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Diuretic agents related to indapamide. III--Synthesis and pharmacological activity of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydroisoquinolines.

A series of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinoline++ + (IV-1) and isoquinoline (IV-2) have been synthesized and their diuretic and antihypertensive activities evaluated. While none of the test compounds was found to be provided with antihypertensive properties, most of them displayed a diuretic activity comparable to (IV-2 a) or higher (IV-1 a,b) (IV-2 c) than those of indapamide and clopamide, taken as reference drugs.

Animals↗

Renal consequences of valvular heart disease.

Three aspects of potential renal involvement in patients with valvular heart disease are discussed. These include (1) disturbances in renal salt and water handling and their implications with respect to diuretic management; (2) the hemodynamic effects of angiographic contrast agents with identification of potentially dangerous effects on the kidneys; and (3) the histologic patterns of bacterial endocarditis in the kidney and their similarity to those of immunologically mediated disease.

Aldosterone↗

(Vinylaryloxy)acetic acids. A new class of diuretic agents. 2. (4-(3-Oxo-1-alkenyl)phenoxy)acetic acids.

A series of (E)-[4-(3-oxo-1-alkenyl)phenoxy]acetic acids was synthesized and tested in dogs for saluretic and diuretic properties. Several compounds exhibited noteworthy activity, e.g., (E)-[2,3-dichloro-4-(3-oxo-1-butenyl)phenoxy]acetic acid (3a). While possessing only half of the dose potency of ethacrynic acid (2), the active compounds act similarly to this diuretic in causing a prompt increase in the excretion of water and in the excretion of sodium and chloride ions in approximately equimolar amounts. Potassium ion excretion is increased but less markedly than sodium excretion.

Acetates↗

Pharmacologic interaction of furosemide and phenylbutazone in horses.

The effect of premedication with phenylbutazone on systemic hemodynamic and diuretic effects of furosemide was examined in 6 healthy, conscious, mares. Mares were instrumented for measurement of systemic hemodynamics, including cardiac output and pulmonary arterial, systemic arterial, and intracardiac pressures, and urine flow. Each of 3 treatments was administered in a randomized, blinded study; furosemide (1 mg/kg of body weight, IV) only, phenylbutazone (8.8 mg/kg, PO, at 24 hours and 4.4 mg/kg, IV, 30 minutes before furosemide) and furosemide, or 0.9% NaCl. Phenylbutazone administration significantly attenuated, but did not abolish, the diuretic effect of furosemide. Phenylbutazone completely inhibited the immediate effect of furosemide on cardiac output, stroke volume, total peripheral resistance, and right ventricular peak pressure. Premedication with phenylbutazone did not inhibit equally the diuretic and hemodynamic effects of furosemide, indicating that some of furosemide's hemodynamic effects are mediated by an extrarenal activity of furosemide.

Analysis of Variance↗

BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy.

BACKGROUND: Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerular feedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown. METHODS AND RESULTS: This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses of BG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day and the same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion were assessed. BG9719 alone caused an increase in urine output and sodium excretion (P<0.05). Although administration of furosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significant at the 0.75-microg/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses. Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearance remained at baseline at the 2 lower doses. CONCLUSIONS: In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increased both urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR. When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deterioration in GFR. A1 adenosine antagonism might preserve renal function while simultaneously promoting natriuresis during treatment for heart failure.

Aged↗

Observations of the early diuretic response after intravenous administration of bumetanide and furosemide in dogs.

A transient natriuretic peak was observed in dogs the third minute after the i.v. administration of the highly active diuretics bumetanide and furosemide. The peak is dependent on the sodium balance such that it is potentiated during positive sodium balance and is not observed in sodium depleted dogs. A relationship exists between the simultaneous occurrence of the peak and abolition of the cortico-medullary electrolyte gradient.

Animals↗

Determinants of bumetanide response in the dog: effect of probenecid.

