Ototoxic effects and mechanisms of loop diuretics

Over the past two decades considerable progress has been made in understanding the ototoxic effects and mechanisms underlying loop diuretics. As typical representative of loop diuretics ethacrynic acid or furosemide only induces temporary hearing loss, but rarely permanent deafness unless applied in severe acute or chronic renal failure or with other ototoxic drugs. Loop diuretic induce unique pathological changes in the cochlea such as formation of edematous spaces in the epithelium of the stria vascularis, which leads to rapid decrease of the endolymphatic potential and eventual loss of the cochlear microphonic potential, summating potential, and compound action potential. Loop diuretics interfere with strial adenylate cyclase and Nat/Kt-ATPase and inhibit the Na-K-2Cl cotransporter in the stria vascularis, however recent reports indicate that one of the earliest effects in vivo is to abolish blood flow in the vessels supplying the lateral wall. Since ethacrynic acid does not damage the stria vascularis in vitro, the changes in Nat/Kt-ATPase and Na-K-2Cl seen in vivo may be secondary effects results from strial ischemia and anoxia. Recent observations showing that renin is present in pericytes surrounding stria arterioles suggest that diuretics may induce local vasoconstriction by renin secretion and angiotensin formation. The tight junctions in the blood-cochlea barrier prevent toxic molecules and pathogens from entering cochlea, but when diuretics induce a transient ischemia, the barrier is temporarily disrupted allowing the entry of toxic chemicals or pathogens.

The use of diuretics in acute heart failure: Evidence based therapy?

The evidence base for the use of diuretics in acute heart failure is limited, with no large double-blind placebo-controlled randomized trials. However, their use as a first line treatment of acute heart failure is firmly established in clinical practice, and endorsed in clinical guidelines. Loop diuretics are typically the first line diuretic strategy for the treatment of acute heart failure. For patients with considerable fluid retention, there is some evidence that initial treatment with continuous infusion or boluses of high dose loop diuretic is superior to an initial lower dose strategy. In patients who are diuretic resistant, the addition of an oral thiazide or thiazide-like diuretic to induce sequential nephron blockade can be beneficial. Intravenous low-dose dopamine has also been used to assist diuresis and preserve renal function in such circumstances, but trials are underway to confirm the clinical value of this agent. Mechanical ultrafiltration has been used to treat patients with heart failure and fluid retention, but the evidence base is not secure, and its place in clinical practice is yet to be established.

Determination of 8 Diuretics and Probenecid in Human Urine by Gas Chromatography-Mass Spectrometry: Confirmation Procedure

A fast and sensitive method for determination of 8 diuretics (acetazolamide, bendroflumethiazide, bumetanide, chlorthalidone, furosemide, hydrochlorothiazide, metolazone, triamterene) and masking agent (probenecid) in human urine using gas-chromatography with mass spectrometric detection is described. The extraction of the substances as function of the nature of organic solvent, mixing time and pH of aqueous phase was studied. The tandem mass spectrometry was used to increase selectivity of diuretics determination due to elimination of background interferences. Fragmentation reactions were studied for each compound and their collision energies were optimized to obtain the best selectivity. The results of method’s validation demonstrate its suitability in routine analysis for confirmation purposes.

