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1.
Effect of the chemical environment of the DNA guanine quadruplex on the free energy of binding of Na and K ions.
Sharawy, M, Consta, S
The Journal of chemical physics. 2018;(22):225102
Abstract
Guanine quadruplex (G-quadruplex) structures play a vital role in stabilizing the DNA genome and in protecting healthy cells from transforming into cancer cells. The structural stability of G-quadruplexes is greatly enhanced by the binding of monovalent cations such as Na+ or K+ into the interior axial channel. We computationally study the free energy of binding of Na+ and K+ ions to two intramolecular G-quadruplexes that differ considerably in their degree of rigidity and the presence or absence of terminal nucleotides. The goal of our study is two-fold. On the one hand, we study the free energy of binding every ion, which complements the experimental findings that report the average free energy for replacing Na+ with K+ ions. On the other hand, we examine the role of the G-quadruplex structure in the binding free energy. In the study, we employ all-atom molecular dynamics simulations and the alchemical transformation method for the computation of the free energies. To compare the cation-dependent contribution to the structural stability of G-quadruplexes, we use a two-step approach to calculate the individual free energy difference ΔG of binding two Na+ and two K+ to two G-quadruplexes: the unimolecular DNA d[T2GT2(G3T)3] (Protein Data Bank ID 2M4P) and the human telomeric DNA d[AGGG(TTAGGG)3] (PDB ID 1KF1). In contrast to the experimental studies that estimate the average free energy of binding, we find a varying difference of approximately 2-9 kcal/mol between the free energy contribution of binding the first and second cation, Na+ or K+. Furthermore, we found that the free energy of binding K+ is not affected by the chemical nature of the two quadruplexes. By contrast, Na+ showed dependency on the G-quadruplex structure; the relatively small size allows Na+ to explore larger configurational space than K+. Numerical results presented here may offer reference values for future design of cationic drug-like ligands that replace the metal ions in G-quadruplexes.
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2.
Beneficial Effects of High Potassium: Contribution of Renal Basolateral K+ Channels.
Staruschenko, A
Hypertension (Dallas, Tex. : 1979). 2018;(6):1015-1022
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Effect of Patiromer in Hyperkalemic Patients Taking and Not Taking RAAS Inhibitors.
Kloner, RA, Gross, C, Yuan, J, Conrad, A, Pergola, PE
Journal of cardiovascular pharmacology and therapeutics. 2018;(6):524-531
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Abstract
INTRODUCTION Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. METHODS Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. RESULTS Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. CONCLUSIONS Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.
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The ratio of urinary sodium and potassium and chronic kidney disease progression: Results from the KoreaN Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD).
Koo, H, Hwang, S, Kim, TH, Kang, SW, Oh, KH, Ahn, C, Kim, YH
Medicine. 2018;(44):e12820
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Abstract
The Na/K ratio in urine stands for the dietary of sodium and potassium intake in patients with chronic kidney disease remains unclear for the renal progression. We aimed to determine the risk of progression of chronic kidney disease based on the Na/K ratio in a 24-hour urine collection.We determined the association between the progression of renal disease and 24-hour urinary sodium and potassium (Na/K) ratios in 2238 patients over a 5-year timespan using data obtained from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease (KNOW-CKD). Renal events were defined as a 50% decrease in the glomerular filtration rate (GFR) below baseline, or the onset of end-stage renal disease (ESRD). Patients were divided into 4 groups based on the quartile range of the 24-hour urinary sodium and potassium ratio. We analyzed those variables in the 4 groups. Multiple logistic regression analyses were performed using the data of 1001 patients to identify the independent factors associated with renal events.Age and male sex accounted for the greatest number of patients in the group with the highest values (group 4) of the 24-hour urinary Na/K ratio (≥3.85). There was no difference in the prevalence of hypertension or diabetes mellitus, the ratio of use of antihypertensive drugs, blood pressures, or estimated GFRs. In the group with the highest urinary Na/K ratio, the 24-hour urinary Na concentration mean ± standard deviation was 188.7 ± 70.6 mmol and that of urinary K was 39.9 ± 16.1 mmol. The urinary protein excretion was highest in the group with the highest urinary Na/K ratio. In the logistic regression analysis, the effect on renal events increased with increasing urinary Na/K ratios. After adjusting for other factors, the risk of renal events was 2.48 (95% confidence interval (CI) 1.30-4.90) in group 3, and 3.75 (95% CI: 1.35-11.27) in group 4. In the Kaplan-Meier analysis, the higher the urinary Na/K ratio, the higher the rate of CKD progression.Based on our analyses, we concluded that the higher the urinary Na/K ratio, the greater the risk of CKD progression.
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Association of serum potassium concentration with mortality and ventricular arrhythmias in patients with acute myocardial infarction: A systematic review and meta-analysis.
