Effects of combined administration of furosemide and kanamycin on rat auditory nerve

Objective To determine the effects of combined administration of furosemide and kanamycin on inner ear structures and the auditory nerve in rats. Methods The rats in the treatment group received intravenous injections of combined furosemide and kanamycin sulfate, and the rats in the normal control group received no treatment. The auditory brainstem response （ABR） test was carried out 7 days after drug administration to determine the effects of drug administration on hearing. Cochlear slice and cochlear wholcmount were prepared after 7 days of drug treatment. Results After 7 days of drug administration, ABR thresholds were significantly higher in the treatment group than in the control group and neurofilaments were significantly reduced, although the number of spiral ganglia showed no decrease and there were no signs of supporting cell injury. Conclusions Combined administration of furosemide and kanamyein sulfate has an apparent synergistic ototoxic effect. Although spiral ganglion damage may not be apparent within a short time period of drug administration, damage to auditory nerve fibers is obvious.

Increased mortality in elderly heart failure patients receiving infusion of furosemide compared to elderly heart failure patients receiving bolus injection

Heart failure(HF)is a condition of cardiac dysfunction and fluid overload.Neurohormonal activation via the reninangiotensin-aldosterone system and the sympathetic nervous system are the pathophysiological cornerstones.[1]Furthermore,HF is a disorder widely associated with grave adverse outcomes and poor prognosis.[2]A loop diuretic is the fundamental drug used to prevent multiorgan failure and improve symptoms in these patients.[3]

Is mannitol combined with furosemide a new treatment for refractory lymphedema?A case report

BACKGROUND Mannitol is a hyperosmolar agent and the combination of mannitol and furosemide is a widely used treatment for intracranial pressure control.Considering the hypertonic properties of mannitol to move water out of intracellular spaces,we hypothesized that mannitol combined with furosemide could relieve focal tissue swelling in refractory lymphedema.CASE SUMMARY A 90-year-old female had been diagnosed with intracranial hemorrhage and received a combination of mannitol and furosemide for intracranial pressure control.Independent of the intracranial hemorrhage,she had refractory lymphedema of the left lower extremity since 1998.Remarkably,after receiving the mannitol and furosemide,the patient’s lower extremity lymphedema improved dramatically.After the mannitol and furosemide were discontinued,the lymphedema worsened in spite of complete decongestive therapy(CDT)and intermittent pneumatic compression treatment(IPC).To identify the presumed effect of mannitol and furosemide on the lymphedema,these agents were resumed,and the lymphedema improved again.CONCLUSION The present case raises the possibility that a combination of mannitol and furosemide might be considered another effective therapeutic option for refractory lymphedema when CDT and IPC are ineffective.

Sequential Combination Diuretic-Therapy for Massive Fluid Overload in Furosemide-Refractory Patients with Diabetic Kidney Disease

Patients with renal disease are at risk of fluid overload which escalates as the disease progresses. In the present study, we evaluated the efficacy of sequential combination diuretic-therapy (SCDT) in management of massive fluid overload in Furosemide-refractory renal patients. The added diuretics were Spironolactone 25 mg daily for 3 days, to those without risk of hyperkalemia, followed by Hydrochlorothiazide 25 mg/Metolazone 5 mg daily for 3 more days. Excluded patients were those with 1) acute renal disease, 2) echocardiographic evidence of: a) left ventricular ejection fraction < 40%, b) significant stenotic or incompetent valvular disease, c) ASD or VSD, d) significant pericardial disease, and 3) significant limb venous disease or on drugs likely to cause limb-oedema. To assess the extent of fluid overload;clinical examination was complemented with radiological imaging as well as echocardiographic measurement of systolic pulmonary arterial pressure (sPAP). SCDT led to significant symptomatic, clinical, and radiological improvement of fluid overload without significant side effects. The latter were limited to hyperkalemia and hyponatremia which improved with dietary compliance. Moreover, hyperkalemia improved after subsequent addition of Thiazide/Metolazone. SCDT led to significant (p < 0.001) increase in fractional excretion of sodium and decrease in body weight and sPAP. In conclusion;SCDT is a safe and efficacious measure to control fluid overload in patients with renal diseases.

