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Sustained antihypertensive response with Minizide: long-term follow-up in a multicentre study.

The safety and effectiveness of prazosin hydrochloride combined with polythiazide for the treatment of hypertension was studied in four European countries by ten investigators. One-hundred and seventy-seven adult male and female patients, 91% with essential hypertension were treated for an average of 7 months. Reductions from placebo-controlled baseline blood pressure exceeded 15% over the 8-week short-term phase of the study with further reductions of up to 22% observed at the end of the study. Ninety-six per cent of all patients completed therapy with a diastolic blood pressure of 90 mm Hg or less. Most patients were adequately controlled on 2 tablets or less once daily. Each tablet contained 0.5 mg prazosin hydrochloride and 0.25 mg polythiazide. Long-term toleration was excellent. Side-effects were typical of those expected with antihypertensive medication and nearly all were reported during the first 8 weeks of treatment with no interruption or discontinuation of drug. Nearly all patients were followed throughout for laboratory changes. There were minimal changes consistent with the therapy and there was no pattern indicative of toxic potential. It is concluded that the drug combination, Minizide, is effective and well tolerated as initial and long-term therapy in hypertension and that the convenient dosage regimen will lead to enhanced treatment compliance for this chronic condition.

Adolescent↗

Clinical evaluation of prazosin in 20 private practice patients.

The safety and efficacy of prazosin alone and in combination with polythiazide are being assessed in an ongoing study of private patients. All patients entering the study have diastolic pressures consistently greater than 100 mm Hg while taking placebo. Thus far, 20 patients have been given therapy for periods ranging from three to 10 months. In patients with mild hypertension, prazosin in a dosage of 5 mg three or four times a day was consistently effective in lowering blood pressure to less than 100 mm Hg and often reduced it to less than 95 mm Hg. The patients with moderate to severe hypertension responded particularly well when polythiazide was added to prazosin, while those continuing to receive prazosin alone for a comparable period showed no further improvement. Few if any side effects were observed which can be attributed to prazosin.

Adult↗

A long-term clinical trial of prazosin.

The efficacy of prazosin given either alone or in combination with polythiazide was assessed in a study of 50 outpatients with essential hypertension. Among the 29 who completed 42 months of therapy, blood pressure fell significantly in 76%. Of the 21 who dropped out of the study after 1 to 41 1/2 months, 43% showed improvement, 38% showed no change, and 19% showed worsening of hypertension. The most common side effects were lack of energy and weakness. Diabetics and alcoholics tolerated prazosin well. Of the 50 patients who started treatment with prazosin alone, only 23 required addition of polythiazide.

Adult↗

Long-term diuretic therapy in patients with chronic renal failure.

Ten patients with chronic renal failure from different genesis (serum creatinine levels 150-200 mumol/l), were evaluated from the aspect of the effect of the diuretic therapy. The effects of furosemide (FUR) and polythiazide (POL) were assessed after 3-month application. The mean values of the estimated parameters before treatment, after 3-month administration of FUR as a monotherapy and after the next 3 months simultaneously used (FUR + POL), presented a stable increase of the diuresis, without statistically significant changes of the global renal function, and triglyceride disorders. On the contrary, the improvement of calciuria through combined using of furosemide and polythiazide is statistically and clinically significant.

Diuretics↗

Cell cultures in the investigation of thiazide phototoxicity.

The NHIK 3025 cell line (Norsk Hydro Institutt for Kreftforskning), a human in situ carcinoma of the cervix cell line, was used to investigate the thiazides bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlortalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide and xipamide for their potential phototoxic properties. Cell death following UVA irradiation and dependent on test substance concentration was observed in the presence of all the tested substances except chlortalidone, furosemide, indapamide and xipamide. Bendroflumethiazide was phototoxic at concentrations of 0.05 mM and higher; bemetizide, benzylhydrochlorothiazide, bumetanide and hydroflumethiazide were phototoxic at 0.25 mM and higher and butizide, hydrochlorothiazide, piretanide, polythiazide and trichlormethiazide were phototoxic at 0.5 mM and higher.

Benzothiadiazines↗

Effects of doxazosin and other antihypertensives on serum lipid levels and lipoprotein lipase in the C57BR/cdJ mouse.

