Effect Of Furosemide Research Articles

Furosemide diminishes ¹⁸F-fluoroethylcholine uptake in prostate cancer in vivo.

(18)F-Fluoroethylcholine ((18)F-FECh) is excreted via the urinary system with high activity accumulation in the urinary bladder. Furosemide and oral hydration can be administered concomitantly to reduce urinary activity to provide better detectability of retroperitoneal and pelvic lesions. Currently it is unknown if there is any effect of furosemide on (18)F-FECh uptake in organs, tissues and tumour lesions and the extent to which image quality along the urinary tract may be improved by furosemide. We retrospectively analysed 217 (18)F-FECh PET/CT examinations from 213 patients with known prostate cancer (PCa), performed either with oral hydration (109) or furosemide 20mg together with oral hydration (108). Maximum (18)F-FECh uptake in different organs, tissues, lymph nodes and osseous metastases was quantified in terms of standardized uptake value (SUV) in a volume of interest and compared between the two groups. To characterize the impact of furosemide on lesion detectability a three-point rating scale was used to assess the presence of focal activity spots in the ureters and of perivesicular artefacts. Patient characteristics and distribution of tumour lesions were well balanced between the two groups. Overall, SUVmax values from normal organs were increased after furosemide compared to the values in patients scanned without furosemide. Significant changes were observed in the salivary glands, liver, spleen, pancreas, kidneys, gluteus muscle and perirenal fat. SUVmax values were significantly decreased after furosemide in lymph node metastases (SUVmax 4.81 ± 2.68 vs. 6.48 ± 4.22, p = 0.0006), but not in osseous metastases. Evaluation of image quality along the urinary tract revealed significantly better depiction of the perivesicular space and significantly less focal tracer accumulation in the ureters in patients receiving furosemide, but the number of detected lymph nodes was not significantly different. Furosemide administration reduced choline uptake in tumour lesions, especially significant in pelvic lymph node metastases. Although furosemide administration improved image quality, optimal image quality may also be obtained by adequate hydration without the risk of diminishing choline uptake in PCa lesions. Therefore a controlled hydration protocol seems more appropriate than administration of furosemide.

The combined effect of furosemide and propranolol on GSH homeostasis in ACHN renal cells

Objectives: Propranolol, a beta-adrenergic blocker, is used in the treatment of a large number of cardiovascular diseases such as hypertension and arrhythmias. Propranolol, in combination with furosemide, is used to treat hypertensive disorders although their side effect profile is not very obvious. In present study, the effects of the drugs furosemide and propranolol were in corporately investigated both on glutathione homeostasis and their antioxidant effect on ACHN cells.Methods: The cytoxicities and antioxidant effects of these two clinically important drugs on human kidney cell lines were evaluated using MTT following by the determination of glutathione reductase (GR) and glutathione peroxidase (GPx) activities and measuring the level of reduced glutathione (GSH).Results: Propranolol induced a significant cytotoxic effect at 100 µM, while furosemide was cytotoxic at doses of 250 and 1000 µg/ml. A slight increase in GPx and GR activities and GSH level was observed with propranolol and furosemide treatment alone, while the two drugs together caused a significant increase in GPx and GR activities (35% and 42%, respectively) and GSH content (35%) in ACHN cell lysates (p < 0.05).Conclusions: Our results demonstrate that although high doses of furosemide and propranolol are cytotoxic, co-administration of low doses may improve the antioxidant defense in patients undergoing treatment with these two important drugs.

