Potent Diuretic Research Articles

Na+-K+-2Cl- cotransporter 2 located in the human and murine gastric mucosa is involved in secretagogue-induced gastric acid secretion and is downregulated in lipopolysaccharide-treated mice

Na+-K+-2Cl- cotransporter (NKCC) is expressed at exceptionally high levels in gastric parietal cells. Bumetanide, a potent loop diuretic that blocks NKCC, usually causes a decrease in gastric acid secretion. Endotoxaemia causes hypochlorhydria in vivo, in which lipopolysaccharide (LPS) plays an important role. This study aimed to investigate the effect of NKCC2 on gastric acid secretion and its alteration in LPS-treated mice. The scanning ion-selective electrode technique and real-time pH titration combined with RNA interference were used to determine the effects of bumetanide on gastric acid secretion. Immunochemistry and Western blotting were performed to investigate the changes in NKCC2 expression in LPS-treated mice. Immunoreactivity of NKCC1 and NKCC2 was mainly observed near the basolateral and apical membranes of parietal cells, respectively. Pretreatment with bumetanide reduced the histamine-stimulated H+ flux in the mouse gastric mucosa. The apical, but not the basolateral, addition of bumetanide inhibited forskolin- or histamine/3-isobutyl-1-methylxanthine(IBMX)-induced gastric acid secretion. In vivo treatment with NKCC2 siRNA inhibited forskolin-induced acid secretion. Upon histamine stimulation, the majority of NKCC2 was targeted to the apical membrane in the gastric mucosa and in primary cultured parietal cells. The expression of NKCC2 and vesicle-associated membrane protein-2 (VAMP2), but not that of H+/K+-ATPase, was decreased in the gastric mucosa of LPS-treated mice. Blocking apical NKCC2, but not basolateral NKCC1, by bumetanide inhibited secretagogue-induced gastric acid secretion, during which the membrane trafficking of NKCC2 may be necessary. The downregulation of NKCC2 and VAMP2 may be related to the reduced gastric acid secretion induced by LPS.

Urea Transporters Identified as Novel Diuretic Drug Targets.

Urea Transporters are a family of membrane channel proteins that facilitate the passive transport of urea across the plasma membrane. UTs are divided into two subgroups, UT-A and UT-B. UT-As are primarily located in renal tubule epithelia and UT-Bs are highly expressed in renal descending vasa recta and extrarenal multiple tissues. Various urea transporter knockout mice exhibit low urine concentrating ability, which suggests that UTs are novel diuretic targets. With highthroughput screening of small molecule drug-like compound libraries, various potent UT inhibitors with IC50 at nanomolar level were identified. Furthermore, selective UT inhibitors exhibit diuretic activity without disturbing electrolyte and metabolism balance, which confirms the potential of UTs as diuretic targets and UT inhibitors as novel diuretics that do not cause electrolyte imbalance. This review article summarizes the identification and validation of urea transporter as a potential diuretic target and the discovery of small molecule UT inhibitors as a novel type of diuretics. UTs are a potential diuretic target. UT inhibitors play significant diuresis and can be developed to diuretics without disturbing electrolyte balance.

Short-term effects of low-dose tolvaptan in acute decompensated heart failure patients with severe aortic stenosis: The LOHAS registry