Urea transporter inhibitors identified as novel diuretics

Urea transporters （UT）, including isoforms of UT-A endothelia and erythrocytes, play an important role in the urine in kidney tubule epithelia and UT-B in vasa recta concentration mechanism by mediated an intrarenalurea recycling, suggesting that functional inhibition of these proteins could have therapeutic use as diuretic. By in- tegrated cell based high throughput screening and in silico methods, a class of small-molecule drug-like compounds with thienoquinolin core structure was found to have inhibition activity on both UT-A and UT-B. The structure and activity relationship analysis showed a compound PU-48, named chemically as methyl 3-amino-6-methoxythieno[ 2, 3-b] quinoline-2-carboxylate, had the best UT-A and UT-B inhibition activity. IC50s of PU-48 on UT-B facilitated as determined by erythrocyte lysis assay. In vivo urea transport were micromole level in human, rat, and mouse, activity of PU-48 on urinary concentrating function was evaluated in rats fed ad libitum in metabolic cages. Urine output significantly increased in a dose-dependent manner in rats subcutaneously administered PU-48. Urinary os- molality and urea concentration were significantly decreased. The peak changes of urine output, urinary osmolality and urinary urea concentration occurred between 2 and 4 h after PU/18 administration, with values returning to was subcutaneously injected every 6 h the 24 h urine output in baseline by 10 h. When PU-48 at 50 mg · kg^-1 PU-48 treated rats was significantly higher than that in vehicle control rats. Urinary osmolality and urea concentra- tion in PU-48 treated rats were significantly lower than in vehicle control rats. The excretion of Na ＋ , K ＋ , C1- was PU-48 treated rats had significantly higher urea excre- similar in PU-48 treated and vehicle control rats. However, tion than vehicle control rats. The data suggest that PU-48 caused a urea-selective diuresis without disturbing elec- TGs, and LDL-C in PU-48-treated rats were similar with those trolyte metabolism. Notably, blood urea, T-CHO, in vehicle control rats, which are normal levels. These data indicate that the diuretic effect of PU-14 does not cause electrolyte imbalance and abnormal metabolism. It is predicated that UT inhibitors have potential clinical applica- tions as sodium-sparing diuretics in edema from different etiologies, such as congestive heart failure and cirrhosis.

GC-MS STUDY ON DIURETICS IN URINE Ⅱ.DETECTION METHOD USING TRIMETHYLSILYLATION

A reliable method is described for the detection of amitoride,triamterene. canrenone and spironolactone in human urine using GC-MS analysis after trimethytsitytation.The mass spectrometric and metabotic features of the compounds are discussed

GC-MS STUDY ON DIURETICS IN URINE Ⅰ.BETECTION METHOD USING METHYLATION

A reliable and sensitive method is developed for the detection of common diuretics in human urine. diuretics along with probenecid are methylated and subjected to GC-MS analysis.Both chromatographic and mass spectrometric data are obtained in selected ion monitoring and full scanning modes.The average detection limit is 0.1-1.0 ag/mi urine.This method is suitable to large-scale and routine screening or confirmation of diuretics in doping control.

The Effect of Loop Diuretics on Sarcopenia and Long-Term Prognosis in Patients with Refractory Hepatic Ascites Treated with Tolvaptan

We investigated sarcopenia, focusing on the dose of loop diuretics used in 70 patients with refractory hepatic ascites treated with tolvaptan. Bloating improved in 68.5% of patients, as determined using the Japanese version of the Support Team Assessment Schedule. The psoas muscle index (PMI) was used to define sarcopenia. A statistically significant difference was observed in the PMI between patients receiving low-dose (3.6 ± 1.2 cm2/m2) and high-dose furosemide (3.1 ± 1.2 cm2/m2) before tolvaptan treatment (P = 0.048). The PMI increased from 3.2 ± 1.1 cm2/m2 to 3.5 ± 1.3 cm2/m2 (P = 0.002) in responders, but decreased from 3.4 ± 1.2 cm2/m2 to 3.0 ± 1.0 cm2/m2 (P = 0.106) in non-responders before and after tolvaptan treatment, respectively. The long-term prognosis improved in responders compared with non-responders (mean survival time: 646 days vs. 228 days, P < 0.001). Early introduction of tolvaptan treatment is necessary to prevent the progression of sarcopenia.

