
Kheirandish-Gozal, L, Bandla, HP, Gozal, D
Annals of the American Thoracic Society. 2016;(10):1736-1741
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RATIONALE Obstructive sleep apnea (OSA) is highly prevalent in children and is usually treated by adenotonsillectomy. Nonsurgical therapies for OSA consist primarily of antiinflammatory approaches and have gained popularity, but their efficacy remains to be critically examined. OBJECTIVES To determine the effect of montelukast on pediatric OSA. METHODS A prospective randomized double-blind controlled trial of polysomnographically diagnosed OSA in children ages 2-10 years who were treated with either oral montelukast (4 or 5 mg daily) or placebo for 16 weeks. Adherence to the medication was ascertained using automated timed pill dispensers along with weekly telephonic reminders. MEASUREMENTS AND MAIN RESULTS Ninety-two children diagnosed with OSA were approached, and 64 (69.6%) agreed to participate. Of these, 57 (89.0%) completed the 16-week trial, 28 in the montelukast group and 29 in the placebo group. Age, sex, and percentage of obesity were similar in the two groups, as were initial apnea-hypopnea index (AHI) scores. Overall, intention-to-treat analyses revealed that beneficial effects occurred in 20 children receiving montelukast (71.4%), whereas only 2 (6.9%) of the children receiving placebo showed reductions in AHI score (P < 0.001). Indeed, AHI decreased from 9.2 ± 4.1/hour total sleep time (TST) to 4.2 ± 2.8/hour TST (P < 0.0001) in montelukast-treated children, whereas in children receiving placebo, the AHI did not change (from 8.2 ± 5.0/h TST before to 8.7 ± 4.9/h TST at completion of the trial). CONCLUSIONS When compared with placebo, montelukast for 16 weeks effectively reduced the severity of obstructive sleep apnea in children 2-10 years of age. These results support a therapeutic role for leukotriene modifiers in pediatric OSA provided that long-term trials confirm current findings. Clinical trial registered with www.clinicaltrials.gov (NCT 00599534).
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Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation.
Williams, KM, Cheng, GS, Pusic, I, Jagasia, M, Burns, L, Ho, VT, Pidala, J, Palmer, J, Johnston, L, Mayer, S, et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2016;(4):710-716
Abstract
Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.
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Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome.
Meyers, CD, Tremblay, K, Amer, A, Chen, J, Jiang, L, Gaudet, D
Lipids in health and disease. 2015;:8
Abstract
BACKGROUND Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS. METHODS Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored. RESULTS Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events. CONCLUSION The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT01146522 .
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CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast.
Karonen, T, Neuvonen, PJ, Backman, JT
British journal of clinical pharmacology. 2012;(2):257-67
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AIM: According to product information, montelukast is extensively metabolized by CYP3A4 and CYP2C9. However, CYP2C8 was also recently found to be involved. Our aim was to study the effects of selective CYP2C8 and CYP3A4 inhibitors on the pharmacokinetics of montelukast. METHODS In a randomized crossover study, 11 healthy subjects ingested gemfibrozil 600 mg, itraconazole 100 mg (first dose 200 mg) or both, or placebo twice daily for 5 days, and on day 3, 10 mg montelukast. Plasma concentrations of montelukast, gemfibrozil, itraconazole and their metabolites were measured up to 72 h. RESULTS The CYP2C8 inhibitor gemfibrozil increased the AUC(0,∞) of montelukast 4.3-fold and its t(1/2) 2.1-fold (P < 0.001). Gemfibrozil impaired the formation of the montelukast primary metabolite M6, reduced the AUC and C(max) of the secondary (major) metabolite M4 by more than 90% (P < 0.05) and increased those of M5a and M5b (P < 0.05). The CYP3A4 inhibitor itraconazole had no significant effect on the pharmacokinetic variables of montelukast or its M6 and M4 metabolites, but markedly reduced the AUC and C(max) of M5a and M5b (P < 0.05). The effects of the gemfibrozil-itraconazole combination on the pharmacokinetics of montelukast did not differ from those of gemfibrozil alone. CONCLUSIONS CYP2C8 is the dominant enzyme in the biotransformation of montelukast in humans, accounting for about 80% of its metabolism. CYP3A4 only mediates the formation of the minor metabolite M5a/b, and is not important in the elimination of montelukast. Montelukast may serve as a safe and useful CYP2C8 probe drug.