Doxazosin has been shown to lower serum cholesterol levels in the cholesterol-fed (0.75% in a synthetic diet that contains sucrose and cholic acid) C57BR/cdJ mouse. These studies show that the drug's main effect is to lower low-density lipoprotein (LDL) cholesterol and leave high-density lipoprotein (HDL) cholesterol levels unchanged. The drug had cholesterol-lowering effects in this model at doses down to 3 mg/kg. In order to determine if these effects are unique to selective alpha 1-inhibitors, other antihypertensives including hydralazine, papaverine, and captopril were investigated. None of the drugs has any effects on the plasma lipid metabolite levels. The effects of propranolol and polythiazide on plasma lipid levels were also examined in these mice. Propranolol had no effect, whereas the diuretic increased plasma cholesterol levels. Both propranolol and polythiazide increased plasma triglycerides. Doxazosin has been shown to inhibit cGMP phosphodiesterase in the laboratory. The effects of zaprinast, a cGMP phosphodiesterase inhibitor, were tested in order to determine if this property of the drug could be responsible for its lipid-lowering activity. The data show that there are no effects on plasma lipids in zaprinast-treated animals. Doxazosin treatment increased heparin-releasable lipoprotein lipase in fasted chow-fed mice. The drug was without effect on the activity of hepatic lipase present in the plasma after heparin release. No effects were observed on the tissue levels of either hepatic or lipoprotein lipases (heart or adipose tissue).

3',5'-Cyclic-AMP Phosphodiesterases↗

A search for a model tissue for studying effects of thiazide diuretics.

A search was made for a model tissue of NaCl absorption which would be sensitive to inhibition by diuretics of the thiazide type. A lack of such a model through the years has hampered the analysis of the cellular mechanism of action of this important class of drugs. Using the short-circuit current technique, the urinary bladders of the toads Bufo spinosus and Bufo marinus, and the frog Rana temporaria were investigated regarding the effects of various thiazides. These bladders have NaCl absorptive properties similar to those of the distal renal tubules, and are claimed to be sensitive to the inhibitory effect of thiazides on sodium transport. The short-circuit current (SCC), which is representative of the sodium transport across the epithelium, was reduced by cyclopenthiazide and polythiazide, but only at high concentrations (above 0.1 mM). To rule out the possibility that this was an unspecific effect, attempts were made to block the effect by the 'thiazide blocker' Ex 4877, but without success. This finding, together with the fact that dose-response curves were difficult to obtain, would indicate that these epithelia are not suitable for the stated purpose. Preliminary studies were also conducted on the urinary bladder of the plaice, Pleuronectes platessa, which has a different system of NaCl absorption that is claimed to be rapidly and reversibly inhibited by thiazides. Polythiazide, added to both sides of the bladder, had no effect on SCC.

Animals↗

[Lack of effect of cicletanine and its sulfoconjugated metabolite on the thiazide receptor expressed in Xenopus oocytes].

UNLABELLED: Although the renal receptor at which cicletanine acts is unknown, cicletanine was assumed to act like thiazide diuretics. Here we tested cicletanine and its natriuretic metabolite, cicletanine-sulfate, for inhibitory activity against the thiazide-sensitive NaCl cotransporter expressed in Xenopus oocytes. The renal thiazide-sensitive NaCl cotransporter was expressed in Xenopus laevis oocytes injected with rat cRNA TSCr (TSCr: thiazide-sensitive cotransporter from rat kidney) and both, racemic (+/-) cicletanine and its sulfoconjugated metabolite were tested for inhibitory activity against oocyte 22Na+ uptake catalyzed by this cotransporter. Polythiazide was used as reference thiazide. Polythiazide fully inhibited NaCl cotransporter function with IC50 approximately 1.2 x 10(-7) M. Conversely, neither cicletanine, nor cicletanine sulfate were able to inhibit such cotransporter, i.e.: a minimum concentration of 10(-4) M of cicletanine was necessary to induce a slight cotransporter inhibition (29.5 +/- 18.2%). Cicletanine sulfate was inactive, even at 10(-4) M. IN CONCLUSION: (i) the natriuretic metabolite of cicletanine (cicletanine sulfate) is unable to inhibit thiazide-sensitive NaCl cotransporter and (ii) inhibition of such cotransporter by cicletanine required concentrations equal or higher than 10(-4) M--concentrations much more higher than urinary therapeutic ones in humans (approximately 10(-6) M). These results clearly demonstrate that cicletanine does not act like thiazide diuretics.

Animals↗

Effect of trimazosin on serum lipid profiles in hypertensive patients.