The pharmacokinetics and pharmacodynamics of intravenous bumetanide (0.250 mg/kg), alone (treatment I) and after probenecid pretreatment (treatment II), were studied in four mongrel dogs. Lactated Ringer's solution was administered by vein throughout both treatments at a flow rate of 2 ml/min to avoid fluid and electrolyte depletion. Bumetanide and probenecid concentrations were analyzed by HPLC, sodium by flame photometry, and creatinine by colorimetry. Although the probenecid markedly reduced the plasma and renal clearances of bumetanide, as well as the fraction excreted unchanged in the urine, there was no significant difference between treatments I and II in the 4-hr natriuretic and diuretic responses. However, analysis of the dose-response curves between treatments I and II showed that sodium excretion was better correlated with bumetanide urinary excretion rate than with plasma concentration. The reasons for a poor correlation between treatments during the early time periods are discussed.

Animals↗

Low-salt diet and diuretic effect on blood pressure and organ damage.

This review focuses on some aspects of the complex relationship among dietary salt intake, BP, organ complication, and genetic factors. First, the reason regarding the debate in the effect of a low-salt diet on BP and organ damage is discussed. Certainly, the lack of controlled long-term studies, taken together with the opposite effect of a low-salt diet on cardiovascular risk factors, justifies the contrasting opinions about the opportunity to reduce the sodium (Na) content in the diet of the general population. Second, the contribution that the genetic polymorphisms may furnish to explain the BP response in studies that apply either a moderate or a brisk reduction of salt intake is considered. Finally, the long-term effects of diuretics that produce a decrease in body Na similar to that achieved by moderate long-term dietary salt reduction are examined. Diuretics are able to reduce organ complications in the general population. However, these beneficial effects may be the net results of opposite effects in a subset of patients. Recently, the results of an observational study on hypertensive patients who were treated with a variety of antihypertensive drugs have been published. These results show that in carriers of the 460Trp ADD1 allele (38% of the population), the administration of diuretics halves the incidence of myocardial infarction and stroke when compared with other antihypertensive treatments that produce similar reduction of BP. These data support the notion that matching of the genetic mechanism with the drug mechanisms of action produces a clear therapeutic benefit.

Blood Pressure↗

[The phenomenon of resistance to a thiazide diuretic in acute kidney failure].

The resistance to hypothiazid (hydrochlorothiazide) during the development of acute renal insufficiency (ARI) induced by glycerin injection was studied in rat experiments. Natriuretic, kaliuretic, and hydrouretic activity of the diuretic decreased two days after injection of a glycerin solution. In this period hypothiazid excretion with the urine was least. Ten days later, despite the restoration of the water- and electrolyte-excretion function of the kidneys and normalization of hypothiazid excretion with the urine, the natriuretic effect of the drug was still very poor. This is indirect evidence of the long-term affection of the receptors for the thiazid diuretics during the development of ARI. The affection remains even after the excretory function of the kidneys is restored. The high correlation between the cumulative excretion of hypothiazid with the urine and natriuresis encountered in intact animals was weaker in rats with acute renal insufficiency.

Acute Kidney Injury↗

Bumetanide and frusemide: a comparison of dose-response curves in healthy men.

1 Log dose-responses for the loop diuretics bumetanide and frusemide in healthy subjects deviated significantly from parallelism as regards urine volume and sodium excretion. Ignoring the nonparallelism the best estimate of natriuretic potency (bumetanide: frusemide) was 46:1 in the bumetanide dose range 0.5-2 mg. 2 For a given natriuresis the urinary potassium excretion following bumetanide was significantly lower than that for frusemide within this dose range. 3 The data illustrate the limitations of studies comparing diuretics at a single dose level. Extrapolation of the observed log dose-response curves provides one possible explanation for the relative potency (bumetanide: frusemide) of 20:1 reported when the drugs are used at high dosage in patients with renal failure.

Adult↗

Effects of combination of low doses of angiotensin-converting enzyme inhibitor and diuretics on renal function in spontaneously hypertensive rats: comparison between acute and chronic treatment.