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Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution.
Davies, PG, Venkatesh, B, Morgan, TJ, Presneill, JJ, Kruger, PS, Thomas, BJ, Roberts, MS, Mundy, J
Critical care (London, England). 2011;(1):R21
Abstract
INTRODUCTION As even small concentrations of acetate in the plasma result in pro-inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio-pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB. METHODS Thirty adult patients were systematically allocated 1:1 to CPB prime with either bicarbonate-balanced fluid (24 mmol/L bicarbonate) or Plasma-Lyte 148. Arterial blood acetate, gluconate and interleukin-6 (IL-6) levels were measured immediately before CPB (T1), three minutes after CPB commencement (T2), immediately before CPB separation (T3), and four hours post separation (T4). RESULTS Acetate concentrations (normal 0.04 to 0.07 mmol/L) became markedly elevated at T2, where the Plasma-Lyte group (median 3.69, range (2.46 to 8.55)) exceeded the bicarbonate group (0.16 (0.02 to 3.49), P < 0.0005). At T3, levels had declined but the differential pattern remained apparent (Plasma-Lyte 0.35 (0.00 to 1.84) versus bicarbonate 0.17 (0.00 to 0.81)). Normal circulating acetate concentrations were not restored until T4. Similar gluconate concentration profiles and inter-group differences were seen, with a slower T3 decay. IL-6 increased across CPB, peaking at T4, with no clear difference between groups. CONCLUSIONS Use of acetate containing prime solutions result in supraphysiological plasma concentrations of acetate. The use of acetate-free prime fluid in CPB significantly reduced but did not eliminate large acetate surges in cardiac surgical patients. Complete elimination of acetate surges would require the use of acetate free bolus fluids and cardioplegia solutions. TRIAL REGISTRATION Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000267055.
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One-year evaluation of combined treatment with an intranasal corticosteroid and montelukast for chronic rhinosinusitis associated with asthma.
Nonaka, M, Sakanushi, A, Kusama, K, Ogihara, N, Yagi, T
Journal of Nippon Medical School = Nippon Ika Daigaku zasshi. 2010;(1):21-8
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OBJECTIVES Chronic rhinosinusitis associated with asthma is often difficult to treat effectively with intranasal corticosteroids alone. Thus, the aim of this study was to evaluate the effectiveness of combination treatment with an intranasal corticosteroid and a leukotriene-receptor antagonist (montelukast) in reducing the size of nasal polyps. METHODS The subjects of this study were 20 patients with chronic rhinosinusitis associated with adult-onset asthma, which was being treated with inhaled corticosteroids. All patients were treated with intranasal fluticasone propionate, 200 microg/day, and montelukast, 10 mg/day, for 1 year. The size of nasal polyps and the score of sinus shadows were assessed with nasal endoscopy and computed tomography (CT), respectively, before and after treatment. The peripheral blood eosinophil counts were also evaluated before and after treatment. RESULTS Nasal polyps were significantly smaller after both 6 months (p<0.01) and 12 months of treatment (p<0.01) than before treatment. The decrease in the shadow score was statistically significant after both 6 months (p<0.01) and 12 months of treatment (p<0.01). Significant reductions in peripheral blood eosinophil counts were also seen after both 6 months (p<0.05) and 12 months of treatment (p<0.01). A significant correlation was found between the rate of change in the peripheral blood eosinophil count and that in the CT score after both 6 months (r=0.578, p=0.012) and 12 months (r=0.625, p=0.007). CONCLUSION Combined treatment with intranasal fluticasone propionate and montelukast, for at least 1 year, is effective for chronic rhinosinusitis associated with adult-onset asthma.
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Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients.
