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[Formulation and in vitro examination of furosemide-containing suppositories and preliminary experiences of their clinical use].

Rectal suppositories containing Furosemide (4-Chloro-N-furfuryl-5-sulfamoylanthranilic acid) and Furosemide Sodium were formulated with various suppository bases. The in vitro drug release of Massa Estarinum 299 proved to be the best from among the vehicles having various physical-chemical properties. The diuretic effect of the two suppositories was compared in a prospective, cross-over clinical trial including 8 patients. Both preparations have induced and increase of urine flow, which was comparable to the diuretic effect of the tablet. Thus the possibility of rectal use has been added to the modalities of therapeutic Furosemide administration.

Cross-Over Studies↗

Diuretic effect of oxytocin in a patient with reversed diurnal rhythm of water and electrolyte excretion.

A reversed diurnal excretory rhythm of water, creatinine and electrolytes was observed in a woman with fluid retention that first appeared following a head injury 21 years previously. Synthetic oxytocin injections were given on the premise that she had a selective deficiency of oxytocin with normal vasopressin production. This treatment produced a diuresis and restored a normal excretory rhythm of water, creatinine and electrolytes. Inulin and PAH clearance studies showed that oxytocin increased the daytime glomerular filtration rate. These results suggest the possibility that oxytocin has an additional non-obstetrical physiologic function, viz. the regulation of the normal diurnal rhythm of glomerular filtration rate.

Acid-Base Imbalance↗

A method for screening diuretic agents in the rat.

A reproducible screening method for diuretic agents has been developed based upon the selection of a group of homogenous rats with a similar excretory pattern of water and electrolytes. Normal saline (4% body weight) was used as a hydrating fluid to select appropriate rats and to validate the diuretic activity of standard diuretics. The method required only a small number of rats for screening compounds and produced consistent responses in increasing water and electrolyte excretion.

Animals↗

Phytochemical and pharmacological studies on Orthosiphon stamineus Benth. (Lamiaceae) hydroalcoholic extracts.

The main components of Orthosiphon stamineus Benth. leaves and extracts are the pharmacologically active polyphenols: the polymethoxylated flavonoids and the caffeic acid derivatives. Two tinctures, having different alcohol concentration, were studied from phytochemical and pharmacological point of view. The main polyphenols were identified and quantitatively determined by HPLC. Comparison of the retention parameters and UV-Vis spectra of standards and those of the separated compounds performed the identification of caffeic-, cichoric- and rosmarinic acids, respectively, of sinesetine and eupatorine. The quantitative determination was performed by external standard method. The diuretic, saluretic and uricosuric actions of the studied tinctures were compared by experiments on rats.

Animals↗

Diuretic and antihypertensive activity of ZENECA ZM224,832: a novel eukalemic diuretic with calcium channel blocking activity.

ZENECA ZM224,832 is a novel eukalemic diuretic from the aminomethylphenol pyrazine series which demonstrated a profile of calcium channel blockers. It produced diuretic and saluretic effects in animals but had only minimal alterations in kaliuresis after oral administration. In contrast to standard diuretics, the plasma K+ concentration was not altered in conscious dogs treated for 14 days with ZENECA ZM224,832 and the concurrent plasma renin activity was also minimally elevated. The isolated rat aorta evaluation indicated that ZENECA ZM224,832, like tiapamil and nifedipine, inhibited vascular smooth muscle tone by inhibiting voltage-dependent calcium channels. ZENECA ZM224,832 produced a dose-dependent decrease of blood pressure in spontaneously hypertensive rats (SHR) in which the antihypertensive activity was not noted with HCTZ. In addition, ZENECA ZM224,832, similar to diltiazem, produced an acute blood pressure lowering effect in nephrectomized SHR which was independent of its diuretic activity. It is concluded that ZENECA ZM224,832 is a potent eukalemic diuretic with calcium channel blocking properties.

Animals↗

Diuretic and cardiovascular effects of indapamide in hypertensive subjects: a dose-response curve.

In a single-blind, placebo-controlled study, the effects were evaluated of increasing doses of indapamide (1.0, 2.5 and 5.0 mg/day, each dose for 4 weeks) on volume and haemodynamic status of 10 hypertensive subjects. Body weight showed a decrease of 0.5 kg at the 1 mg dose, of 1.0 kg at the 2.5 mg dose and no further decrease at 5 mg. Plasma volume did not change. Mean arterial pressure decrease in 8 subjects by about 20 mmHg; 2 patients were classified as 'non-responders'. The decrease in blood pressure was accompanied by a reduction in total peripheral resistance and no change in cardiac output. LV end-diastolic volume decreased by about 20 ml. These results suggest that indapamide not only has a diuretic effect, but also acts as a veno-arterial vasodilator.

Adult↗

Diuretic therapy, magnesium deficiency and lipid metabolism.