BackgroundTolvaptan exerts potent diuretic effects in heart failure patients without hemodynamic instability. Nonetheless, its clinical efficacy for acute decompensated heart failure (ADHF) due to severe aortic stenosis (AS) remains unclear. This study aimed to evaluate the short-term effects of tolvaptan in ADHF patients with severe AS. MethodsThe LOw-Dose Tolvaptan (7.5 mg) in Decompensated Heart Failure Patients with Severe Aortic Stenosis (LOHAS) registry is a multicenter (7 centers) prospective registry that assessed the short-term effects of tolvaptan in subjects hospitalized for ADHF with severe AS. A total of 59 subjects were enrolled between September 2014 and December 2017. The primary endpoints were changes in body weight and fluid balance measured daily from baseline up to 4 days. ResultsThe median [interquartile range] patient age and aortic valve area were 85.0 [81.0–89.0] years and 0.58 [0.42–0.74] cm2, respectively. Body weight continuously decreased, and fluid balance was maintained from baseline to day 4 (p < 0.001, p = 0.194, respectively). Median serum B-type natriuretic peptide concentration significantly decreased from 910.5 to 740.0 pg/mL by day 4 (p = 0.002). However, systolic blood pressure and heart rate were non-significantly changed (p = 0.250, p = 0.656, respectively). Hypernatremia (>150 mEq/L) and worsening renal function occurred in 2 (3.4%) and 4 (6.8%) patients, respectively. ConclusionsShort-term treatment with low-dose tolvaptan is safe and effective, providing stable hemodynamic parameters in patients with ADHF and severe AS.

P055 Effect of Mimosa caesalpiniifolia extract on DSS-induced colitis in Wistar rats

Abstract Background Iinflammatory bowel disease (IBD) is a chronic disease characterised by dysregulation of the immune function response and imbalanced release of cytokines and unresolved inflammatory progress associated with the intestinal mucosa. In this way, new drugs are constantly tested as a novel treatment option. Mimosa caesalpiniifolia (MC) has been described as a potent analgesic, anti-inflammatory, anti-haemorrhagic, astringent, anthelmintic and diuretic. This study aimed to evaluate the effect of MC extract on dextran sulphate sodium (DSS)-induced colitis in Wistar rats. Methods Forty male Wistar rats were randomised into five groups: Sham; 5% DSS-induced colitis; control MC extract (125 mg/kg/day); 5% DSS-induced colitis treated with MC (125 mg/kg/day); 5% DSS-induced colitis treated with MC + 5-ASA (125 mg/kg/day for both). Colitis was induced by administration of 5% DSS (MP Biomedicals), diluted in drinking water and offered ad libitum for 5 days. MC plant extract was diluted in water and administered by oral gavage per 6 days. The leaf extracts were prepared in 70 gl ethanol and dried in a Buchi B19 Mini-spray dryer using 20% aerosol. The selection of the operating conditions used was followed by the Laboratory of Medicinal and Phytotherapeutic Plants of Unifal-MG. After the induction of colitis, body weight, general health status and faecal characteristics will be evaluated daily. All rats were euthanised on the ninth day of the experiment. The entire colon was dissected and fixed in 10% neutral-buffered formalin at room temperature and embedded in paraffin to provide sections for histological evaluation (Ethics Committee on the Use of Animals number 4362180119). The severity of colitis was evaluated in sections stained with Hematoxylin and Eosin. Parameters such as inflammation extent, regeneration and crypt damage were graded according to Dieleman et al. Statistical analysis was performed by one-way analysis of variance (ANOVA), followed by Tukey post hoc test using Graph Pad Prism (version 6.0). Results MC extract treatment reduced significantly the severity of DSS-induced colitis evidenced by a decreased in clinical symptoms (p &amp;lt; 0.0001). The rats treated with MC extract showed a decreased in diarrhoea episodes and rectal bleeding. We observed histopathological changes of colon tissue between the DSS-treatment and control groups, however, without statistical significance. The MC extract treatment reduced the damage to the colonic tissue evidenced by a decreased of inflammatory cells, ulcerations, and goblet cell preservation. Conclusion MC extract reduces the clinical signs and suggests a potential anti-inflammatory effect on DSS-induced colitis.