Furosemide Administration Affects Mineral Excretion in Exercised Thoroughbreds

IntroductionFurosemide is widely administered to Thoroughbred and Standardbred racehorses to reduce the incidence and severity of EIPH. The magnitude and duration of mineral loss following furosemide administration has not previously been measured in horses.MethodsSix fit Thoroughbreds (age 6.8 ± 1.2 y; bwt 585 ± 19 kg) were used in a 3 x 3 Latin square design trial to measure the effect of furosemide on urinary and fecal mineral excretion for 24 h before (−24 h) and 24 h, 48 h and 72 h after a standardized exercise test (SET) on an inclined (3o) high speed treadmill. The treatment groups consisted of an untreated control (C) and two groups (F and FE) which received furosemide (0.5 mg/kg, IV) 4 h before the SET. C and F were fed 60 g/d NaCl and (FE) was fed 200 g/d of an electrolyte mix (14 g K, 37.7 g Na and 43.3 g Cl) for 21 days before the SET. Following the SET the FE group was supplemented with an additional 10 g/d Ca and 10 g/d Mg.ResultsUrinary Ca, P, Na and Cl excretion increased 24 h post treatment in the F and FE groups (P&lt;0.05). 72 h Ca and Cl balance was decreased in F (P&lt;0.05) and 72 h Mg and Cl balance was decreased in FE (P&lt;0.05). The digestibility of P and Mg was decreased in FE (P&lt;0.05) and Na digestibility was increased in F and FE (P&lt;0.05).ConclusionsA single dose of furosemide negatively affected calcium balance in horses for 72 h post administration. Further research is needed to assess the effect of chronic furosemide use in racehorses on mineral balance and soundness.Ethical Animal ResearchStudy approved by the Kentucky Equine Research Institutional Animal Care and Use Committee. Sources of funding: Kentucky Equine Research. Competing interests: none.

In vitro characterization and pharmacodynamic evaluation of furosemide loaded self nano emulsifying drug delivery systems (SNEDDS)

Poor water solubility is one of the reasons for erratic absorption after oral administration of furosemide (FSM), an antihypertensive loop diuretic. Self nano emulsifying drug delivery system (SNEDDS) is a novel drug delivery system utilized to improve the water solubility, permeability and ultimately bioavailability. FSM solubility was determined in various vehicles oils, surfactants and co surfactants. Self emulsification region for the rational design of SNEDDS formulations were identified by pseudoternary diagrams. Developed formulations were characterized by zeta potential determination, droplet size analysis, dilution test, viscosity determination, in vitro dissolution studies and in vivo pharmacodynamic evaluation. A remarkable increase in dissolution was observed for the optimized SNEDDS when compared with the plain FSM and marketed formulation by in vitro dissolution studies. The pharmacological effect of FSM was improved by SNEDDS formulation as compared to plain FSM. The study confirmed that the SNEDDS formulation can be used as a possible alternative to traditional oral formulations of FSM to improve its bioavailability.

Effects of furosemide on cochlear neural activity, central hyperactivity and behavioural tinnitus after cochlear trauma in guinea pig.

Cochlear trauma causes increased spontaneous activity (hyperactivity) to develop in central auditory structures, and this has been suggested as a neural substrate for tinnitus. Using a guinea pig model we have previously demonstrated that for some time after cochlear trauma, central hyperactivity is dependent on peripheral afferent drive and only later becomes generated intrinsically within central structures. Furosemide, a loop diuretic, reduces spontaneous firing of auditory afferents. We investigated in our guinea pig model the efficacy of furosemide in reducing 1) spontaneous firing of auditory afferents, using the spectrum of neural noise (SNN) from round window recording, 2) hyperactivity in inferior colliculus, using extracellular single neuron recordings and 3) tinnitus at early time-points after cochlear trauma. Tinnitus was assessed using gap prepulse inhibition of acoustic startle (GPIAS). Intraperitoneal furosemide, but not saline, caused a marked decrease in both SNN and central hyperactivity. Intracochlear perfusion with furosemide similarly reversed central hyperactivity. In animals in which GPIAS measurements suggested the presence of tinnitus (reduced GPIAS), this could be reversed with an intraperitoneal injection with furosemide but not saline. The results are consistent with furosemide reducing central hyperactivity and behavioural signs of tinnitus by acting peripherally to decrease spontaneous firing of auditory afferents. The data support the notion that hyperactivity may be involved in the generation of tinnitus and further suggest that there may be a therapeutic window after cochlear trauma using drug treatments that target peripheral spontaneous activity.