Effects of Three Commonly-used Diuretics on the Urinary Proteome

Biomarker is the measurable change associated with a physiological or pathophysiological process. Unlike blood which has mechanisms to keep the internal environment homeostatic, urine is more likely to reflect changes of the body. As a result, urine is likely to be a better biomarker source than blood. However, since the urinary proteome is affected by many factors, including diuretics, careful evaluation of those effects is necessary if urinary proteomics is used for biomarker discovery. Here, we evaluated the effects of three commonly-used diuretics （furosemide, F; hydrochlorothiazide, H; and spirolactone, S） on the urinary proteome in rats. Urine samples were collected before and after intragastric administration of diuretics at therapeutic doses and the proteomes were analyzed using label-free liquid chromatography-tandem mass spectrometry （LC-MS/MS）. Based on the criteria of P ≤ 0.05, a fold change ≥2, a spectral count ≥ 5, and false positive rate （FDR） ≤1%, 14 proteins （seven for F, five for H, and two for S） were identified by Progenesis LC-MS. The human orthologs of most of these 14 proteins are stable in the healthy human urinary proteome, and ten of them are reported as disease biomarkers. Thus, our results suggest that the effects of diuretics deserve more attention in future urinary protein biomarker studies. Moreover, the distinct effects of diuretics on the urinary proteome may provide clues to the mechanisms of diuretics.

Discovery of novel diarylamides as orally active diuretics targeting urea transporters

Urea transporters(UT)play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics.Thus,UT inhibitors are promising for development as novel diuretics.In the present study,a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening.Optimization of the inhibitor led to the identifi-cation of a promising preclinical candidate,N-[4-(acetylamino)phenyl]-5-nitrofuran-2-carboxamide(1 H),with excellent in vitro UT inhibitory activity at the submicromolar level.The half maximal inhibitory concentrations of 1 H against UT-B in mouse,rat,and human erythrocyte were 1.60,0.64,and0.13 mmol/L,respectively.Further investigation suggested that 8 mmol/L 1 H more powerfully inhibited UT-A1 at a rate of 86.8%than UT-B at a rate of 73.9%in MDCK cell models.Most interestingly,we found for the first time that oral administration of 1 H at a dose of 100 mg/kg showed superior diuretic effect in vivo without causing electrolyte imbalance in rats.Additionally,1 H did not exhibit apparent toxicity in vivo and in vitro,and possessed favorable pharmacokinetic characteristics.1 H shows promise as a novel diuretic to treat hyponatremia accompanied with volume expansion and may cause few side effects.

Extracorporeal veno-venous ultrafiltration in congestive heart failure:What’s the state of the art?A mini-review

Hospitalizations for heart failure exceed 1 million per year in both the United States and Europe and more than 90%are due to symptoms and signs of fluid overload.Rates of rehospitalizations or emergency department visit at 60 days are remarkable regardless of whether loop diuretics were administered at low vs high doses or by bolus injection vs continuous infusion.Ultrafiltration(UF)has been considered a promising alternative to stepped diuretic therapy and it consists in the mechanical,adjustable removal of iso-tonic plasma water across a semipermeable membrane with the application of hydrostatic pressure gradient generated by a pump.Fluid removal with ultrafiltration presents several advantages such as elimination of higher amount of sodium with less neurohormonal activation.However,the conflicting results from UF studies highlight that patient selection and fluid removal targets are not completely understood.The best way to assess fluid status and therefore establish the fluid removal target is also still a matter of debate.Herein,we provide an up-to-date systematic review about the role of ultrafiltration among patients with fluid overload and its gaps in daily practice.

人尿中美托拉宗的液相色谱-质谱研究

A sensitive and reliable procedure for analysis of metolazone in human urine by HPLC-MS was describes.The extraction recovery of liquid-liquid extraction (LLE) at various pH were studied.The detection limit of the compound was below 0.2ng at absolute amount.It is suitable for metolazone screening and confirmation in doping control.

Current approaches to the management of patients with cirrhotic ascites

This review describes current approaches to the management of patients with cirrhotic ascites in relation to the severity of its clinical manifestations. The PubMed database, the Google Scholar retrieval system, the Cochrane Database of Systematic Reviews, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 1991-2018 using the keywords:“liver cirrhosis,”“portal hypertension,”“ascites,”“pathogenesis,”“diagnostics,” and “treatment.” Uncomplicated and refractory ascites in patients with cirrhosis were the inclusion criteria. The literature analysis has shown that despite the achievements of modern hepatology, the presence of ascites is associated with poor prognosis and high mortality. The key to successful management of patients with ascites may be the stratification of the risk of an adverse outcome and personalized therapy. Pathogenetically based approach to the choice of pharmacotherapy and optimization of minimally invasive methods of treatment may improve the quality of life and increase the survival rate of this category of patients.