Herbal tea for the treatment of Urinary diseases as Potent diuretic and Anti-inflammatory agent

The herbal tea of previously patented composition for the treatment of urinary diseases containing twelve plants (St. John's wort, Wild pansy, Horsetail field, Common heather, Elecampane i.a.) was analyzed for the qualitative composition and quantitative content of phenolic compounds. The diuretic and anti-inflammatory activity of herbal tea thick extract was assessed. The determination of phenolic compounds was carried out by high performance liquid chromatography using standards of phenolic acids and flavonoids. Diuretic activity was checked by the method of Berkhin for the dosage in the range from 100 to 700mg/kg. Level of urination was assessed during 1, 2, and 3 hours of experiment. Edema was induced with 1% carrageenan. The dosage of oral treatment was from 100 to 250mg/kg. Paw volume was checked at time equal to 1, 2, 3, 4, and 5 hours. Several groups of phenolic compounds were detected, and six substances were identified individually. The total content of phenolic compounds was 23.8mg/g, with the content of flavonoids 10.4mg/g and chlorogenic acid 2.7mg/g. The herbal tea showed diuretic activity of 100% growth at the dosage of 200mg/kg. Further increase of dosage led to antidiuretic activity. From the dosage of 500mg/kg we observed the diuretic activity again, which was the highest for the dosage of 700mg/kg showing 271% growth in relation to the control group. The antiinflammatory activity was the highest at the dosage of 200 and 250mg/kg and was equal to 25% in relation to the control group.

Anaphylactic shock with intravenous furosemide: a rare undesired effect

Furosemide is a potent diuretic, with structural similarity to sulphonamide antibiotics. Its relative safety profile is one of the reasons to account for its widespread use. We report a rare case of fatal anaphylaxis with intravenous furosemide administered in our critical care settings for pulmonary edema. Chemical similarity of furosemide with sulphonamide antibiotics shares the possibility of similar allergic side effects. Thus, a more careful clinical use of furosemide, especially if administered intravenous should be kept in mind to avoid such catastrophic events.

Діуретична активність похідного метилксантину фуроксану за одноразового та тривалого застосування на функцію видільної системи щурів на тлі спонтанного діурезу

The study of the effect of furoxane on renal activity under conditions of spontaneous diuresis was performed by the method of Berkhin. Hydrochlorothiazide was chosen as a reference drug. Furoxane and hydrochlorothiazide were administered intragastrically at a dose of 25 mg/kg for 7 days. The content of Na+ and K+in the urine was determined by flame photometry. The concentration of creatinine in the urine was studied by the method of Folin in the modification of Berkhin. The obtained results were calculated using the methods of variation statistics. The analysis of the results shows that under one-time action of furoxane in rats the daily urination increased by 210.4 % (p &lt;0.001), the concentration of Na+ in the urine of rats increased by 51.9 % (p &lt;0.05), and the concentration of K+ in the urine tended to increase by 5.6 %. Natriuresis increased 1.7 times (p &lt;0.05), potassium - 1.23 times (p &lt;0.05). Excretion of endogenous creatinine increased 1.49 times (p &lt;0.05), indicating an improvement in glomerular ultrafiltration. After administration of hydrochlorothiazide there was an increase in diuresis by 92.2 % (p &lt;0.05), urinary Na+ concentration increased by 49% (p &lt;0.05) and increased Na+excretion from urine by 23.3 % (p &lt;0.05). K+ concentration in urine increased by 12.6 %, and K+excretion - by 27.5 % (p &lt;0.05). Thus, a single administration of furoxane at a dose of 25 mg/kg led to an increase in daily diuresis, Na+ and K+ diuresis, which indicates the potential diuretic and saluretic properties of the drug. Long-term (7 days) furoxane administration contributed to the increase of urination in animals. After 3 days diuresis increased by 226,1 % (p &lt;0.001), on 7th day – by 236,3 % (p &lt;0.001). Salures was increased: the excretion of Na+ after 3 days increased by 2.27 times (p &lt;0,05), after 7 days - by 2,38 times (p &lt;0,05), K+ - 1.83 times (p &lt;0.05). The gradual increase in creatinine excretion in the dynamics of the use of furoxane, indicated a possible prolongation of the effect of furoxane. Thus, furoxane, which by its chemical structure belongs to methylxanthine derivatives is a promising pharmacologically active substance for further study of its specific activity and safety in order to create a highly effective diuretic and implementation in clinical practice.