Design of a gastroretentive mucoadhesive dosage form of furosemide for controlled release

The aim of the present study was to develop and characterize a gastroretentive dosage form suitable for controlled drug release.It consists of a drug loaded polymeric film made up of a bilayer of immediate(IR)and controlled release(CR)layers folded into a hard gelatin capsule.Gast roretention results from unfolding and swelling of the film and its bioadhesion to the gastric.mucosa.Furosemide,a drug with a narrow absorption window,was selected as the model drug.Inclusion of hydroxypropyl β-cyclodextrin in both layers and Carbopol■ 971P NF in the CR layer of the bilayer film resulted in optimum drug release,bioadhesion and mechanical properties.The film with zig-zag folding in the capsule was shown to unfold and swell under acidic conditions and provide IR of drugover 1 hand CR for up to 12 h in acidic medium.X-ray diffraction,differential scanning calorimetry and scanning electron microscopy revealed uniform dispersion of furosemide in the polymeric matrices.The results indicate the dosage form is gastroretentive and can provide controlled release of drugs with narrow therapeutic wind ows.

The interaction between furosemide-palladium (Ⅱ) chelate and basic triphenylmethane dyes by resonance Rayleigh scattering spectra and resonance non-linear scattering spectra and their analytical applications

In pH 4.5-7.0 Britton-Robinson buffer solution,furosemide (FUR) reacted with Pd (II) to form a 1:1 anionic chelate.This chelate could further react with such basic triphenylmethane dyes (BTPMD) as ethyl violet (EV),crystal violet (CV),methyl violet (MV),methyl green (MeG) and brilliant green (BG) to form 1:1 ion-association complexes.This not only resulted in the change of absorption spectra,but also led to the significant enhancement of resonance Rayleigh scattering (RRS),second-order scattering (SOS) and frequency doubling scattering (FDS).The maximum RRS wavelengths were located at 324 nm for the EV,CV and MV system,and 340 nm for the BG and MeG system.The maximum SOS wavelengths were located at 550 nm for the EV,CV,BG and MeG system,and 530 nm for the MV system.The maximum scattering peaks of all the systems were at 392 nm for FDS.The enhanced RRS,SOS and FDS intensities were directly proportional to the concentration of FUR.The detection limits for the different dye systems were 0.3-4.9 ng mL-1 for the RRS method,3.2-33.1 ng mL-1 for the SOS method and 9.0-85.7 ng mL-1 for the FDS method.These methods could be used for the determination of trace amounts of FUR.The effects of the formation of ternary ion-association complexes on the spectral characteristics and intensities of absorption,RRS,SOS and FDS have been investigated.The optimum conditions of these reactions,the influencing factors and the analytical properties have been tested.The influences of coexisting substances were tested by RRS method and the results showed that this method exhibited a high sensitivity.Based on the aforementioned research,the highly sensitive,simple and rapid methods for the determination of trace amounts of FUR by resonance light scattering technique have been established,which could be applied to the determination of FUR in tablet,injection,human serum and urine samples.The composition and structure of the ternary ion-association complex and the reaction mechanism were discussed.

Transmission FTIR derivative spectroscopy for estimation of furosemide in raw material and tablet dosage form

A Fourier transform infrared derivative spectroscopy(FTIR-DS)method has been developed for determining furosemide(FUR)in pharmaceutical solid dosage form.The method involves the extraction of FUR from tablets with N,N-dimethylformamide by sonication and direct measurement in liquid phase mode using a reduced path length cell.In general,the spectra were measured in transmission mode and the equipment was configured to collect a spectrum at 4 cm^(-1) resolution and a 13 s collection time(10 scans co-added).The spectra were collected between 1400 cm^(-1) and 450 cm^(-1).Derivative spectroscopy was used for data processing and quantitative measurement using the peak area of the second order spectrum of the major spectral band found at 1165 cm^(-1)(SO_(2) stretching of FUR)with baseline correction.The method fulfilled most validation requirements in the 2 mg/mL and 20 mg/mL range,with a 0.9998 coefficient of determination obtained by simple calibration model,and a general coefficient of variation <2%.The mean recovery for the proposed assay method resulted within the(100±3)%over the 80%–120% range of the target concentration.The results agree with a pharmacopoeial method and,therefore,could be considered interchangeable.

Inhibitory Effect of Furosemide on Carbonic Anhydrase

This study investigated the inhibitory effect of a high efficiency diuretic, furosemide, on carbonic anhydrase （CA）. First, comparing the inhibitory effect of acetazolamide, a low efficiency diuretic, on CA, shows that furosemide or acetazolamide can quickly make CA inactive when its concentration is close to the enzyme concentration, different from the usual inhibitory kinetics in which the concentration of the inhibitor is far higher than the enzyme concentration. Secondly, the reaction of the enzyme indicates that the inhibitory effect of furosemide or acetazolamide on carbonic anhydrase is quickly reversible. Finally, the degree of the inhibitory effect of furosemide and of acetazolamide on CA are compared. The results show that furosemide inhibits CA less than acetazolamide.