Current and future pharmacological therapies for managing cirrhosis and its complications

Due to the restrictions of liver transplantation,complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis.This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications,together with discussion of current controversies and potential future directions.PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety,efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis.Non-selective betablockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices,but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation.Recent observational studies suggest protective,haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation.The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy;recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis.Diuretics remain the mainstay of uncomplicated ascites treatment,and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites.Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications.Despite initial hepatotoxicity concerns,safety of statin administration has been demonstrated in compensated cirrhosis.Furthermore,statins are suggested to have protective effects upon fibrosis progression,decompensation and mortality.Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting.Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis,and may impede hepatic fibrogenesis and decompensation.Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management,nutritional optimisation and patient education.

Twenty-four-hour ambulatory blood pressure changes in older patients with essential hypertension receiving monotherapy or dual combination antihypertensive drug therapy

Objective To evaluate the differences in 24-hour ambulatory blood pressure (BP) in older patients with hypertension treated with the five major classes of antihypertensive drugs,as monotherapy or dual combination therapy,to improve daytime and nighttime BP control. Methods We enrolled 1920 Chinese community-dwelling outpatients aged ≥ 60 years and compared ambulatory BP values and ambulatory BP control (24-hour BP < 130/80 mmHg;daytime mean BP < 135/85 mmHg;and nighttime mean BP < 120/70 mmHg),as well as nighttime BP dip patterns for monotherapy and dual combination therapy groups. Results Patients’ mean age was 71 years,and 59.5% of patients were women. Calcium channel blockers (CCBs) constituted the most common (60.3% of patients) monotherapy,and renin–angiotensin system (RAS) blockers combined with CCBs was the most common (56.5% of patients) dual combination therapy. Monotherapy with beta-blockers (BB) provided the best daytime BP control. The probabilities of having a nighttime dip pattern and nighttime BP control were higher in patients receiving diuretics compared with CCBs (OR = 0.52,P = 0.05 and OR = 0.41,P = 0.007,respectively). Patients receiving RAS/diuretic combination therapy had a higher probability of having controlled nighttime BP compared with those receiving RAS/CCB (OR = 0.45,P = 0.004). Compared with RAS/diuretic therapy,BB/CCB therapy had a higher probability of achieving daytime BP control (OR = 1.27,P = 0.45). Conclusions Antihypertensive monotherapy and dual combination drug therapy provided different ambulatory BP control and nighttime BP dip patterns. BB-based regimens provided lower daytime BP,whereas diuretic-based therapies provided lower nighttime BP,compared with other antihypertensive regimens.

Fluid and electrolyte overload in critically ill patients: An overview

Fluids are considered the cornerstone of therapy for many shock states, particularly states that are associated with relative or absolute hypovolemia. Fluids are also commonly used for many other purposes, such as renalprotection from endogenous and exogenous substances, for the safe dilution of medications and as "maintenance" fluids. However, a large amount of evidence from the last decade has shown that fluids can have deleterious effects on several organ functions, both from excessive amounts of fluids and from their non-physiological electrolyte composition. Additionally, fluid prescription is more common in patients with systemic inflammatory response syndrome whose kidneys may have impaired mechanisms of electrolyte and free water excretion. These processes have been studied as separate entities(hypernatremia, hyperchloremic acidosis and progressive fluid accumulation) leading to worse outcomes in many clinical scenarios, including but not limited to acute kidney injury, worsening respiratory function, higher mortality and higher hospital and intensive care unit lengthof-stays. In this review, we synthesize this evidence and describe this phenomenon as fluid and electrolyte overload with potentially deleterious effects. Finally, we propose a strategy to safely use fluids and thereafter wean patients from fluids, along with other caveats to be considered when dealing with fluids in the intensive care unit.