Formulation, optimization, and in vitro/in vivo evaluation of furosemide nanosuspension for enhancement of its oral bioavailability

Furosemide is a poorly soluble diuretic used for treatment of hypertension and edema. It has very poor or variable oral bioavailability due to its reduced solubility in gastric fluid and reduced permeability in intestinal fluid. The aim of this study was to prepare nanosuspension of furosemide to enhance its oral bioavailability by increasing its dissolution in stomach where it has better permeability. Full factorial design was used for a systematic approach of formulation and optimization. The nanosuspensions were prepared by precipitation with ultrasonication method. Polyvinyl acetate was used for sterically stabilizing the nanosuspensions. The diffusing drug concentration and stabilizer were used as the factors and the particle size, polydispersity index, and drug release were selected as dependent variables and characterized. The effect of nanoprecipitation on enhancement of oral bioavailability of furosemide nanosuspension was studied by in vitro dissolution and in vivo absorption studies in rats and compared to pure drug. Quality by design using full factorial design provided a systematic approach in optimizing nanosuspensions to produce products with desired quality. Stable nanosuspension were obtained with average size range of the precipitated nanoparticles between 150 and 300 nm and were found to be homogenous showing a narrow polydispersity index of 0.3 ± 0.1. The in vivo studies on rats revealed a significant increase in the oral absorbtion of furosemide in the nanosuspension compared to pure drug. The AUC0→24 and C max values of nanosuspension were approximately 1.38- and 1.68-fold greater than that of pure drug, respectively. Furosemide nanosuspension showed 20.06 ± 0.02 % decrease in systolic blood pressure compared to 13.37 + 0.02 % in plain furosemide suspension, respectively. The improved oral bioavailability and pharmacodynamic effect of furosemide may be due to the improved dissolution of furosemide in simulated gastric fluid which results in enhanced oral systemic absorption of furosemide from stomach region where it has better permeability.

Diuretic activity of aqueous extract of roots of &amp;lt;i&amp;gt;Cissampelos pareira&amp;lt;/i&amp;gt; in albino rats

Background: Diuretic compounds that stimulate the excretion of water with small traceable ions are potentially useful in most of disorders including those exhibiting edema such as congestive heart failure, nephritis, toxemia of pregnancy, premenstrual tension, and hypertension. The aim was to evaluate the diuretic activity of aqueous extract of roots of Cissampelos pareira (AQERCP) by Lipschitz method in albino rats. Methods: Five groups of Albino rats were used to evaluate the diuretic activity of AQERCP by using metabolic cages. The Group I serves as normal control received vehicle (carboxymethyl cellulose 2% in normal saline), the Group II furosemide (10 mg/Kg, p.o) in vehicle; other Groups III, IV, and V were treated with low (100 mg/kg), medium (200 mg/kg), and high (400 mg/kg) doses of AQERCP in vehicle. Immediately, after the extract treatment all the rats were hydrated with saline (15 ml/kg, p.o) and placed in the metabolic cages (3/cage), specially designed to separate urine and faeces, kept at 21°C±0.5°C.The total volume of urine collected was measured at the end of 5th hr. During this period, no food and water was made available to animals. Various parameters such as total urine volume and concentration of sodium, potassium, chloride ions in the urine were measured and estimated respectively. Results: In this model, when compared to vehicle treated control group the AQERCP at different dose levels (100, 200 and 400 mg/kg) has significantly increased the urine volume and also enhanced the elimination of sodium, potassium and chloride ions in urine. Conclusion: The results showed that single dose administration of AQERCP as 100, 200 and 400 mg/Kg and standard frusemide (10 mg/kg b.wt) has significantly (p&lt;0.05*, p&lt;0.01**, p&lt;0.001***) increased the urine output along with an increase in concentration of sodium, potassium, and chloride. AQERCP 400 mg/Kg produced a greater diuretic activity, which is comparable to the effect of standard furosemide (10 mg/kg).The present study has supported and justified the basis for folklore use of roots of C. pareira as a diuretic agent.

Torasemide reduces dilated cardiomyopathy, complication of arrhythmia, and progression to heart failure.

