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.

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.

Diuretic and antioxidant activities of the aqueous extract of leaves of Cassia occidentalis(Linn.) in rats

Objective: To assess the putative diuretic and antioxidant properties of Cassia occidentalis(C. occidentalis) leaves' aqueous extract. Methods: Adult rats were administered with C. occidentalis leaves aqueous extract acutely(24-h) and subchronically(7 d), at doses 80, 160, 240, 320, and 400 mg/kg(per os). Negative control group received only an equivalent volume of distilled water, while the two positive control groups received the diuretic drugs furosemide(20 mg/kg, i.p.) and hydrochlorothiazide(HCTZ, 20 mg/kg, i.p.). Urinary elimination of electrolytes in response to treatments was evaluated, together with changes in concentrations of creatinine, urea, aldosterone, glucose, and albumin in urine and plasma. Various urinary indicators of kidney function and plasmatic markers of oxidative stress were also assessed. Results: The acute administration of C. occidentalis increased the urinary excretion of 107.58% at the higher dose tested, compared to negative control. The reference drugs furosemide and HCTZ induced increases of 84.27 % and 48.05 %, respectively. Acutely, the extract induced Na+ and Cl- elimination, whereas subchronically an increase in K+ elimination was also observed. The extract also improved the kidney function indexes and oxidative stress markers. These effects were dose-dependent and comparable with positive control observations. Conclusions: Our i ndings strongly suggest that C. occidentalis aqueous extract has diuretic and antioxidant activities, and deserves further studies considering the potential for the treatment of hypertension.

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.

Diuretic window hypothesis in cirrhosis: Changing the point of view

Since the 1970s,non-selective beta-blockers(NSBB)have been used to prevent variceal upper bleeding in advanced cirrhotic patients.However,several recent studies have raised the doubt about the benefit of NSBB in end-stage cirrhotic patients.In fact,they suggested a detrimental effect in these patients that even reduced survival.All of these studies have been assembled to compose the“window therapy hypothesis”,in which NSBB would have traditional indication to be initiated to prevent variceal upper bleeding;however,treatment should be stopped(or not be initiated)in patients with end-stage cirrhosis.NSBB would reduce the cardiac reserve of these patients,worsening systemic perfusion and prognosis.However,it should be emphasized that these studies present important bias issues,and their results also suggested that diuretic treatment may also be behind the effects observed.In this opinion review,we changed the point of view from NSBB to diuretic treatment,based on a physiopathogenic approach of circulatory parameters of cirrhotic patients studied,and based on diuretic effect in blood pressure lowering and in other hypervolemic disease,as heart failure.We suggest a“diuretic window hypothesis”,composed by an open window in hypervolemic phase,an attention window when patient present in a normal plasma volume phase,and a closed window during the plasma hypovolemic phase.

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.

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.

Diuretic activity of Phyllanthus niruri (Linn.) in rats

Aqueous extract of Phyllanthus niruri (200 mg/kg and 400 mg/kg. p.o. single dose) was tested for its diuretic activity and compared with the standard drug hydrochlorothiazide (10 mg/ kg p.o.;single dose). Significant increase in the volume of urine and excretion of sodium, potassium and chloride was recorded when aqueous extract of Phyllanthus niruri was administered to hydrated albino rats.

Diuretic Effect of <em>Cymbopogon jwarancusa</em>after Single and Multiple Doses in Rats

Diuretics are efficaciously used in management of various clinical emergencies like hypertension, heart failure, cirrhosis, hypercalciuria, hematuria and nephrotic syndrome. Cymbopogon jwarancusa is an aromatic perennial grass used in both traditional and Unani system of medicine to eradicate diseases like colds, seasonal fever, asthma, tuberculosis, rheumatic pain, back pain, toothache and nervous disorders. C. jwarancusa essential oils are used in perfumery, soap, detergents, medicines and pharmaceutical industry. Monoterpenes and sesquiterpenes constitute the highest composition in essential oil of C. jwarancusa. The present was designed to compare the diuretic activity of C. jwarancusa after single and multi-doses. Furosemide (20 mg/kg) was used as reference drug and 10% DMSO was used as vehicle. Diuretic activity was noticed by measuring urine volume and calculating diuretic and Lipchitz values. Maximum diuretic response was observed at 500 mg/kg of extract after both single and multi-dose administration. On basis of results it may be concluded that C. jwarancusa may be used as diuretic agent.

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.