Rosenson, RS, Hislop, C, Elliott, M, Stasiv, Y, Goulder, M, Waters, D
Journal of the American College of Cardiology. 2010;(14):1079-88
Abstract
OBJECTIVES The purpose of this study was to investigate the effects of varespladib on cardiovascular biomarkers in acute coronary syndrome patients. BACKGROUND Secretory phospholipase A(2) (sPLA(2)) represents a family of proatherogenic enzymes that hydrolyze lipoprotein phospholipids, increasing their affinity for intimal proteoglycans; contribute to cholesterol loading of macrophages by nonscavenger receptor mediated pathways; and activate inflammatory pathways. In prospective studies, high sPLA(2)-IIA levels predicted major adverse cardiovascular events in acute coronary syndrome (ACS) and stable coronary heart disease patients. METHODS This randomized, double-blind, prospective controlled clinical trial (phase 2B) was designed to investigate the effects of sPLA(2) inhibition with varespladib 500 mg daily versus placebo as adjunctive therapy to atorvastatin 80 mg daily on biomarkers (low-density lipoprotein cholesterol [LDL-C], high-sensitivity C-reactive protein [hsCRP], and sPLA(2)-IIA levels), major adverse cardiovascular events (unstable angina, myocardial infarction, death), and safety. In all, 625 ACS subjects were randomized within 96 h of the index event and treated for a minimum of 6 months. RESULTS After 8 weeks (primary efficacy end point), varespladib/atorvastatin reduced mean LDL-C levels from baseline by 49.6% compared with 43.4% with placebo/atorvastatin (p = 0.002). Respective 8-week median reductions in sPLA(2)-IIA levels were 82.4% and 15.6% (p < 0.0001), and hsCRP levels were lowered by 75.0% and 71.0% (p = 0.097). At 24 weeks, respective reductions with varespladib and placebo were as follows: LDL-C 43.5% versus 37.6% (p < 0.05), hsCRP 79.8% versus 77.0% (p = 0.02), and sPLA(2)-IIA 78.5% versus 6.4% (p < 0.0001). Major adverse cardiovascular events were not different from placebo 6 months post-randomization (7.3% varespladib vs. 7.7% placebo). No treatment differences in elevated liver function studies on >1 occasion were observed. CONCLUSIONS Varespladib therapy effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional therapy including atorvastatin 80 mg daily. There were no treatment differences in clinical cardiovascular events. (FRANCIS [Fewer Recurrent Acute Coronary Events With Near-Term Cardiovascular Inflammation Suppression]-ACS Trial: A Study of the Safety and Efficacy of A 002 in Subjects With Acute Coronary Syndromes; NCT00743925).
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Urinary leukotriene E4/exhaled nitric oxide ratio and montelukast response in childhood asthma.
Rabinovitch, N, Graber, NJ, Chinchilli, VM, Sorkness, CA, Zeiger, RS, Strunk, RC, Bacharier, LB, Martinez, FD, Szefler, SJ, ,
The Journal of allergy and clinical immunology. 2010;(3):545-51.e1-4
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BACKGROUND A subset of children with asthma respond better to leukotriene receptor antagonists than to inhaled corticosteroids. Information is needed to identify children with these preferential responses. OBJECTIVE We sought to determine whether the ratio of urinary leukotriene E(4) (LTE(4)) to fractional exhaled nitric oxide (FE(NO)) delineates children with preferential responsiveness to montelukast compared with fluticasone propionate (FP) therapy. METHODS Data from 318 children with mild-to-moderate asthma enrolled in 2 National Heart, Lung, and Blood Institute Childhood Asthma Research and Education Network studies (Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid [CLIC] and the Pediatric Asthma Controller Trial [PACT]) were analyzed. The association between LTE(4)/FE(NO) ratios at baseline and improved lung function or asthma control days (ACDs) with montelukast and FP therapy was determined, and phenotypic characteristics related to high ratios were assessed. RESULTS LTE(4)/FE(NO) ratios were associated with a greater response to montelukast than FP therapy for FEV(1) measurements (2.1% increase per doubling of ratio, P = .001) and for ACDs per week (0.3-ACD increase, P = .009) in the CLIC study. In PACT the ratio was associated with greater ACD responsiveness to MT than FP therapy (0.6 ACD increase, P=.03) [corrected]. In a combined study analysis, LTE(4): FE(NO) ratios were associated with greater response to MT than FP therapy for FEV(1) (1.8% increase, P =.0005) and ACDs (0.4 increase, P =.001)[corrected].Children with LTE(4)/FE(NO) ratios at or above the 75th percentile were likely (P < .05) to be younger and female and exhibit lower levels of atopic markers and methacholine reactivity. CONCLUSION LTE(4)/FE(NO) ratios predict a better response to montelukast than FP therapy in children with mild-to-moderate asthma.