The aim of this study was to analyze the incidence and types of arrhythmia and their relationship with the severity and prognosis of chronic heart failure (CHF) in patients with dilated cardiomyopathy (DCM), and to investigate the therapeutic effect of torasemide versus furosemide on CHF and incidence of arrhythmia. DCM patients with NYHA cardiac function II-IV were continuously monitored using a 24-h dynamic electrocardiogram (Holter), and arrhythmia incidence was analyzed by computer automatic analysis combined with manual assessment. In total, 125 participants were evenly divided into two groups: torasemide group which received 10 mg oral torasemide once daily) and regular anti-heart failure treatment (N=65), and furosemide group which received torasemide (20 mg once daily orally) and regular antiheart failure treatment (N=60). Another 60 normal healthy persons served as the normal control group. Incidence and severity of arrhythmia increased when degree of CHF was elevated. Size of left atrium was related to atrial fibrillation and size of left ventricle was related to malignant arrhythmia. At 3 months after treatment, cardiac function in both groups improved and incidence and severity of arrhythmia in both groups were reduced. However, left ventricular ejection fraction (LVEF) was higher in the torasemide group than in the furosemide group, while incidence of arrhythmia was lower in the torasemide group. Arrhythmias frequently occurred in patients with DCM and HF. Type of cardiac arrhythmia is closely related to ventricular enlargement and cardiac function grade. Torasemide is better for improving cardiac function to reduce arrhythmia and CHF compared to furosemide.

Spironolactone, not furosemide, improved insulin resistance in patients with chronic heart failure

Background/objectivesInsulin resistance plays an important role in the pathophysiology in chronic heart failure (CHF). Diuretics generally have harmful effects on glucose metabolism, however, the effect of mineral corticoid receptor blockers on insulin resistance in CHF is unclear. This study aimed to evaluate the effects of the aldosterone blocker spironolactone, in comparison with furosemide, on insulin resistance in CHF patients. MethodsThe effect of spironolactone (25mg/day) and furosemide (20mg/day) on IR for 16weeks each was analyzed in 16 CHF patients using a double-blind, placebo-controlled, randomized cross-over study design. ResultsPlasma BNP and left ventricular ejection fraction were improved with both treatments (furosemide: p=0.02 and p=0.009, respectively, spironolactone: p=0.03 and p=0.007, respectively). Fasting plasma glucose was not changed; however, plasma insulin levels decreased and insulin sensitivity (by homeostasis model assessment: HOMA-IR) improved with spironolactone as compared to furosemide (p<0.0005). TNF-α, IL-6 and MCP-1 decreased with spironolactone (p=0.002, p=0.02 and p=0.02 vs. baseline, respectively), but not with furosemide. Matrix metalloproteinase (MMP)-2 and MMP-9 were decreased with spironolactone (p=0.003 and p=0.04 vs. baseline, respectively), but not furosemide. Changes in TNF-α, IL-6 and MCP-1 levels after spironolactone treatment were significantly correlated with changes in HOMA-IR (r=0.61, r=0.55 and r=0.65, respectively; p=0.01, p=0.03 and p=0.01, respectively). Furthermore, changes in MMP-2 and MMP-9 levels were significantly correlated with changes in HOMA-IR (r=0.58 and r=0.58, respectively; p=0.02 and p=0.02, respectively). ConclusionsSpironolactone, not furosemide, improved insulin resistance in CHF patients probably by the inhibition of inflammatory cytokines and MMPs.

Loop diuretics are open-channel blockers of the cystic fibrosis transmembrane conductance regulator with distinct kinetics

Loop diuretics are widely used to inhibit the Na(+), K(+), 2Cl(-) co-transporter, but they also inhibit the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. Here, we investigated the mechanism of CFTR inhibition by loop diuretics and explored the effects of chemical structure on channel blockade. Using the patch-clamp technique, we tested the effects of bumetanide, furosemide, piretanide and xipamide on recombinant wild-type human CFTR. When added to the intracellular solution, loop diuretics inhibited CFTR Cl(-) currents with potency approaching that of glibenclamide, a widely used CFTR blocker with some structural similarity to loop diuretics. To begin to study the kinetics of channel blockade, we examined the time dependence of macroscopic current inhibition following a hyperpolarizing voltage step. Like glibenclamide, piretanide blockade of CFTR was time and voltage dependent. By contrast, furosemide blockade was voltage dependent, but time independent. Consistent with these data, furosemide blocked individual CFTR Cl(-) channels with 'very fast' speed and drug-induced blocking events overlapped brief channel closures, whereas piretanide inhibited individual channels with 'intermediate' speed and drug-induced blocking events were distinct from channel closures. Structure-activity analysis of the loop diuretics suggests that the phenoxy group present in bumetanide and piretanide, but absent in furosemide and xipamide, might account for the different kinetics of channel block by locking loop diuretics within the intracellular vestibule of the CFTR pore. We conclude that loop diuretics are open-channel blockers of CFTR with distinct kinetics, affected by molecular dimensions and lipophilicity.