Abnormalities in the serum lipid profile correlate strongly with the presence and severity of atherosclerosis. Increases in serum lipids and a reduction in high-density lipoprotein (HDL) cholesterol have been demonstrated following treatment with some beta blockers and diuretics, either alone or in combination. A new alpha-1-adrenoceptor antagonist, trimazosin, was studied to determine its effects on serum lipids. Ninety-six hypertensive patients were randomly assigned in double-blind fashion to trimazosin or placebo for 8 weeks. Trimazosin was associated with a significant reduction (p less than or equal to 0.01) in total cholesterol when compared with the placebo group. This effect was seen in all patients regardless of whether or not they were taking a diuretic concomitantly. In addition, a 9-month, double-blind parallel comparison was made of trimazosin and propranolol. Trimazosin was found to be superior to propranolol in its effect on HDL cholesterol and the HDL/total cholesterol ratio. These studies have demonstrated that, in contrast to placebo and propranolol, trimazosin lowers total serum cholesterol without undesirable effects on other serum lipid fractions. When polythiazide is given concomitantly, it diminishes the favorable effects of trimazosin and accentuates the opposite, adverse effects of propranolol.

Antihypertensive Agents↗

Effects of prazosin and propranolol on serum lipids in patients with essential hypertension.

The effects of prazosin and propranolol on total serum cholesterol concentration, low-density lipoprotein and high-density lipoprotein cholesterol fractions, and serum triglyceride concentration were compared in a crossover study in 29 patients with mild to moderate essential hypertension. All patients received polythiazide at a constant dose throughout control and drug treatment periods. Comparable blood pressure reduction was achieved with prazosin (9.3 +/- 7.1 mg per day) and propranolol (183.6 +/- 154.5 mg per day). Prazosin administration was associated with a significant reduction in the concentrations of total serum cholesterol (-5.5 percent), triglyceride (-20.0 percent), and low-density lipoprotein cholesterol (-10.1 percent). High-density lipoprotein cholesterol concentration increased (+8.0 percent) as did the ratio high-density lipoprotein: total cholesterol (+14.1 percent). No significant changes in any of the serum lipid fractions were observed during propranolol administration.

Blood Pressure↗

Comparative effects of propranolol and prazosin upon serum lipids in thiazide- treated hypertensive patients.

Earlier reported thiazide-induced changes in serum lipid concentrations were confirmed with increased triglyceride and total cholesterol levels. However, lipoprotein cholesterol ratios were unchanged. Propranolol caused further increases in triglyceride and very low-density lipoprotein cholesterol, and lowered high-density lipoprotein cholesterol and the high-density lipoprotein:total cholesterol ratio. With the addition of prazosin to the polythiazide regimen, there was a significant increase in serum high-density lipoprotein cholesterol when compared with the placebo.

Adult↗

Prazosin versus captopril as initial therapy. Effect on hypertension and lipid levels.

A randomized, parallel group study evaluated the safety, efficacy, and effect of the alpha blocking agent prazosin and the angiotensin converting enzyme inhibitor captopril on serum lipid levels in patients with mild to moderate hypertension. Baseline evaluations were performed on 31 patients after a four-week placebo washout period. Patients were randomly assigned to receive either prazosin (n = 15) or captopril (n = 16). Daily doses were titrated as follows: for prazosin, 1 mg two times daily to maximum of 20 mg per day; for captopril, 25 mg three times daily to a maximum of 450 mg per day. If diastolic blood pressure was not adequately controlled (less than 85 mm Hg) after four weeks of monotherapy, 1 mg of polythiazide was added to the daily regimen. There were no statistically significant differences between the drug groups for the measured variables in either the parallel or crossover phase of the study. Five of 15 prazosin-treated patients and six of 16 captopril-treated patients required the addition of thiazide to achieve blood pressure control.

Adult↗

Epithelial Na channels and short-term renal response to salt deprivation.

To test the role of epithelial Na channels in the day-to-day regulation of renal Na excretion, rats were infused via osmotic minipumps with the Na channel blocker amiloride at rates that achieved drug concentrations of 2-5 microM in the lumen of the distal nephron. Daily Na excretion rates were unchanged, although amiloride-treated animals tended to excrete more Na in the afternoon and less in the late evening than controls. When the rats were given a low-Na diet, Na excretion rates were elevated in the amiloride-treated group within 4 h and remained higher than controls for at least 48 h. Adrenalectomized animals responded similarly to the low-Na diet. In contrast, rats infused with polythiazide at rates designed to inhibit NaCl transport in the distal tubule were able to conserve Na as well as did the controls. Injection of aldosterone (2 microg/100 g body wt) decreased Na excretion in control animals after a 1-h delay. This effect was largely abolished in amiloride-treated rats. On the basis of quantitative analysis of the results, we conclude that activation of amiloride-sensitive channels by mineralocorticoids accounts for 50-80% of the immediate natriuretic response of the kidney to a reduction in Na intake. Furthermore, the channels are necessary to achieve minimal rates of Na excretion during more chronic Na deprivation.

Aldosterone↗

Detection, treatment and follow-up of hypertension in a community sample of 55-year-old men.