Diuretic combinations in critically ill patients with respiratory failure:A systematic review and meta-analysis

BACKGROUND In patients with respiratory failure,loop diuretics remain the cornerstone of the treatment to maintain fluid balance,but resistance is common.AIM To determine the efficacy and safety of common diuretic combinations in critically ill patients with respiratory failure.METHODS We searched MEDLINE,Embase,Cochrane Library and PROSPERO for studies reporting the effects of a combination of a loop diuretic with another class of diuretic.A meta-analysis using mean differences(MD)with 95%confidence interval(CI)was performed for the 24-h fluid balance(primary outcome)and the 24-h urine output,while descriptive statistics were used for safety events.RESULTS Nine studies totalling 440 patients from a total of 6510 citations were included.When compared to loop diuretics alone,the addition of a second diuretic is associated with an improved negative fluid balance at 24 h[MD:-1.06 L(95%CI:-1.46;-0.65)],driven by the combination of a thiazide plus furosemide[MD:-1.25 L(95%CI:-1.68;-0.82)],while no difference was observed with the combination of a loop-diuretic plus acetazolamide[MD:-0.40 L(95%CI:-0.96;0.16)]or spironolactone[MD:-0.65 L(95%CI:-1.66;0.36)].Heterogeneity was high and the report of clinical and safety endpoints varied across studies.CONCLUSION Based on limited evidence,the addition of a second diuretic to a loop diuretic may promote diuresis and negative fluid balance in patients with respiratory failure,but only when using a thiazide.Further larger trials to evaluate the safety and efficacy of such interventions in patients with respiratory failure are required.

Diuretic Activity of Ethanol Extract of Piper attenuatum Leaves Might Be Due to the Inhibition of Carbonic Anhydrase Enzyme:An in vivo and in silico Investigation

Background:Ayurvedic system of medicine is well established for prevention and treatment of renal problems.There are vast number of medicinal plants mentioned in Ayurvedic system of medicine,including Piper attenuatum Buch.-Ham.ex Miq.,which has been known to exhibit diuretic properties.Objective:To investigate possible mechanism and diuretic activity of ethanol extract of P.attenuatum leaves.Methods:Present study reports an in vivo diuretic activity of ethanol extracts of P.attenuatum leaves.Twenty-four Sprague-Dawley male rats were deprived from food and water for 20 h,followed by being divided into four groups to receive normal saline,Furosemide,and two doses of the ethanol extract,respectively.Further,the ethanol extract were subjected for prelimnary phytochemical screening test,and analytical investigation was performed via high-performance thin-layer chromatography(HPTLC),followed by effectiveness exploration of putative bioactive compounds from P.attenuatum against human carbonic anhydrase(hCA)enzyme using molecular docking tool.Results:During phytochemicals screening,several groups of compounds such as amides,terpenoids,proteins,flavonoids,and glycosides have been identified.Further,HPTLC reveals presence of carbohydrates,proteins,amino acids,steroids,alkaloids,flavonoids,tannins,glycosides,and terpenoids.Significant diuretic action was revealed for both 200 mg/kg bw and 400 mg/kg bw of ethanol extract of P.attenuatum leaves.Interestingly,molecular docking analysis demonstrated greater binding affinity of compounds such as Cepharadione A,Nor-cepharadione B,Galbelgin,Crotepoxide,and Pipoxide chlorohydrin out of total 23 studied compounds against hCA isoforms(a key biomarker for diuretic)and score is comparable with standard drug Acetazolamide.Conclusion:It was concluded from the present studies that ethanol extract of P.attenuatum leaves exhibits signifi-cant diuretic activity.The activity may be correlated due to the presence of Cepharadione A,Norcepharadione B,Galbelgin,Crotepoxide,and Pipoxide chlorohydrin as key component responsible for inhibition of hCA isoforms.

Accumulation of biomass and four triterpenoids in two-stage cultured Poria cocos mycelia and diuretic activity in rats

Poria cocos(Schw.) Wolf, an important medicinal and food fungus, is well known in East Asia. Due to growing market demand, long cultivation period, and consumption of pine trunk during cultivation, developing alternative methods for producing P. cocos and/or its active components is of interest. In the present study, the effects of different culture methods on biomass and accumulation of four triterpenoids were investigated. The ethanol extract of fermented mycelium(EFM) was orally administered to rats. Urine output and concentrations of electrolytes(Na^+, K^+, and Cl^-) were measured. Our results showed that mycelia grew better under continuous shaking culture condition(7.5 g DW·L^(-1)), and higher triterpenoid levels were accumulated in two-stage culture(112 mg·L-1, 2.03%). The optimal starting time of static culture for triterpenoid yield was 4^(th) d after shaking culture. Single administration of middle and high dose of EFM significantly increased urine output, Na^+ and Cl^- excretion, and Na^+/K^+ ratio. These results suggested that ethanol extract of cultured mycelia showed significant diuretic activity in rats and two-stage culture of P. cocos could be an alternative way to produce mycelia and triterpenoids.