Effect of NSAIDs and Diuretics on Nephrogenesis in an Ex Vivo Embryogenic Kidney Model

The kidney is one of the key organs in clearing foreign compounds. The effects of drugs on the developing kidney are relatively unknown. We studied the direct effect of furosemide, hydrochlorothiazide, ibuprofen, and indomethacin on kidney development in an ex vivo embryonic kidney model. At embryonic day 13, metanephroi were dissected from mice and cultured in control media or media supplemented with various clinically relevant concentrations of drugs. The ureteric tree was visualized by whole-mount staining and branching was evaluated by counting. Additionally, gene expression levels of Wt1, Sox9, Bmp7, Fgf8, and Gdnf were investigated. No distinct differences were noted on either ureteric tip development or gene expression analysis for each drug after 24 hr of exposure. Even though short-term exposure to clinically relevant concentrations seems not to disturb renal development, future research is needed to study prolonged or repeated exposures.

Effect of Furosemide on denaturation of lysozyme in the presence of ionic surfactant at different temperatures

The thermodynamics of Furosemide–lysozyme interaction has been studied using conductivity in combination with viscosity, density and speed of sound measurements. Lysozyme binds preferentially with Furosemide in the presence of surfactants, sodium dodecyl sulfate (SDS) and cetyltrimethylammonium bromide (CTAB). A number of physico-chemical parameters viz. critical micelle concentration (CMC), standard enthalpy of micellization (ΔHm°), standard entropy of micellization (ΔSm°), standard free energy of micellization (ΔGm°), apparent molar volume (ϕv), apparent molar adiabatic compressibility (ϕk) and relative viscosity (ηr) have been calculated from experimentally measured conductivity (κ), density (d), speed of sound (v) and viscosity (η). The critical micelle concentration data were found to pass through a broad minimum at 303K, which tends to become sharp with the increase in the [lysozyme] in case of SDS. Whereas for CTAB, CMC values, in general increase with the temperature and decrease with the increase in concentration of lysozyme. Experiments at different lysozyme concentrations and in the presence of surfactants suggest the predominant involvement of electrostatic interactions in the complexation process of Furosemide with lysozyme in the presence of SDS which induce unfolding of lysozyme as the surfactant concentration approaches its critical micelle concentration value, and non-specific interaction behaviour of Furosemide with lysozyme in the presence of CTAB.

Comparative Effect of Carperitide and Furosemide on Left Atrial Pressure in Dogs with Experimentally Induced Mitral Valve Regurgitation

The effects of carperitide on left atrial pressure (LAP) in dogs with mitral valve disease (mitral regurgitation, MR) have not been documented. The objective was to compare the short-term effects of carperitide versus furosemide on LAP and neurohumoral factors in MR dogs. Six healthy Beagle dogs weighing 9.8-12.6 kg (2 males and 4 females; aged 3 years) were used. Experimental, randomized, cross-over, and interventional study. Carperitide 0.1 μg/kg/min or furosemide 0.17 mg/kg/h (1 mg/kg/6 h) was administered to dogs with surgically induced MR for 6 hours, and after a 14 day wash-out period, the other drug was administered. LAP, plasma renin activity, plasma aldosterone, and echocardiographic variables were measured. Left atrial pressure was decreased similarly after the administration of carperitide 0.1 μg/kg/min and furosemide 0.17 mg/kg/h (1 mg/kg/6 h) compared with baseline in dogs with MR (Baseline 14.75 ± 3.74 mmHg, carperitide 10.24 ± 4.97 mmHg, P < .01, furosemide 10.77 ± 5.06 mmHg, P < .05). Plasma renin activity and plasma aldosterone were significantly lower after the administration of carperitide than after the administration of furosemide (P < .05, respectively). Carperitide significantly decreased LAP in dogs with acute MR caused by experimental chordal rupture. Carperitide can have additional benefits from the viewpoint of minimal activation of neurohumoral factors in the treatment of dogs with MR. Additional studies in dogs with spontaneous disease are warranted.