Colombo, MG, Kirchberger, I, Amann, U, Dinser, L, Meisinger, C
European journal of preventive cardiology. 2018;(6):576-595
Abstract
Background Challenging clinical practice guidelines that recommend serum potassium concentration between 4.0-5.0 mEq/L or ≥4.5 mEq/L in patients with acute myocardial infarction, recent studies found increased mortality risks in patients with a serum potassium concentration of ≥4.5 mEq/L. Studies investigating consequences of hypokalemia after acute myocardial infarction revealed conflicting results. Therefore, the aim of this systematic review and meta-analysis was to combine evidence from previous studies on the association of serum potassium concentration with both short and long-term mortality as well as the occurrence of ventricular arrhythmias. Design Systematic review and meta-analysis. Methods A structured search of MEDLINE and EMBASE databases yielded 23 articles published between 1990 and January 2017 that met the inclusion criteria. Study selection, data extraction and quality assessment were carried out by three reviewers. Random effects models were used to pool estimates across the included studies and sensitivity analyses were performed when possible. Results Twelve studies were included in the meta-analysis. Both pooled results from six studies investigating short-term mortality and from five studies examining long-term mortality revealed significantly increased risks in patients with serum potassium concentrations of <3.5 mEq/L, 4.5-<5.0 mEq/L and ≥5.0 mEq/L after acute myocardial infarction. In addition, a serum potassium concentration of <3.5 mEq/L was significantly associated with the occurrence of ventricular arrhythmias. Conclusions Mortality, both short and long term, and the occurrence of ventricular arrhythmias in patients with acute myocardial infarction seem to be negatively associated with hypokalemic serum potassium concentration. There is evidence for adverse consequences of serum potassium concentrations of ≥4.5 mEq/L. Due to the heterogeneity among existing studies, further research is necessary to confirm the need to change clinical practice guidelines.
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Effect of food on the pharmacokinetics of YH4808, a potassium-competitive acid blocker, after single- and multiple-oral dosing in healthy subjects.
Kim, E, Kim, A, Yi, S, Kim, YK, Jang, SB, Byun, HM, Yoon, SH, Cho, JY, Jang, IJ, Yu, KS, et al
European journal of clinical pharmacology. 2018;(10):1261-1272
Abstract
PURPOSE YH4808 is a potassium-competitive acid blocker, developed for the treatment of acid-related disorders. Two clinical studies in healthy male subjects were conducted to evaluate the effect of food on the pharmacokinetics of YH4808. METHODS The first study, a randomized, three-treatment, three-period, crossover study, compared pharmacokinetics of YH4808 (300 mg) after a single dose at fed state with a standard or a high-fat meal to those at fasted state. The second study, a randomized, two-treatment, two-period, crossover study, investigated pharmacokinetics at fasted or fed state with a standard meal after twice daily dose of YH4808 (100 mg) for 7 days. Bloods for pharmacokinetic evaluation were sampled up to 48 h post-dose and 24 h post-dose at steady state, respectively. The pharmacokinetic parameters were estimated by non-compartmental method. RESULTS After single dosing, the geometric means of maximum plasma concentration increased by 1.2 and 2.1 times in the fed states with a standard meal and a high-fat meal, respectively, of that in fasted state. Corresponding values of area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time point increased by 1.8 and 2.8 times, respectively. After multiple dosing, the geometric mean for 24-h AUC at steady state slightly increased in fed state by 1.1 times of that in fasted state. CONCLUSIONS As fat content of the food increased, the systemic exposure of YH4808 after single dosing increased. However, systemic exposures at steady state after multiple dosing between fasted and fed states were similar. TRIAL REGISTRATION ClinicalTrials.gov registry no.: NCT01520012.
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Sodium Zirconium Cyclosilicate: A Review in Hyperkalaemia.
Hoy, SM
Drugs. 2018;(15):1605-1613
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Sodium zirconium cyclosilicate (Lokelma™) [hereafter referred to as SZC] is a non-absorbed, non-polymer zirconium silicate compound that preferentially exchanges hydrogen and sodium for potassium and ammonium ions in the gastrointestinal tract (GIT), thereby increasing faecal potassium excretion and lowering serum potassium levels. It is available as a powder for oral suspension (in water) and is approved in the EU and the USA for the treatment of hyperkalaemia in adults. In two multinational, phase III studies in adults with hyperkalaemia, SZC 10 g three times daily lowered serum potassium levels to within the normal range (3.5-5.0 mmol/L) during the first 48 h of treatment, and SZC 5 and 10 g once daily maintained normokalaemia over ≤ 28 days' therapy. These beneficial effects were consistent across all patient subgroups (e.g. chronic kidney disease, diabetes, heart failure, concomitant use of RAAS inhibitor therapy), and appeared to be maintained over the longer term (≤ 12 months). SZC was generally well tolerated in adults with hyperkalaemia. Its tolerability profile was generally similar to that seen with placebo over ≤ 28 day, and its safety profile appeared to remain consistent over the longer term (≤ 12 months). Moreover, the incidence of hypokalemia was low. Current evidence indicates that SZC is a promising therapy for the management of hyperkalaemia in adults.
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Hyperkalaemia in Heart Failure-Pathophysiology, Implications and Therapeutic Perspectives.