Medical management of symptomatic severe aortic stenosis in patients non-eligible for transcatheter aortic valve implantation

1 Transcatheter aortic valve implantation in symptomatic severe aortic stenosis: where do we stand? Aortic stenosis occurs in 2%-9% of patients over the age of 65, the most common cause being degenerative.^([1,2]) The preferred treatment in symptomatic severe aortic stenosis(SAS) is surgical aortic valve replacement(SAVR), but in the elderly, the surgical risk can be greater than the benefit.([3]).

Management of acute heart failure-Is there a paradigm shift around the corner?

It has become increasingly apparent that the looming epidemic of heart failure calls for systematic treatment approaches tailored to the needs of individual patient phenotypes. Although chronic heart failure (CHF) therapies are continuously evolving based on the increasing understanding of the involved etiology, acute heart failure (AHF) therapies are still based on hemodynamic improvements and symptom alleviation. Guidelines on AHF management have highlighted that the currently administered AHF therapies lack evidence and have raised concerns on the safety and efficacy of some of the hitherto accepted treatment modalities. Additionally, the high mortality and morbidity rates associated with the current AHF therapies also add to the imperative need to revisit AHF management. The last decade has witnessed a paradigm shift in the way we define and diagnose AHF. Apart from it being recognized as a distinct clinical entity, research has also led to new data on the pathophysiological changes associated with AHF. These developments along with the limited short- and long-term effects of currently used therapies may herald a paradigm shift in the way we plan and deliver management strategies to treat the pathological progression of heart failure.

Diuretic Agents in Treatment of Sudden Deafness

Objective To study the role of diuretic agents in treating sudden deafness (SD) and explore the possibility of endolymphatic hydrops as a potential cause of SD. Methods Twenty-eight SD cases were reviewed. In 23 cases, treatment was initiated with routine agents. Diuretic agents were later added in 8 of these cases that failed to respond to routine treatment agents. Diuretic agents were included in the initial treatment in the rest 5 cases. In total, 13 cases received diuretics in addition to routine treatment agents and 15 cases received conventional treatment only. Results In the 8 cases who received diuretics after failed conventional treatments, 4 showed hearing improvement, whereas all 5 cases in which diuretics were included in the initial treatment demonstrated hearing improvement. Conclusion These results suggest a possible role of endolymphatic hydrops in the pathophysiologic course of SD. Diuretics should be considered when clear indications exist with no conflicts to other medical conditions.

Sodium glucose cotransporter 2 inhibitors:New horizon of the heart failure pharmacotherapy

Sodium-glucose cotransporter 2(SGLT2)inhibitors have gained momentum as the latest class of antidiabetic agents for improving glycemic control.Large-scale clinical trials have reported that SGLT2 inhibitors reduced cardiovascular outcomes,especially hospitalization for heart failure in patients with type 2 diabetes mellitus who have high risks of cardiovascular disease.Accumulating evidence has indicated that beneficial effects can be observed regardless of the presence or absence of type 2 diabetes mellitus.Accordingly,the Food and Drug Administration approved these agents specifically for treating patients with heart failure and a reduced ejection fraction.It has been concluded that canagliflozin,dapagliflozin,empagliflozin,or ertugliflozin can be recommended for preventing hospitalization associated with heart failure in patients with type 2 diabetes and established cardiovascular disease or those at high cardiovascular risk.In the present review,we explore the available evidence on SGLT2 inhibitors in terms of the cardioprotective effects,potential mechanisms,and ongoing clinical trials that may further clarify the cardiovascular effects of the agents.

The Evaluation of Tolvaptan Therapy and Long-Term Prognosis in Hepatocellular Carcinoma with Refractory Ascites

We investigated Tolvaptan efficacy and long-term prognosis with focus on nutrition in 20 patients with refractory hepatic ascites in hepatocellular carcinoma (HCC). Bloating improved in 55% of patients, as determined using a Japanese version of the Support Team Assessment Schedule. Nutritional status improved with Tolvaptan treatment, based on the Controlling Nutritional Status score and Onodera’s prognostic nutritional index. Long-term prognosis was better in responders than in non-responders (mean survival time: 308 days vs. 97 days, p = 0.031). Tolvaptan was even effective in many patients with HCC, with additional improvement in long-term prognosis expected with improvement in the nutritional status.