Effect of furosemide and high-dosage pimobendan administration on the renin-angiotensin-aldosterone system in dogs

To determine whether a high dosage of pimobendan, when administered concurrently with moderate-dosage furosemide to healthy dogs, would activate the renin-angiotensin-aldosterone system (RAAS) more than furosemide alone. 12 healthy dogs. 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) only, as an RAAS activator, for 10 days. The other 6 dogs received furosemide (2.0 mg/kg, PO, q 12 h) and pimobendan (0.6 mg/kg, PO, q 12 h) for 10 days. The effect of these drugs on the RAAS was determined by measurement of the aldosterone-to-creatinine ratio (A:C) in urine collected in the morning and evening of study days -2, -1, 1, 5, and 10. Although there was an increase in the urine A:C during the study period in both groups, it was significant only for dogs that received both drugs. The urine A:C only differed significantly between groups on day 1, at which time A:C was greater in the group that received both drugs. High-dosage pimobendan administration neither substantially suppressed nor potentiated the RAAS when administered with furosemide in healthy dogs.

Effects on survival of loop diuretic dosing in ambulatory patients with chronic heart failure using a propensity score analysis

To ascertain whether increasing doses of orally administered furosemide are associated with impaired survival in outpatients with chronic heart failure (CHF) and left ventricular (LV) systolic dysfunction. Transthoracic echo-Doppler examination was carried out at baseline in 813 consecutive CHF outpatients with LV ejection fraction ≤ 45%. The total daily dose of furosemide was assessed for each patient. Chronic kidney disease (CKD) was defined by a glomerular filtration rate < 60 ml/min/1.73 m(2). The end-point was all-cause mortality. To control the prognostic effect of furosemide for the propensity of using high doses of the drug, the Cox model was stratified by the propensity score, itself computed from a multivariable logistic model. Mean follow up was 44 months. After stratification for the propensity score, the risk of death increased linearly across quartiles of furosemide dose (HR 1.38, 95% CI 1.14-1.68, p < 0.001). A daily dose of 50 mg was identified as the best threshold value to predict a high risk of death within 3 years with an area under the ROC curve of 0.68 (95% CI 0.64-0.72). Increasing doses of furosemide were associated with an increased risk of death regardless of LV filling pattern, CKD and background therapy with ACE-inhibitors or beta-blockers. In outpatients with CHF, after stratification for the propensity score, the risk of death increased linearly across quartiles of furosemide daily dose. A threshold furosemide dose of 50 mg was related with the worse outcome.

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Alveolar fluid clearance driven by active epithelial Na(+) and secondary Cl(-) absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na(+) channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl(-) secretion and alveolar Cl(-) influx were quantified by radionuclide tracing and alveolar Cl(-) imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl(-) secretion and alveolar Cl(-) influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na(+)-K(+)-Cl(-) cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR(-/-) mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl(-) secretion that were again CFTR-, NKCC-, and Na(+)-K(+)-ATPase-dependent. Our findings show a reversal of transepithelial Cl(-) and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl(-) and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.

Influence of oral glucosamine supplementation in young horses: Intra-articular lipopolysaccharide challenge

Influence of oral glucosamine supplementation in young horses: Intra-articular lipopolysaccharide challenge

Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs

The aim of the present study was to develop and evaluate a novel drug solubilization platform (so-called solid nanodispersion) prepared by a simple co-grinding and solvent-free process. Using structurally diverse model compounds from the Pfizer drug library, including ingliforib, furosemide and celecoxib, we successfully prepared stable solid nanodispersions (SNDs) without the use of solvent or heat. Stable colloidal particles (<350nm) containing drug, polyvinylpyrrolidone (PVP) K12 and sodium dodecyl sulfate (SDS) in 1:2.75:0.25 ratio were produced after 2h of co-grinding. The composition and particle size of SNDs were optimized by varying the grinding media size, powder-to-grinding media ratio, milling speed and milling time. The resulting formulations contained crystalline drug and were stable at room temperature for over one month. Greater than 80% of the drug was released from the SND in less than 30min, with sustained supersaturation over 4h. Using furosemide (BCS class IV compound) as a model compound, we conducted transport studies with Madin–Darby canine kidney cells transfected with human MDR1 gene (MDCK/MDR1), followed by pharmacokinetics studies in rats. Results showed that the SND formulation enhanced the absorptive flux of furosemide by more than 3-fold. In the pharmacokinetics studies, the SND formulation increased Cmax and AUC of furosemide by 36.6 and 43.2 fold respectively, relative to Methocel formulation. Interestingly, physical mixture containing furosemide, PVP K12 and SDS produced a similar level of oral exposure as the SNDs, albeit with a longer Tmax than the SND formulation. The results suggest that PVP K12 and SDS were able to increase the furosemide free fraction available for oral absorption. Low solubility, poor permeability, and high first-pass effect of furosemide may also have produced the effect that small improvements in solubilization resulted in significant potentiation of the oral exposure of the physical mixture. However the use of a physical mixture of drug, polymer and surfactant, to increase drug bioavailability cannot be generalized to all drugs. There are only a few reported cases of such phenomenon. While SNDs may not be the only option to solubilize compounds in every case, SNDs are expected to be applicable to a broader chemical space of pharmaceutical compounds compared to a physical mixture. Ultimately, the formulation scientist will have to exercise judgment in choosing the appropriate formulation strategy for the compound of interest. SNDs represent a significant improvement over current enabling technologies such as nanocrystal and spray-dried dispersion technologies, in that SNDs are simple, do not require solvent or heat, are applicable to a structurally diverse chemical space, and are readily amenable to the development of solid dosage forms.

Comparison of Cochlear Cell Death Caused by Cisplatin, Alone and in Combination with Furosemide

Establishment of appropriate animal models is an important step in exploring the mechanisms of drug-induced ototoxicity. In the present study, using guinea pigs we compared cochlear lesions induced by cisplatin administered in two regimens: consecutive application alone and in combination with furosemide. The effects of furosemide alone were also evaluated; it was found to cause temporary hearing loss and reversible damage to the stria vascularis. Consecutive application of cisplatin alone appeared to be disadvantageous because it resulted in progressive body weight loss and higher mortality compared to the combined regimen, which used a smaller cisplatin dose. The combined regimen resulted in comparable hearing loss and hair cell loss but a markedly lower mortality. However, their coadministration failed to cause similar damage to spiral ganglion neurons (SGN), as seen in animals that received cisplatin alone. This difference suggests that the combined regimen did not mimic the damage to cochlear neuronal innervation caused by the clinical application of cisplatin. The difference also suggests that the SGN lesion is not caused by cisplatin entering the cochlea via the stria vascularis.

The Effect of Furosemide on Intravascular Volume Status and Electrolytes in Patients Receiving Mannitol

Mannitol is often used during intracranial surgery to improve surgical exposure. Furosemide is often added to mannitol to augment this effect. The concern exists, however, that the augmented diuresis caused by the addition of furosemide to mannitol may cause hypovolemia and hypoperfusion, hypokalemia, and hyponatremia. We examined the intraoperative safety of low-dose furosemide (0.3 mg/kg) combined with mannitol (1 g/kg). We observed 23 patients in a double-blind, block randomized, placebo-controlled study to examine the effects of furosemide (0.3 mg/kg) when combined with mannitol (1 g/kg) on surgical brain relaxation for tumor surgery. Mannitol and the study drug (furosemide or placebo) were administered, and arterial blood gases with electrolytes (sodium, potassium, and lactic acid) and urine output volume were recorded every 30 minutes for 3 hours. Plasma sodium, potassium, and lactic acid concentrations, and interval urine outputs, were compared across time and between furosemide-placebo assignment groupings, with a P<0.01 considered significant. Although mannitol produced a large volume of diuresis (1533±335 mL), the addition of a low dose of furosemide substantially increased both the rate of production of urine for the first 90 minutes after administration and the total volume of urine produced (2561±611 mL, P<0.001, compared with placebo group). The addition of furosemide did not produce a serum potassium level below 3.8±0.7 mEq/L, a serum sodium level below 128.3±3.4 mEq/L, or a serum lactic acid level above 2.4±0.9 mmol/L. There were no differences in the plasma potassium concentration, sodium concentration, or lactic acid concentration between the drug groups at any time point. Despite an increase in urine output by as much as 67%, adding low-dose furosemide to mannitol does not seem to produce significant electrolyte derangements or hypovolemia compared with the administration of mannitol alone.