Simultaneous Determination of Hydrochlorothiazide in Combination with Some Antihypertensive Drugs in The Presence of Its Main Impurities in Pure Form and Pharmaceutical Formulations

Background:Hydrochlorothiazide (HCTZ) is potent diuretic that is used alone or in combination with other drugs such as labetalol (Lab) (mixtures Ι) or nebivolol (Neb) (mixtures ΙΙ) to control moderate to sever hypertension.Introduction:This paper demonstrates the establishment of different validated spectrophotometric and chemometric methods for simultaneous estimation of these mixtures in pure form and pharmaceutical formulations in the presence of HCTZ related impurities in quality control laboratories.Methods:(A) Derivative method (D3) of Lab and HCTZ and its related impurities at 245.3nm and 278.5nm respectively, (D1) of Neb and HCTZ at 294.2nm and 282.2nm, respectively. (B) First derivative of ratio spectra method (DD 1) of Lab at 244.3nm, HCTZ at 261.2nm and 275.4nm, while at 294nm for Neb and 269.4nm for HCTZ. (C) Ratio difference method which depends on measuring the distinction between the amplitudes of ratio spectra at 240nm and 288.3nm for Lab and at 270.1nm and 277.4nm for HCTZ for mixture Ι while at 290.4nm and 299.2nm for Neb and at 232.2nm and 254nm for HCTZ for mixture ΙΙ. (D) Mean centering of ratio spectra (MC) and (E) partial least squares regression (PLS) and principal component regression (PCR).Results:These methods were applied over concentration ranges of 10-100 µg/ml, 10-75 µg/ml and 2.5- 25 µg/ml of Lab, Neb and HCTZ, respectively. Methods were validated according to ICH guidelines and statistical comparison of results of reported and proposed methods revealed no difference.Conclusion:The methods were successfully used for the frequent analysis of selected mixtures in quality control laboratories.

Advanced spectrophotometric methods for quantitative assessment of two antihypertensive drugs in mixture with hydrochlorothiazide in pure form and pharmaceutical formulations

Labetalol (Lab) and nebivolol (Neb) are β-adrenoceptor blocking agents that are employed for control of hypertension alone or co-administered with hydrochlorothiazide (HCTZ) as a potent diuretic for synergistic antihypertensive effect. Advanced, accurate and simple spectrophotometric methods with minor manipulation of zero-order spectra were suggested for simultaneous quantitation of Lab or Neb in mixture with HCTZ for quality control purpose in pure form and pharmaceutical formulations. These methods include (a) constant center method, (b) advanced absorbance subtraction method for Lab and HCTZ, (c) absorption factor method (AFM) and (d) the ratio subtraction method. The established methods were successfully applied over concentration ranges 10–100 µg/mL, 10–75 µg/mL and 2.5–25 µg/mL of Lab, Neb and HCTZ, respectively. Results were compared statistically to those of official and reported methods revealing no remarkable difference. Validation of methods followed international conference of harmonization guidelines. Suggested methods require minor processing of zero-order spectra with accurate results that facilitate the quantitative estimation of studied mixtures in quality control laboratories.

Acetazolamide as a potent chloride-regaining diuretic: short- and long-term effects, and its pharmacologic role under the 'chloride theory' for heart failure pathophysiology.

According to the "chloride theory" for heart failure (HF) pathophysiology, manipulation of the serum chloride concentration is an important therapeutic target. This study determined the short- and long-term effects of acetazolamide (Diamox), a potential chloride-regaining diuretic, on peripheral blood, serum electrolytes, and renal function. Effects of low-dose Diamox (250-500mg/day) were evaluated in 30 HF patients for whom Diamox was added as de-novo/add-on decongestion therapy for acutely worsening HF (n = 18) or as modification therapy for serum hypochloremia in stable HF ( < 100mEq/L; n = 12). Peripheral hematologic tests were performed at baseline, and at short- ( ≤ 10days) and long-term ( ~ 60days) time-points. In all 30 study patients of both groups, the serum chloride concentration increased in the short-term and even further over the long-term. The serum potassium concentration constantly decreased throughout the study period. Both the blood urea nitrogen and serum creatinine concentrations increased in the short-term, but returned to baseline levels over the long-term. Responders to Diamox (n = 13; defined by HF resolution and body weight loss ≥ 1kg) in the decongestion group exhibited reduced serum b-type natriuretic peptide levels and a markedly increased serum chloride concentration, but the hemoglobin/hematocrit and serum creatinine concentrations did not change after treatment. In conclusion, acetazolamide is a potent candidate "chloride-regaining diuretic" for treating HF patients under the "chloride theory". Its effect to enhance the serum chloride concentration occurred within 10days and persisted for at least ~ 60days. Plasma volume and renal function were preserved under adequate diuretic treatment with acetazolamide.