In connection with a population study including 703 randomly selected 55-year-old men, 20 men with the highest blood pressure were selected for a careful follow-up and treatment for 1 year. Controls without hypertension were randomly selected from the remainder of the same population. Electrocardiogram at rest and in connection with an exercise test, changes in fundus oculi, orthostatic tests, peripheral arterial blood flow, chemical analyses and other variables were recorded on three occasions during the observation year. Drug treatment was standardized. Basic treatment was induced with polythiazide, which normalized the blood pressure in the majority of the hypertensive cases. The most striking findings in the hypertensive group before treatment were, besides the high blood pressure at rest, high blood pressure during exercise, an increased peripheral blood-flow through the calves, and an increased heart rate. During treatment, the blood pressure were selected for a careful follow-up and blood-flow were almost "normalized"; the heart-rate remained elevated. The investigation shows that it is quite easy to achieve adequate reduction of blood pressure in hypertension among middle-aged men, as found in the "real world" outside the hospital. The main problem today is not to normalize the blood pressure but rather to detect hypertension and to maintain the therapy for several years. Hypertension is considered to be the cardiovascular risk factor that is probably most amenable to preventive approaches to public health.

Anthropometry↗

A three-phase clinical evaluation of prazosin.

A preliminary study of cardiac hemodynamics with measurement in both supine and tilt positions showed that the antihypertensive effect of prazosin given intravenously is associated with a fall in total peripheral resistance, with minor effects on cardiac output and heart rate, and with no consistent orthostatic hypotension. The postural reflexes appear to remain intact. The results are entirely similar to those reported by Lund-Johansen. In a second, short-term study of ambulatory patients, prazosin alone exerted an antihypertensive effect somewhat less than that of methyldopa, but the difference in blood pressure reduction between supine and standing positions was less with prazosin than with methyldopa. Both drugs were well tolerated. In a third, long-term study, prazosin alone gave satisfactory antihypertensive results, and prazosin used in combination with polythiazide produced a satisfactory response in 80% of the patients.

Adult↗

Changes in urea clearance after a single dose of diuretics during water diuresis.

The action of various diuretics on the excretion fraction of urea (Curea/Ccr) was studied in 91 healthy volunteers under conditions of maintained maximal water diuresis. On the basis of previous data on transtubular transport or urea it should be expected that with an increase in the excretion fraction of water (V/Ccr) under the given experimental conditions we should find an increase in Curea/Ccr. After administration of polythiazide, which has a predominantly distal localisation of action in the nephron, Curea/Ccr did not change. After administration of chlorothiazide, furosemide and after i.v. administration of ethacrynic acid there was a marked increase in V/Ccr, ranging from 5.4 to 18%. Despite this there was no significant increase in Curea/Ccr. After i.v. administration of acetazolamide or oral administration of ethacrynic acid Curea/Ccr even showed a statistically significant decrease. These findings suggest that a decrease in proximal tubular reabsorption of water after administration of diuretics during maximal water diuresis is not a decisive factor for the renal excretion of urea. The data suggest that the diuretics affected the permeability of the distal segment of the nephron for urea in the sense of an increase of tubular reabsorption.

Acetazolamide↗

Prazosin and clonidine for moderately severe hypertension.

In a single-blind comparative study of the cases of 30 moderately hypertensive patients, clonidine hydrochloride and prazosin hydrochloride had similar effectiveness in lowering blood pressure. Neither agent had significant effects on the renin-aldosterone axis. Addition of polythiazide to prazosin and chlorthalidone to clonidine notably increased the antihypertensive effect of both drugs. Serum cholesterol levels were observed to decrease when prazosin and clonidine were given and to rise when the diuretics were added to the regimen. The patients treated with clonidine were troubled by side effects, particularly drowsiness and dry mouth. Prazosin was better tolerated, with side effects tending to diminish with time. The "first-dose" effect was seen in two patients given prazosin, but it did not limit treatment. Both diuretics induced notable hypokalemia.

Adult↗

HPLC determination of benzthiazide in biologic material.

An assay was developed for benzthiazide in plasma, urine and feces, using high performance liquid chromatography (HPLC). A reverse-phase column was employed, with quantitation af 280 nm, using polythiazide as an internal standard. In three of four human subjects who received a 50 mg benzthiazide tablet the plasma concentrations were below the 10 ng ml-1 sensitivity limit of the assay, and the urinary recovery averaged less than one per cent of the dose. One subject received a 50 mg dose as both a tablet and a solution; the urinary recoveries for these two doses were 1.7 and 10.4 per cent, respectively. Fecal samples, obtained from two subjects who received 50 mg tablets, were estimated to contain approximately 80 per cent of the administered dose.

Adult↗