Effectiveness of enalapril for lowering extremity edema caused by levamlodipine in essential hypertensive population:a randomized comparison to furosemide

Background The incidence of leg edema caused by calcium channel blockers（CCB） is so high, some studies tried combination with angiotension converting enzyme inhibitors（ACEI） or diuretics to overcome this problem.However, there is no comparison about which is better to improve edema at present. Methods This study was designed as a single-center, prospective, randomized, double-blind, parallel-group, clinical trial. 224 hypertensive patients with leg edema after 4 weeks since taking levamlodipine were enrolled, and they were randomly divided into levamlodipine ＋ furosemide（CD） group and levamlodipine ＋ enalapril（CA） group for another 4 weeks. Ankle circumference（AC）, edema score（ES）, blood pressure（BP） and cure rate of leg edema were evaluated. Results Altogether 179 patients（89 in CD group and 90 in CA group） completed the 4-week treatment. After the 4-week therapy with furosemide or enalapril, most subjects were free of edema in either group（96.51% vs.96.67%, P 〉 0.05）. Only 4 in CD group and 3 in CA group had mild edema. Enalapril was more effective than furosemide to reduce AC（10.92 ± 1.84 mm vs. 12.97 ± 2.46 mm, P 〈 0.05）. But for ES, there was no significant difference. And there were no significant differences in antihypertensive effect between them. Uric acid（UA）was increased significantly in CD group（10.70 ± 18.48 μmol/L vs. 0.22 ± 28.13 μmol/L, P 〈 0.05）. Conclusion Enalapril is more effective than furosemide in attenuating lower extremity edema caused by levamlodipine in essential hypertensive population, with equal antihypertensive efficacy and less uric acid increasing.

Renal elimination of organic anions in cholestasis

The disposition of most drugs is highly dependent on specialized transporters. OAT1 and OAT3 are two organic anion transporters expressed in the basolateral membrane of renal proximal tubule cells, identified as contributors to xenobiotic and endogenous organic anion secretion. It is well known that cholestasis may cause renal damage. Impairment of kidney function produces modifications in the renal elimination of drugs. Recent studies have demonstrated that the renal abundance of OAT1 and OAT3 plays an important role in the renal elimination of organic anions in the presence of extrahepatic cholestasis. Time elapsed after obstructive cholestasis has an important impact on the regulation of both types of organic anion transporters. The renal expression of OAT1 and OAT3 should be taken into account in order to improve pharmacotherapeutic efficacy and to prevent drug toxicity during the onset of this hepatic disease.

An efficient strategy for establishing a model of sensorineural deafness in rats

Ototoxic drugs can be used to produce a loss of cochlear hair cells to create animal models of deafness. However, to the best of our knowledge, there is no report on the establishment of a rat deafness model through the combined application of aminoglycosides and loop diuretics. The aim of this study was to use single or combined administration of furosemide and kanamycin sulfate to establish rat models of deafness. The rats received intravenous injections of different doses of furosemide and/or intramuscular injections of kanamycin sulfate. The auditory brainstem response was measured to determine the hearing threshold after drug application. Immunocytochemistry and confocal microscopy were performed to evaluate inner ear morphology. In the group receiving combined administration of furosemide and kanamycin, the auditory brainstem response threshold showed significant elevation 3 days after administration, higher than that produced by furosemide or kanamycin alone. The hair cells showed varying degrees of injury, from the apical turn to the basal turn of the cochlea and from the outer hair cells to the inner hair cells. The spiral ganglion cells maintained a normal morphology during the first week after the hair cells completely disappeared, and then gradually degenerated. After 2 months, the majority of spiral ganglion cells disappeared, but a few remained. These findings demonstrate that the combined administration of furosemide and kanamycin has a synergistic ototoxic effect, and that these drugs can produce hair cell loss and hearing loss in rats. These findings suggest that even in patients with severe deafness, electronic cochlear implants may partially restore hearing.

Efficacy of tolvaptan for the patients with advanced hepatocellular carcinoma

To investigate the factors influenced the efficacy of tolvaptan (TLV) in liver cirrhosis. METHODSWe retrospectively enrolled 61 consecutive patients with refractory hepatic ascites. All of them had been treated with furosemide and spironolactone before admission, and treated with TLV for 7 d in our hospital. The effect of TLV was defined by the rate of body weight loss, and the factors that influenced TLV efficacy were analyzed using multiple regression. RESULTSCoexistent hepatocellular carcinoma (HCC) was the only significant predictive variable that attenuated the efficacy of TLV. In stratified analysis, high doses of furosemide decreased the efficacy of TLV in patients with HCC, and increased efficacy in those without HCC. In the latter, a high Child-Pugh-Turcotte score had a positive influence and a high concentration of lactate dehydrogenase had a negative influence on the effectiveness of TLV. CONCLUSIONDevelopment of ascites may differ between patients with liver failure and those with HCC progression. A sufficient preceding dose of furosemide decreases diuretic effect of TLV.