Off-Label Use of Bumetanide for Brain Disorders: An Overview.

Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl− gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl− importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl− levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.

Stability-indicating methods for determination of hydrochlorothiazide in combination with some antihypertensive drugs in the presence of its main impurities

Hydrochlorothiazide (HCTZ) is potent diuretic that used alone or in combination with other antihypertensive drugs such as labetalol hydrochloride (Lab) or nebivolol hydrochloride (Neb) to control moderate to severe hypertension. As there is no published method for simultaneous determination of HCTZ and Lab (mixture Ι) or Neb (mixture ΙΙ) in pharmaceutical formulations in presence of HCTZ-related impurities, it was important to develop validated stability-indicating HPLC methods for analysis of these mixtures in quality control laboratories. These methods based on gradient RP-HPLC separation of mixture Ι at 215 nm using acetonitrile:0.1% triethylamine pH = 2 (12:88 v/v) as mobile phase at flow rate 1.0 mL/min using Promosil C18 (150 mm × 4.6 mm i.d.; 5 µm) column. While mixture ΙΙ separation was performed at 220 nm using BDS Hypersil C18 (250 mm × 4.6 mm i.d.; 5 µm) column with mobile phase of acetonitrile:phosphate buffer pH = 3 (15:85 v/v) at flow rate 1.0 mL/min. The responses were linear over concentration ranges 2.0–100 µg/mL (r = 0.9997) and 1.0–100 µg/mL (r = 0.9998) with mean recoveries 100.16% and 100.43% of Lab and HCTZ, respectively meanwhile 5.0–100 µg/mL (r = 0.9997) and 2.0–100 µg/mL (r = 0.9996) with mean recoveries 99.99% and 100.63% of Neb and HCTZ, respectively. Methods were validated according to ICH guidelines; the results were statistically compared with the company methods and there was no significant difference. The proposed methods have the advantages of being stability-indicating and time saving with low solvent consumption which favors their usage in quality control routine analysis of selected mixtures in their pharmaceutical formulations.

Factors associated with disease progression in dogs with presumed preclinical degenerative mitral valve disease attending primary care veterinary practices in the United Kingdom.

BackgroundFactors associated with disease progression in dogs with preclinical (stage B) degenerative mitral valve disease (DMVD) have not been evaluated previously in primary care veterinary practice.ObjectivesTo evaluate whether plasma cardiac biomarkers, clinical signs, and physical examination findings are associated with clinical progression (reaching the composite endpoint of initiation of treatment with a potent diuretic or cardiac death) in dogs presumed to have stage B DMVD.AnimalsSix‐hundred and eighty‐four dogs diagnosed with DMVD recruited from 73 primary care practices in the United Kingdom. Dogs were not receiving potent diuretics at recruitment.MethodsProspective cohort study design. Primary care veterinarians recorded the presence or absence of clinical signs and physical examination findings. Baseline plasma N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) and cardiac troponin I were measured. Cox regression models measured associations between risk factor variables and clinical progression. Flexible parametric models generated predicted probabilities of reaching the composite endpoint for dogs with different combinations of prognostic risk factor variables.ResultsPlasma NT‐proBNP, heart rate, heart murmur intensity, presence of a cough, being a Cavalier King Charles Spaniel, and being prescribed pimobendan were associated with clinical progression to initiation of treatment with a potent diuretic or cardiac‐related death.Conclusions and Clinical ImportanceDogs with stage B DMVD identified as having a high risk of disease progression might benefit from more frequent monitoring or further diagnostic evaluation. The prognostic factors identified could facilitate risk stratification of dogs presenting with preclinical DMVD.