The goal of this study was to assess the effect of acute or chronic treatment with S5590, a combination of the angiotensin-converting enzyme inhibitor perindopril (0.76 mg/kg/day) and the diuretic indapamide (0.24 mg/kg/day) on renal function in spontaneously hypertensive rats with moderate renal injury. Renal function was evaluated in conscious rats by clearance methods using labelled inulin and PAH, after catheterisation of the carotid artery, jugular vein and bladder. Both acute and chronic treatment normalised renal vascular resistance, although the effect on blood pressure was more marked after chronic than after acute treatment. Although acute treatment with S5590 increased glomerular filtration rate and renal blood flow, chronic treatment did not affect these parameters. Diuresis and natriuresis were only slightly modified and the results suggest a marked renal vasodilatation. In conclusion, the maintenance of renal function after chronic treatment, in a setting of normalisation of arterial pressure, suggest that such a combined treatment may exert marked renal functional protective effects in hypertension.

Animals↗

[Diuretic activity of benzimidazole urea derivatives].

The chemical structure of benzimidazol urea derivatives and physico-chemical properties of these compounds conditioned by it play a significant role in the manifestation of the emictory effect. Among the study substances a number of compounds displaying a marked, but short-lived diuretic action have been educed. In the manifestation of emictory properties in benzimidazol urea derivatives of importance is the character of the side chain and its ramification and also an even number of carbon atoms in the acyl radical.

Animals↗

[The diuretic activity of bumetanide in a controlled comparison with furosemide in patients with various degrees of impaired renal function (author's transl)].

The effect of bumetanide (6 and 12 mg) was compared with that of furosemide (250 and 500 mg) in 13 patients with chronic renal insufficiency in a double-blind study using each patient as his own control. In the dose ratio of 1:40 previously obtained in normal subjects furosemide showed a significantly higher diuretic response than bumetanide. Comparing the relative natriuretic effects in chronic renal insufficiency a ratio of 1:10 to 1:12 (B:F) seemed to be adequate. More than 12 mg bumetanide cannot be recommended because of the severe muscle pains which occurred in all patients with that dosage.

Adult↗

[Comparative variations in natriuresis and urinary calcium in patients with hypercalciuric lithiasis treated with thiazide diuretics].

Because of the close relation between sodium (Na) and calcium (Ca) tubular reabsorption, restriction of sodium intake has been proposed in hypercalciuric stone formers. We simultaneously measured urinary concentrations of both ions in 30 recurrent stone formers (19 male, 11 female, mean age 40,8 +/- 10,2 years) with fasting hypercalciuria, before and after reduction of calciuria using long-term thiazide (TZ) treatment associated with moderate restriction of calcium intake, without concomitant Na restriction. No recurrence of stones was observed in this group with a 12 to 49 month follow-up. UCa strongly correlated with UNa in both conditions. However, UCa significantly decreased with TZ (128 +/- 32 vs 73 +/- 26 mumol/kg/day, p less than 0.001), whereas neither UNaV (190 +/- 60 vs 202 +/- 57 mmol/day) nor diuresis significantly varied. We conclude that calciuria can be lowered without reduction in Na intake in hypercalciuric stone formers controlled by thiazide treatment.

Adult↗

Renal and hemodynamic effects of atrial natriuretic peptide in patients with cirrhosis.

The effects of anaritide, a 25-amino-acid synthetic analogue of ANP, were evaluated in 28 patients with cirrhosis complicated by ascites and/or edema. Each patient received two doses of the agent, as well as an infusion of placebo. Six different doses were tested ranging from 0.015-0.300 microgram/kg/min. The infusions lasted for 2 hours and were flanked by both baseline and recovery periods. There was a significant effect of placebo on urinary sodium and chloride excretion rates but no effect on urine flow rate. In response to anaritide, the urine flow rate increased at 0.03, 0.06, 0.075, and 0.100 microgram/kg/min. The sodium and chloride excretion rates increased at all doses except the highest dose. There was no definite effect of anaritide on urinary potassium, calcium, and phosphate excretion rates. There was also no significant effect on creatinine clearance. The mean arterial pressure decreased in response to the 0.060, 0.075, and 0.100 microgram/kg/min doses. In addition, five of the patients receiving the highest dose (0.300 microgram/kg/min) had decreases in their systolic pressures to 90 mm Hg or less. In conclusion, anaritide is natriuretic and diuretic in patients with cirrhosis complicated by ascites and/or edema. Its effect, however, on arterial pressure may limit its therapeutic potential in this patient population.