Llubani, R, Vukadinović, D, Werner, C, Marx, N, Zewinger, S, Böhm, M
Current heart failure reports. 2018;(6):390-397
Abstract
PURPOSE OF REVIEW Hyperkalaemia is a frequent and sometimes life-threatening condition that may be associated with arrhythmia and cardiac dysfunction. Evaluating the prevalence of hyperkalaemia in patients with heart failure (HF) and potential treatments of this condition is essential for patients using renin-angiotensin-aldosterone system inhibitors or angiotensin receptor-neprilysin inhibitor and mineralocorticoid receptor antagonists, which represent the cornerstone and highly proven life-saving therapy. RECENT FINDINGS Novel findings from the past few years include data regarding the epidemiology, pathomechanisms, implications and novel therapeutic approaches to counteract hyperkalaemia in patients with HF. Whilst older potassium-binding agents are associated with serious adverse events, novel potassium-binding drugs are effective in lowering potassium levels and are generally well tolerated. Hyperkalaemia represents both a direct risk of cardiovascular complication and an indirect biomarker of the severity of the underlying disease such as neurohormonal activation and renal dysfunction. Novel potassium-binding drugs such as patiromer and sodium zirconium cyclosilicate may help to optimize therapy in HF and achieve guideline-recommended doses.
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Incident Hyperkalemia, Hypokalemia, and Clinical Outcomes During Spironolactone Treatment of Heart Failure With Preserved Ejection Fraction: Analysis of the TOPCAT Trial.
Desai, AS, Liu, J, Pfeffer, MA, Claggett, B, Fleg, J, Lewis, EF, McKinlay, S, O'Meara, E, Shah, SJ, Sweitzer, NK, et al
Journal of cardiac failure. 2018;(5):313-320
Abstract
BACKGROUND In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up. METHODS We defined the region-specific incidence of hypokalemia (potassium [K+] <3.5 mmol/l) and hyperkalemia (K+ ≥5.5 mmol/l) among both placebo- and spironolactone-assigned patients in TOPCAT. Factors associated with incident hypokalemia and hyperkalemia and the relationship between incident K+ abnormalities and the risk of subsequent mortality were analyzed in multivariable regression models restricted to the Americas. RESULTS In the Americas, assignment to spironolactone increased risk for hyperkalemia (hazard ratio 3.21, 95% confidence interval 2.46-4.20, P < .001) and reduced risk of hypokalemia (hazard ratio 0.43, 95% confidence interval 0.34-0.55, P < .001). Assignment to spironolactone, lower estimated glomerular filtration rate, higher baseline K+, diabetes, and lower hemoglobin were associated with incident hyperkalemia, whereas assignment to placebo, lower K+, younger age, lower estimated glomerular filtration rate, and use of diuretics at baseline were associated with hypokalemia. The combination of spironolactone and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was associated with incremental risk for hyperkalemia and protection from hypokalemia. Independent of region, both hypokalemia and hyperkalemia, were associated with higher risk for cardiovascular and all-cause mortality in multivariable-adjusted Cox regression models. CONCLUSIONS Both hyperkalemia and hypokalemia are associated with heightened risk for mortality in HF-PEF. Use of spironolactone in this population requires careful laboratory surveillance of K+ and creatinine, particularly in high-risk groups.
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Serum Potassium and Cardiovascular Events in Heart Failure With Preserved Left Ventricular Ejection Fraction Patients.
Nishihara, T, Tokitsu, T, Sueta, D, Takae, M, Oike, F, Fujisue, K, Usuku, H, Takashio, S, Hanatani, S, Kanazawa, H, et al
American journal of hypertension. 2018;(10):1098-1105
Abstract
BACKGROUND Although serum potassium (sK) levels are closely associated with the prognosis of chronic heart failure patients, the clinical significance of sK levels in cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF) patients is not fully understood. METHODS This study was a retrospective, single-center, observational study. We enrolled 506 consecutive HFpEF patients admitted to Kumamoto University Hospital and divided them into four groups according to the quartiles of the sK levels at discharge (Q1: sK < 4.1 mEq/l, Q2: 4.1 ≤ sK < 4.4 mEq/l, Q3: 4.4 ≤ sK < 4.7 mEq/l, and Q4: sK ≥ 4.7 mEq/l). RESULTS No significant differences were observed in the use of all drugs (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, β-blockers, and statins) among the four groups. Hemoglobin, the estimated glomerular filtration rate, and pulse wave velocity levels were lower, and the serum sodium levels were higher in the Q4 group compared with those in the Q2 group. Kaplan-Meier analysis revealed significantly higher probabilities of both cardiovascular and HF-related events in the Q1, Q3, and Q4 groups than those in the Q2 group. Multivariate Cox proportional hazard analysis revealed that the Q1, Q3, and Q4 groups had significantly and independently higher probabilities of cardiovascular events compared with those in the Q2 group, indicating a J-shaped association between sK levels and cardiovascular events. CONCLUSIONS sK levels at discharge could provide important prognostic information in regard to HFpEF. Further evaluation in a larger number of patients might be needed. CLINICAL TRIALS REGISTRATION UMIN-CTR (http://www.umin.ac.jp/ctr/). IDENTIFIER UMIN000029600. PUBLIC ACCESS INFORMATION Opt-out materials are available at the website: http://www.kumadai-junnai.com/home/wp-content/uploads/houkatsu.pdf.