Bumepamine, a brain-permeant benzylamine derivative of bumetanide, does not inhibit NKCC1 but is more potent to enhance phenobarbital's anti-seizure efficacy

Based on the potential role of Na-K-Cl cotransporters (NKCCs) in epileptic seizures, the loop diuretic bumetanide, which blocks the NKCC1 isoforms NKCC1 and NKCC2, has been tested as an adjunct with phenobarbital to suppress seizures. However, because of its physicochemical properties, bumetanide only poorly penetrates through the blood-brain barrier. Thus, concentrations needed to inhibit NKCC1 in hippocampal and neocortical neurons are not reached when using doses (0.1–0.5 mg/kg) in the range of those approved for use as a diuretic in humans. This prompted us to search for a bumetanide derivative that more easily penetrates into the brain. Here we show that bumepamine, a lipophilic benzylamine derivative of bumetanide, exhibits much higher brain penetration than bumetanide and is more potent than the parent drug to potentiate phenobarbital's anticonvulsant effect in two rodent models of chronic difficult-to-treat epilepsy, amygdala kindling in rats and the pilocarpine model in mice. However, bumepamine suppressed NKCC1-dependent giant depolarizing potentials (GDPs) in neonatal rat hippocampal slices much less effectively than bumetanide and did not inhibit GABA-induced Ca2+ transients in the slices, indicating that bumepamine does not inhibit NKCC1. This was substantiated by an oocyte assay, in which bumepamine did not block NKCC1a and NKCC1b after either extra- or intracellular application, whereas bumetanide potently blocked both variants of NKCC1. Experiments with equilibrium dialysis showed high unspecific tissue binding of bumetanide in the brain, which, in addition to its poor brain penetration, further reduces functionally relevant brain concentrations of this drug. These data show that CNS effects of bumetanide previously thought to be mediated by NKCC1 inhibition can also be achieved by a close derivative that does not share this mechanism. Bumepamine has several advantages over bumetanide for CNS targeting, including lower diuretic potency, much higher brain permeability, and higher efficacy to potentiate the anti-seizure effect of phenobarbital.

Bumetanide attenuates acute lung injury by suppressing macrophage activation

Bumetanide is a potent loop diuretic that acts as an inhibitor of sodium-potassium-chloride cotransporter 2 (NKCC2) and its isoform NKCC1. Although the expression of NKCC2 is limited to the kidney, NKCC1 is widely expressed in various cells, where it participates in a variety of physiological functions including ion transport, alveolar fluid secretion, and cell volume regulation. We investigated the role of NKCC1 in modulation of host immunity. Lipopolysaccharide (LPS) stimulated the expression and phosphorylation of NKCC1 in RAW264.7 cells in vitro and activated these cells to produce inflammatory cytokines. Enlarging the cell volume in a low-osmotic microenvironment amplified the LPS-induced inflammatory responses and phagocytosis activity of RAW264.7 cells. Pretreatment with the NKCC1 inhibitor bumetanide attenuated LPS-induced activation of inflammatory cells and cell volume-related function. Mice treated with an intratracheal bumetanide spray showed greater resistance to LPS-induced tissue inflammation and acute lung injury in vivo. Our studies suggest that NKCC1 plays a unique role as an amplifier of LPS-induced macrophage functions and that NKCC1 might be a novel target for treating sepsis-related acute respiratory distress syndrome.