Atrial Natriuretic Factor↗

[The influence of inhibitors of kinin and prostaglandin formation on the vascular and tubular effects of osmotic diuretics in the kidney].

Mannit was shown to increase the blood flow in the external, middle and internal zone of the renal cortex in anesthetized rats but exerts no effect on the blood supply to the external zone of the medullary layer. A preliminary administration of contrykal fails to influence the diuretic and natriuretic effects of the preparation and to change the character of the hemodynamic shift at the action of the diuretic in the middle zone of the cortical layer. Indomethacin completely eliminates the blood flow increase in the middle zone of the cortex but it does not prevent the diuretic and natriuretic reaction to mannit administration. It is concluded that realization of the vascular and tubular effects of the diuretic is not related to the increase of kinin biosynthesis in the kidneys. Prostaglandins formed in the kidneys under the influence of mannit are involved in the mechanism of dilatation of the vessels of the cortical layer but do not play the significant role in the formation of its tubular effect.

Animals↗

[Diuretic effect of liniaoling(KLP)].

Experimental results have shown that KLP taken orally helps promote the diuretic action of normal Wistar rats, decrease the urine volume of debilitated rats and increase the urine volume of BPH rats. It has also been shown that KLP(i.v.) can increase the urine volume of anesthetic rats and reduce the remnant urine. In addition, KLP can contract the smooth muscle of rats and rabbits.

Animals↗

Role of diuretics in the preservation of residual renal function in patients on continuous ambulatory peritoneal dialysis.

BACKGROUND: Patients on continuous ambulatory peritoneal dialysis (CAPD) are dependent on residual renal function for solute and water clearances, and this declines with time on dialysis. Loop diuretics have been postulated to slow this decline. METHODS: Sixty-one patients new to dialysis were randomly assigned to either furosemide 250 mg every day or no furosemide at the time of CAPD training and were followed prospectively. Urine volume (UV), urea clearance (C(Urea)), and creatinine clearance on cimetidine (C(Cr)) were measured at randomization at six months and at one year. Patients underwent a standard four-hour peritoneum equilibrium test, and total body water was measured by bioelectrical impedance. Results were expressed on an intention-to-treat basis. RESULTS: UV, C(Cr), and C(Urea) were similar at randomization (1020 +/- 104 vs. 1040 +/- 130 mL/24 hours, 4.95 +/- 0.51 vs. 4.07 +/- 0.40 mL/min/1.73 m2, 0.91 +/- 0.09 vs. 0.84 +/- 0.08, diuretic vs. control). UV in the diuretic-treated group increased, whereas in the control group, it declined (+176 vs. -200 mL/24 hours at 6 months and +48.8 vs. -305 mL/24 hours at 1 year, P < 0.05). C(Cr) and C(Urea) declined at a constant rate and were unaffected by diuretic administration (0.12 +/- 0.05 vs. 0.071 +/- 0.04 mL/min/1.73 m2/month, 0.020 +/- 0.01 vs. 0.019 +/- 0.01 per month). Urinary sodium excretion increased in the diuretic group and declined in the control group (+0.72 +/- 0.85 vs. -2.56 +/- 1.31 mmol/24 hours/month, P = 0.04). Body weight rose in both groups (4.3 vs. 3.0 kg), but the percentage of total body weight rose in the control group and remained constant in the diuretic group (52 +/- 2.4 vs. 64 +/- 6.6%, P = 0.10). CONCLUSIONS: Long-term furosemide produces a significant increase in UV over 12 months when on CAPD and may result in clinically significant improvement in fluid balance. However, furosemide has no effect on preserving residual renal function.

Adult↗