Evaluation of diuretic and laxative activity of hydro-alcoholic extract of Desmostachya bipinnata(L.) Stapf in rats

OBJECTIVE： In continuation to the growing evidence for therapeutical potential of Desmostachya bipinnata （Linn） Stapf, the current pharmacological study was carried out to evaluate the diuretic and laxative activity of its hydro-alcoholic extract in rats. METHODS： The hydro-alcoholic extract of D. bipinnata whole plant was prepared by using Sox- hlet extractor and subjected to analysis by standard preliminary phytochemical tests. Evaluation of both diuretic and laxative activity was carried out using standard methods as reported earlier. Frusemide （20 mg/kg） was served as positive control for diuretic activity and sennosides （10 mg/kg） served as negative control for laxative activity. RESULTS： The hydro-alcoholic extract showed significant diuretic activity and was found to be the most potent in increasing the urinary output at 500 mg/kg when the effect was compared with that of the standard frusemide （P〈0.01）. Moreover, this extract was found to be most effective in increasing urinary electrolyte concentration （Na＋, K＋, and Cl-） at both doses tested. Whereas the results for laxative activity showed minimal increase of feces output at the dose of 500 mg/kg and the increase was negligible when compared with that of the standard drug sennosides. CONCLUSION： Altogether, the above significant findings validate and support its folkloric diuretic use and lend pharmacological credence to the ethno-medical use of this plant in traditional system of medicine, which demands further studies to investigate its active constituents, as well as its use and safety.

Effectiveness of Zhuling decoction(猪苓汤) on diuretic resistance in patients with heart failure:a randomized,controlled trial

OBJECTIVE:To test the effects of Zhuling decoction(猪苓汤)on patients with diuretic resistance in heart failure compared with a group of patients undergoing conventional treatment alone.METHODS:This research was a prospective,randomized,controlled study.From July 2018 to August 2020,96 diuretic resistance patients from the Cardiovascular Research Center of Taicang Hospital affiliated with Nanjing University of Traditional Chinese Medicine(GradeⅢHospital of Traditional Chinese Medicine)were enrolled in the study.The subjects were randomly divided into an observation group(48 cases)and a control group(48 cases).Patients in both groups received conventional treatment.In addition,observation group patients received Traditional Chinese Medicine Zhuling decoction.The primary endpoint was the urine output mean difference between Day 1 and Day 7 after treatment.Secondary endpoints were the changes over time in the N-terminal pro-B type natriuretic peptide(NTproBNP),New York Heart Association(NYHA)functional classification,and Minnesota Living with Heart Failure Questionnaire(MLHFQ).The safety and tolerability of the drug were comprehensively evaluated based on adverse drug reactions,as well as laboratory-assisted tests for liver and kidney function and electrolytes.RESULTS:Significant improvements were demonstrated for urine output in the two groups at Day 7,with a 1325 vs 1045 mL difference in favor of the observation group(P=0.018).The observation group also had greater improvements in NT-proBNP and NYHA functional classification changes than the control group.At the 30 th day of follow-up,a significant reduction in negative findings on the MLHFQ from baseline was observed in both groups,but the observation group demonstrated a significantly greater reduction than the control group(P<0.001).CONCLUSIONS:Zhuling decoction could be used in combination therapy for patients with diuretic resistance in heart failure in addition to standard treatment.

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.

In vivo laxative, anti-diarrheal, hepatoprotective and diuretic investigations of Sterculia diversifolia and its isolated compounds

OBJECTIVE:To investigated the laxative,anti-diarrheal,hepatoprotective and diuretic activity of Sterculia diversifolia and its isolated compounds.METHODS:The laxative activity was studied by counting wet stools while anti-diarrheal activity was performed by measuring gastrointestinal tract motility.Hepatoprotective activity was studied by biochemical and histo-pathological analysis while diuretic activity was performed by urine collection protocol.RESULTS:Doses of 30 and 100 mg/kg of crude methanolic extract of Sterculia diversifolia(MESD)stem bark and leaves,significantly(P<0.05,P<0.01)produced wet feces in subjects pretreated with atropine while 8-hydroxyquercetin and dihydroquercetin showed highly significant(P<0.001)results by increasing fecal weight and water contents without producing diarrhea.MESD stem bark and leaves also dose-dependently lowered diar-rhea while 8-hydroxyquercetin and dihydroquercetin showed highly significant(P<0.001)results by producing shaped stools in mice.MESD,8-hydroxyquercetin and dihydroquercetin offered significant protection against histopathological changes in the liver.Diuretic activity of Crude MESD stem bark and leaves extracts shows highly significant diuretic effect while dihydroquercetin showed better results than 8-hydroxyquercetin.CONCLUSION:It is concluded that Sterculia diversifolia and its isolated compounds bears laxative,anti-diarrheal,hepatoprotective and diuretic effects.

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.