The Diuretic Activity of Ephedra alata and Plumbago europaea in Mice using an Aqueous Extract

Throughout history, man used various natural materials as a remedy for treatment of various diseases and recently witnessing a vastly growing and renewed interest in herbal medicine globally. In Palestinian folk medicine Ephedra alata and Plumbago europaea used as diuretics and for treatment of hypertension. This study aimed to evaluate the diuretic and acute toxicity effects of the aqueous extracts for these two plants in mice following oral administration. Aqueous E. alata and P. europaea extracts (500 mg/kg) were administered orally to adult mice. Urine output and electrolytes were then measured after 4 h of administration and compared with those received furosemide 10 mg/kg (positive control group) and those received normal saline (negative control group). Significant diuresis was noted in those received the aqueous extract of E. alata (p < 0.001), while the P. europaea aqueous extract had shown mild diuresis at the end of the forth hour compared to controls. Moreover, both aqueous extracts had an alkaline pH and a mild increase in the electrolyte excretion (Na, K). Our results revealed that E. alata aqueous extract has potential diuretic effect. Further studies are needed to evaluate this diuretic effect in the relief of diseases characterized by volume overload.

Mechanism of the diuretic activity of Descurainia sophia seed

The diuretic activity of the decoction and the chemical fractions of Descurainia sophia was studied with underlying mechanisms in rats. Rat metabolic cage method was used to study the diuretic activity of the decoction and the chemical fractions of D. sophia. Western blot, ELISA, ion selective electrode method and cryoscopy method were used to study the underlying mechanism. The urinary output increased significantly in rats administrated decoction. Washing elution fractions had the potent diuretic activity. Washing elution fractions could decrease the urine osmolality, increased the concentration of K+, and decreased the concentration of Na+ and ALD, also decreased the expression of aquaporin 1 (AQP1) in kidney. Moreover, compared with washing elution fractions, decoction decreased the levels of AVP, V2R, and AQP2. It is concluded that decoction had significant diuretic activity and washing elution fractions had the potent diuretic activity. The mechanisms of diuretic activity were different between decoction and washing elution fractions.&#x0D; Video Clip of Methodology: &#x0D; 10 min 51 sec: Click to watch

Neither Coffee Nor A Stimulant Containing “Pre-workout” Drink Alter Cardiovascular Drift During Walking In Young Men

Caffeine is a widely used stimulant that is often consumed in coffee. Caffeine is also the main ingredient in many “pre-workout” drinks, which are purported to enhance exercise performance. Due to the stimulatory effects of caffeine on the heart and the potential diuretic effects of caffeine, drinking coffee or a pre-workout drink before exercise may exacerbate cardiovascular drift. PURPOSE: The purpose of this study was to compare the effects of coffee and a commercially available pre-workout drink on cardiovascular drift during prolonged moderate intensity walking. METHODS: Eight healthy, recreationally active males consumed coffee (containing 120 mg caffeine), decaffeinated coffee, a pre-workout drink (containing 120 mg caffeine), or a placebo in a randomly assigned cross over design one hour before walking for 40 minutes on a treadmill at a workload that corresponded to 50% of their VO2 max. RESULTS: Heart rate gradually increased (P<0.05) from 123.2 ± 5.5 beats/min at 10 minutes to 132.8 ± 8.6 beats/min for all treatments, but there was no main effect of treatment or interaction effect of treatment X time on heart rate. Respiratory exchange ratio (RER) gradually decreased (P<0.05) from 0.76 ± 0.02 at 10 minutes to 0.73 ± 0.04 for all treatments, but there was no main effect of treatment or interaction effect of treatment X time on RER. Similarly, there was no main effect of treatment or interaction effect of treatment X time on oxygen consumption. CONCLUSIONS: The gradual increase in heart rate in the present study demonstrates cardiovascular drift during 40 minutes of walking at 50% VO2max , with no changes due to consuming coffee or a pre-workout drink 1 hour prior to exercise. Furthermore, the ingestion of coffee or a pre-workout drink 1 hour prior to exercise did not alter the RER indicating no effects on fat or carbohydrate use. The lack of difference in oxygen consumption indicates that ingesting coffee or a pre-workout drink 1 hour prior to exercise does not alter energy expenditure. Overall, the lack of effects of coffee or a pre-workout drink in the present investigation suggest that while the caffeine dose does not present additional challenges to cardiovascular function, the caffeine dose does not influence exercise performance during 40 minutes of walking at 50% VO2max.