Hypermagnesiuria and hypomagnesaemia are complications of prolonged therapy with loop or distal tubule diuretics. Local and circulating catecholamine levels rise in response to hypomagnesaemia and to the haemodynamic effects of diuretics. The result is an increase in the plasma lipoprotein fraction, thought to constitute a cardiovascular risk factor and partly dependent on dietary and other variables.

Animals↗

[Loop diuretics. Rational pharmacotherapy].

UNLABELLED: The pharmacodynamics and -kinetics as well as rational pharmacotherapy of furosemide and bumetanide is reviewed. In renal insufficiency, a reduced response to diuretics is due to altered pharmacokinetics. The optimum dose can be determined within three to four hours by titration and the effect is measured by the amount of excreted sodium. In nephrotic syndrome, both pharmaco-kinetics and--dynamics are altered. The optimum dose is established as above. Starting and ceiling doses are given in tables for both drugs in renal insufficiency and nephrotic syndrome. In congestive heart failure, the difference is greater between oral and intravenous doses than apparent from the bioavailability of the drugs. If potent diuretics are without effect, the heart failure must be treated more vigorously or a combination with thiazides tried out. Potent diuretics are seldom used in the treatment of liver cirrhosis, but, if used, large doses are necessary. Non-steroidal antiinflammatory drugs are usually considered contra-indicated in patients with severe renal insufficiency, since the pharmacodynamics of the diuretics are altered. CONCLUSION: The general strategy when using potent diuretics is titration to an effective dose and then using this dose as frequently as needed in order to obtain the desired response.

Acute Kidney Injury↗

Comparison of cicletanine with other antihypertensive drugs in SHR-SP models.

The effects of cicletanine were compared with those of four other antihypertensive drugs (prazosin, a highly selective alpha 1 antagonist; captopril, an angiotensin-converting enzyme inhibitor; indapamide, an antihypertensive diuretic; and hydrochlorothiazide, a purely diuretic agent) on young stroke-prone SHR rats with high-salt diet. All the drugs except hydrochlorothiazide prevented the onset of hypertension. The minimal effective dose on blood pressure was 1 mg/kg for both cicletanine and captopril, and 3 mg/kg for indapamide. The action on cardiac hypertrophy and diuresis occurs at a dose of cicletanine 10 to 30 times higher than that required to produce the antihypertensive effect. Renal hypertrophy was also decreased significantly by cicletanine at a dose of 100 mg/kg.

Animals↗

The influence of neuropeptides on Malpighian tubule writhing and its significance for excretion.

Diuretic peptides (locustakinin and Locusta-DH) increase the spontaneous contractile activity of visceral muscle fibers associated with Malpighian tubules from the migratory locust (Locusta migratoria) at concentrations that increase urine production. Muscle activity is shown to assist the flow of material in the tubule lumen, but is not essential for diuresis. Tubule writhing also serves to reduce unstirred layers (USLs) at the basolateral surface of the epithelium and thereby facilitates the excretion of solutes entering the lumen by passive diffusion.

Animals↗

Comparison of renal actions of urodilatin and atrial natriuretic peptide.

A 32-amino acid atrial natriuretic peptide (ANP)-like peptide, putatively synthesized by the kidney, has recently been isolated from human urine. This peptide, urodilatin (Uro), is structurally similar to the 28-amino acid ANP, suggesting that they might have similar actions on renal fluid and electrolyte excretion. The purpose of this study was to characterize the direct renal actions of low doses of Uro infusion and to compare them with the effects of equimolar intrarenal infusions of either ANP or the 24-amino acid atriopeptin III (AP III). Synthetic Uro was infused into the renal artery of pentobarbital sodium-anesthetized mongrel dogs (n = 8) at 0.14, 0.28, and 1.43 pmol.kg-1.min-1 while renal perfusion pressure was servo-controlled at 100 mmHg. Uro infusion at 1.43 pmol.kg-1.min-1 increased sodium excretion from an average control of 57.4 +/- 10.1 to 159.0 +/- 24.4 mueq/min. Uro infusion at the highest dose also increased potassium excretion (28.0 +/- 4.5 vs. 40.4 +/- 7.4 mueq/min), chloride excretion (56 +/- 11 vs. 155 +/- 22 mueq/min), and urine volume (0.54 +/- 0.12 vs. 1.22 +/- 0.25 ml/min). Fractional lithium excretion, a marker for proximal tubular sodium reabsorption, was not altered by Uro infusion, nor were urinary guanosine 3',5'-cyclic monophosphate excretion, glomerular filtration rate, or effective renal plasma flow changed. Equimolar infusions of these low doses of either alpha human ANP (n = 6) or AP III (n = 8) had no effect on any of the measured variables. Thus, within the range of doses used in this study, Uro was a more effective natriuretic and diuretic agent than either ANP or AP III.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Pharmacokinetic and pharmacodynamic studies of piretanide in rabbits. IV. Effect of piretanide on the proximal tubules and the loop of Henle under a hydrated condition.