COMBINATIONAL ADMINISTRATION OF AMINOGLYCOSIDES AND LOOP DIURETICS AS AN EFFICIENT STRATEGY TO ESTABLISH DEAFNESS MODELS IN RATS

It is known that aminoglycoside antibiotics can damage the vestibular and auditory sensory epithelia, and the loop diuretics can enhance the ototoxic effect of aminoglycosides. Previous studies on the synergistic effect of these two types of drugs have used mice, guinea pigs and cats, but not rats. The aim of this study was to determine this synergistic effects in rat cochleae. Rats received intravenous injections of different doses of furosemide and/or intramuscular injections of kanamycin sulfate. Au- ditory brainstem response （ABR）, scanning electron microscopy （SEM） and immunocytochemistry were used to determine the effects of drug administration. In the group receiving combined administration of furosemide and kanamycin, the ABR thresh- old showed significant elevation 3 days after drug administration, greater than single drug administration. The hair cells showed various degrees of injury from the apical turn to the basal turn of the cochlea and from the outer hair cells to the inner hair cells. Neuron fibers of the hair cells showed significant loss 7 days after the drug administration, but the number of spiral ganglia did not decrease and supporting cells showed no signs of injury. Our study suggest that combined administration of fu- rosemide and kanamycin has an synergistic ototoxic effect, and can result in hair cell loss and hearing loss in rats.

常用药物

Drugs Used Uropoiem System Diseases 泌尿系统用药Amiloride 阿米洛利Bumetanide 丁尿胺依他尼酸（利尿酸）Etacrynic Acid 依他尼酸（利尿酸） Furosemide 呋塞米（呋喃苯胺酸，速尿） H ydrochlorothiazide 氢氯噻嗪（双氢克尿塞）

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.

Simple and Rapid Determination of Diuretics by Luminescent Method

Diuretics are drugs widely used in treatment of heart failure and hypertension and as doping agents in sports. Wrong prescription and excessive abuse can lead to negative side effects. Despite the effectiveness of methods usually used for the determination of diuretics (gas or liquid chromatography, capillary electrophoresis), they do not always provide necessary sensitivity. Moreover, sample preparation increases time of analysis. A rapid and sensitive luminescent method for determination of 5 diuretics (amiloride, bendroflumethiazide, bumetanide, furosemide, triamterene) in aqueous solutions and amiloride and triamterene in human urine is described. Intrinsic luminescent properties of protolytic forms of diuretics were studied in order to provide highly sensitive analysis. Investigation of interfering influence of diuretics was carried out to provide selective determination of triamterene, bumetanide and furosemide in aqueous mixtures of diuretics. Influence of urine at luminescent properties of diuretics was studied. The possibility of determination of triamterene and amiloride in human urine as individual substances and in mixture was proved. Simple and rapid technique for their determination in human urine was elaborated. The techniques elaborated for determination of triamterene in presence of other diuretics and furosemide in presence of commensurate amount of bumetanide allow enhancing specifity of analysis. Sufficient selectivity and sensitivity were reached in determination of amiloride and triamterene in human urine. The reduction of time of analysis due to avoiding sample preparation merits the techniques proposed.

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.

Successful Conservative Management of Trimethoprim Induced Life-Threatening Hyperkalaemia in a Patient with <i>Pneumocystis jirovecii</i>Pneumonia

Co-trimoxazole is a combination antibiotic made up of trimethoprim and sulphamethoxazole that is first line treatment for Pneumocystis jirovecii pneumonia (PJP). Hyperkalaemia is a relatively common side effect of the trimethoprim component of co-trimoxazole but it is not well recognised by clinicians. The mechanism of action causing hyperkalaemia due to trimethoprim is similar to the potassium sparing diuretic effect of amiloride. It has been suggested on this basis that the hyperkalaemia can be reversed by the administration of furosemide and 0.9% saline to promote kaliuresis. We present what we believe to be the first published case of successfully managing trimethoprim induced hyperkalaemia with furosemide and 0.9% saline allowing the continued use of co-trimoxazole to treat severe PJP.