Enhanced Both in vitro and in vivo Kinetics by SLNs Induced Transdermal System of Furosemide: A Novel Approach

Furosemide is a potent diuretic agent used to treat pulmonary arterial hypertension. Variable dosage regimen and poor pharmacokinetic parameters have led to the development of transdermal drug delivery system. Patent on suitability of multi-lamellar structures for excellent transdermal delivery (US0367475A1) has encouraged us to formulate the solid lipid nanoparticles (SLNs) induced transdermal systems of furosemide to enhance the kinetic properties without incorporating any penetration enhancer and rate limiting polymers. SLNs were prepared by hot homogenization and ultra-sonication method; optimization was done based on entrapment efficiency and particle size. Optimized SLNs were incorporated in to transdermal patches by solvent casting method. In vitro and in vivo studies were carried out for characterization of transdermal patches. SLNs of F9 (GMS: Span 60: Pluronic F 68 in 6:2.5:0.2) were optimized for incorporating in to transdermal system (entrapment efficiency 96.5±0.045%, particle size 69.6±1.48nm and in vitro release 94.38±1.02%). Transdermal patches were formulated using combinations of hydrophilic and hydrophobic polymers to study the diffusion kinetics. Formulation FS1 (HPMC 4 parts) was optimized for further studies (in vitro release 98.11±1.21% with flux of 58.726±0.023µg/cm2/h) and no significant difference from ex vivo permeation studies was observed. Drug release followed mixed order diffusion kinetics and super case -II transport mechanism. In vivo pharmacokinetic data of SLNs induced transdermal system suggested a 3.6 times increase in AUC and 5.4 times increase in MRT when compared with oral route. The SLNs induced transdermal patch was found to beneficial in enhancing kinetic properties both in vitro and in vivo.

Evaluation of diuretic, saluretic and natriuretic activity of hydrochlorothiazide in combination with misoprostol in Wistar rats

Background: Renal vasodilatation by prostaglandins is well proven facts. Furosemide is better diuretics due to their additional effect on intrarenal hemodynamic changes brought about by increase in local prostaglandin synthesis. No such changes occur with thiazide group of diuretics. Hence, we want to analyze the diuretic effect of hydrochlorothiazide in combination with prostaglandin analog misoprostol. Aims and Objectives: This study aims to evaluate the diuretic, saluretic, and natriuretic activity of hydrochlorothiazide in combination with misoprostol. Materials and Methods: Four groups of Wistar rats with six animals in each group were grouped. One group served as the control and the other three groups received furosemide, hydrochlorothiazide, and hydrochlorothiazide with misoprostol, respectively. Urine output, urinary electrolytes, saluretic activity, and natriuretic of all groups were estimated and then compared with the standard and control groups. Results: There was a statistically difference in the urinary output between groups as determined by oneway ANOVA (F = 33.413, P ≤ 0.001 and F =260.267, P = 0.001) at 5 and 24 h, respectively. The Lipschitz value showed that standard group and test Group 4 indices were >2.0 showing potent diuretic action. There was a statistically significant difference in the urinary excretion of all the electrolytes between groups as determined by one-way ANOVA (F = 645.087, P ≤ 0.001; F = 360.49, P ≤ 0.001; and F = 366.974, P ≤ 0.001) for the levels of Na+, K+, and Cl−, respectively. It has been found that the saluretic activity was significant in all three groups when compared with control group. However, they do not show significant changes in natriuretic activity. Conclusion: This study has shown that the diuretic activity and diuretic index of hydrochlorothiazide can be increased when it is given in combination with prostaglandin analog misoprostol and also found to be almost equivalent to standard drug furosemide effect. There was also a significant effect in the excretion of electrolytes in urine and significant saluretic activity that favors their use in edematous conditions. Saluretic activity of hydrochlorothiazide with misoprostol was also similar to furosemide. Since both the drugs are already approved and safely used for many decades, we can further do a clinical trial to confirm these findings and can be used as a combination of old drugs for a new indication.