In order to evaluate the effect of piretanide on the renal transport of water and osmotic substances, a clearance study was carried out in well hydrated rabbits. After intravenous bolus administration of piretanide, glomerular filtration rate, proximal tubular clearance and urine flow rate, as well as the pharmacokinetics of piretanide, were determined. A pharmacokinetic and pharmacodynamic link model which was developed in the previous paper was applied to the present experimental results. The results indicated that the effect of piretanide on the renal transport of water and osmotic substances in the hydrated rabbits was reasonably described by the model. The model analysis suggested that the diuretic response to piretanide was attributable to the inhibition of reabsorption of electrolytes in the proximal tubule, as well as in the loop of Henle.

Animals↗

Lithium poisoning: pharmacokinetics and clearance during different therapeutic measures.

The clinical features and pharmacokinetics of 22 lithium overdoses are described. Effectiveness of different treatment regimens regarding elimination of lithium is discussed. Origin of overdose was due to deliberate poisoning or precipitated by concomitant diseases, coadministration of drugs, or combination of both. Treatment included supportive care, diuretics (15/22), hemodialysis (HD; 9/22), and mechanical ventilation (3/22). Severity of lithium intoxication was classified in 50% as I degrees, in 41% as II degrees, and in 9% as III degrees according to Hansen and Amdisen. Renal impairment on admission was diagnosed in 82% of the patients. Half-life of lithium in serum was 3.5 +/- 0.8 hours during the first HD, and 29 +/- 14 and 29 +/- 6 hours during therapy with diuretics or supportive treatment, respectively. Lithium clearance during HD was 160 +/- 15 mL/min, and renal clearance during HD or treatment with diuretics was approximately 20 and 15 +/- 9 mL/min, respectively. Renal lithium clearance was not influenced by HD therapy. There was no difference regarding half-life and clearance between the group that had an unspecific treatment or the group treated with diuretics. Hemodialysis is the therapy of choice for emergent extracorporeal lithium elimination. Renal impairment and interaction with other drugs were the main reasons for intoxication; thus, more cautious prescription or more frequent supervision of this patient group is warranted. It seems that treatment with diuretics does not have a beneficial effect in the overdose setting.

Amiloride↗

Relationship between metabolism and pharmacologic activity of SQ 27,786, an angiotensin converting enzyme inhibitor with potent diuretic activity.

SQ 27,786 is a sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor, which also possesses potent diuretic activity in dogs after intravenous administration. The absorption, distribution, metabolism and elimination of 35S-labeled SQ 27,786 was studied in dogs to determine if the observed pharmacologic activities were intrinsic to this compound or the result of metabolism to separate ACE-inhibitory and diuretic moieties. The poor pharmacologic activity observed after oral administration was found to be due to poor absorption of the ACE-inhibitory-diuretic compound. The results of this study indicated that SQ 27,786 was excreted largely intact, either as the parent compound, the symmetrical disulfide of the parent compound, or as mixed disulfides of the parent compound with endogenous sulfhydryl compounds (e.g., SQ 27,786-L-cysteine) in a manner similar to captopril. It was concluded that the observed diuretic and ACE inhibitory activities were the result of intact SQ 27,786 and not of metabolites resulting from cleavage of the molecule to separate diuretic and ACE inhibitory moieties.

Angiotensin II↗

[The mechanism of the diuretic action of the preparation polyosm].

The mechanism of the diuretic effect of the new drug polyosm, polyethylene oxide 400 solution, was studied in experiments on anesthetized cats. Intravenous polyosm infusion was attended with a marked diuretic and natriuretic effect developing due to reduced reabsorption of water and natrium and increased glomerular filtration.

Animals↗

The Na+-excreting efficacy of indapamide in combination with furosemide in massive edema.

BACKGROUND: Massive systemic edema is often observed in patients with severe nephrotic syndrome, including diabetic nephropathy. Although furosemide, a loop diuretic, is often administered to these patients, some patients do not respond to this treatment, still showing massive edema. METHODS: The efficacy of indapamide which has a thiazide-like effect on distal convoluted tubules in combination with furosemide, was evaluated in eight patients with massive edema, in regard to both Na+ excretion and diuresis. Indapamide 2 mg was administered once a day, in the morning, to patients in whom it was considered that furosemide treatment of 40-120 mg a day for 1 week was ineffective. RESULTS: Urinary Na+ excretion was markedly increased, from 83.7 +/- 82.2 mEq/day to 140.7 +/- 33.8 mEq/day after 1 week of the combination therapy compared with furosemide alone (P < 0.01); urine volume was also increased, from 1070 +/- 230 ml to 1359 +/- 296 ml after 1 week of the combination therapy (P < 0.05). In this context, body weight was significantly decreased, from 57.2 +/- 12.3 kg to 53.4 +/- 12.8 kg, after the combination therapy (P = 0.01). Indapamide in combination with furosemide was well tolerated, and no significant changes in serum levels of creatinine and potassium were observed. CONCLUSIONS: This combination therapy appears to be effective in patients with massive edema, as it increased diuresis, and achieved potent Na+ excretion.

Adult↗