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At least 19 recordsLinked to original sources
PubMed1975

The influence of polyvinylpyrrolidone on the dissolution properties of hydroflumethiazide.

The incorporation of hydroflumethiazide with polyvinylpyrrolidone (PVP) was found to retard and to enhance the dissolution of the drug from compressed discs, the magnitude of the effect being dependent on the proportion of PVP present and its method of incorporation. The most active system dissolved sixteen times faster than pure hydroflumethiazide. Low concentrations of PVP were also found to decrease the apparent solubility of hydroflumethiazide while at high concentrations solubility was enhanced. X-ray and infrared analysis of systems suggested the presence of an amorphous form of hydroflumethiazide in coprecipitate systems. The dissolution data were consistent with a physical model which takes account of the roles played by crystalline and amorphous hydroflumethiazide together with the complexing and crystal growth inhibiting effect of PVP on hydroflumethiazide.

Chemical Precipitation↗
PubMed1977

Fluorometric determination of hydroflumethiazide in human plasma and urine after its oral administration.

A spectrofluorometric method for determination of hydroflumethiazide in human plasma and urine has been developed. The limit of detection was 10 ng/ml plasma and 100 ng/ml urine. The plasma concentration of hydroflumethiazide was determined for 9-11 hours and excretion in urine for 24-37 hrs after oral administration of about 1 mg/kg body weight to 7 subjects. Plasma half life in healthy subjects was 1.9-2.1 h, and 2.7-8.6 h in patients during the period 4-9 hrs after dosing. Cumulative excretion in urine was 67-79% of the dose during 31-37 hrs in 6 subjects; one patient with renal disease was found to excrete only 25.8% of dose during 24 hours. Renal clearance of hydroflumethiazide was higher in the healthy subjects (0.29-0.44 1 h-1 kg-1) than in the patients (0.040-0.15 1 h-1 kg-1). Plasma half life of hydroflumethiazide was not closely correlated with renal clearance of the drug, which suggests that other factors may play a role in determining plasma half life.

Administration, Oral↗
PubMed1985

Effects of a thiazide diuretic (hydroflumethiazide) and a loop diuretic (bumetanide) on the endocrine pancreas: studies in vitro.

Treatment with thiazide diuretics causes an impairment of the glucose metabolism. To study whether this is due to a direct effect on the endocrine pancreas, the effects of the thiazide hydroflumethiazide on the release of glucagon, insulin, and somatostatin from the isolated perfused pancreas of normal and alloxan diabetic dogs were examined. Hydroflumethiazide at concentrations ranging from 1 to 50 micrograms/mL stimulated the normal secretion of glucagon (P less than 0.001), insulin (P less than 0.001), and somatostatin (P less than 0.001) in a dose-dependent manner. The normal hormone responses evoked by 50 micrograms/mL of the thiazide were, however, modified by the prevailing glucose level: higher insulin (P less than 0.05) and somatostatin (P less than 0.05) and lower glucagon (P less than 0.05) were obtained at the high glucose concentration of 11 mmol/L rather than at the low glucose concentration of 1.3 mmol/L. In alloxan diabetes, insulin secretion was almost extinct and did not respond to hydroflumethiazide, whereas glucagon was dose-dependently stimulated (P less than 0.001). In addition, we looked at the effect of the loop diuretic, bumetanide. The infusion of bumetanide at doses ranging from 0.5 to 3 micrograms/mL did not alter the release of glucagon, insulin, and somatostatin in the presence of 5.5 mmol/L glucose. The results suggest that hydroflumethiazide possesses the ability to directly stimulate A cell secretion in the normal and alloxan diabetic pancreas. Whether this effect is of clinical importance for the diminution in glucose tolerance observed during thiazide therapy remains, however, uncertain.

Animals↗
PubMed1977

Pharmacokinetics of orally administered hydroflumethiazide in man.

Hydroflumethiazide plasma and urine levels were measured fluorometrically following the oral administration of 100-mg doses (2 X 50 mg tablets) to each of 12 healthy, adult male subjects. The plasma level data as a function of time were fit to a one-compartment open model using a nonlinear regression digital computer program. The means of the individual apparent absorption and disposition rate apparent absorption and disposition rate constants were 0.770+/-0.46 hr(-1) (t1/2=0.9 hr) and 0.358+/-0.17 hr(-1) (t1/2=1.94 hr), respectively, with a 0.49+/-0.26 hr lag time in absorption. The same parameter estimates obtained by fitting the mean plasma concentration-time curve were 0.461+/-0.15 hr(-1), 0.357+/-0.13 hr(-1), and 0.39+/-0.09 hr for the apparent absorption and disposition rate constants and the lag time, respectively. The closeness of the parameter estimates and the lack of intravenous data preclude unequivocal assignment of the rate constants to the absorption or disposition processes. Nevertheless, the disposition of hydroflumethiazide is clearly a rapid process. The means of the individual peak plasma levels and times to peak were 0.301+/-0.94 microgram/ml and 2.12+/-0.59 hours, respectively. The mean area under the plasma level-time curve was 1.95+/-0.78 microgram-hr/ml and 46.7+/-20.0% of the administered dose was recovered in the 24-hour urine. The mean renal clearance of hydroflumethiazide was 453.4+/-256.6 ml/min.

Administration, Oral↗
PubMed1993

Metabolic effects of propranolol and hydroflumethiazide treatment in Kenyans with mild to moderate essential hypertension.

In a prospective single-blind comparative trial, sixty newly diagnosed mild to moderate hypertensives were randomly assigned to either propranolol or hydroflumethiazide monotherapy. Baseline fasting serum glucose lipid profiles, serum uric acid and potassium levels, were determined at the beginning of the trial. Repeat levels were determined at completion of twelve weeks of treatment. Propranolol treatment significantly reduced HDL-cholesterol (p < 0.02) and increased both VLDL and total serum triglycerides (p < 0.01). Hydroflumethiazide significantly increased total and LDL-chole-sterol, fasting serum glucose and uric acid levels (p < 0.01); potassium levels were significantly lowered (p < 0.01). Treatment with either propranolol or hydroflumethiazide is associated with significant metabolic side-effects which require regular monitoring and intervention as appropriate.

Adolescent↗
PubMed1978

Absorption kinetics of hydroflumethiazide.

The pharmacokinetics of hydroflumethiazide after oral administration of a 100-mg dose to 12 volunteers were evaluated to determine whether absorption of the drug is best described by zero-order or first-order absorption. Comparison of the two absorption models was based on three criteria: (1) correlation coefficients; (2) standard deviations of the parameter estimates; and (3) visual fits. Evaluation of the individual results in light of each criterion showed that the zero-order absorption model is the more appropriate one for describing the hydroflumethiazide data.

Administration, Oral↗
PubMed1976

Spectrofluorometric determination of hydroflumethiazide in plasma and urine.

A rapid, accurate, sensitive, and reproducible assay for hydroflumethiazide in plasma and urine was developed after studies of its UV and fluorescence spectral properties and partitioning behavior. The assay is based on initial extraction from acidified plasma or urine into ether, back-extraction into basic solution followed by acidification to about pH 1, and measurement of the fluorescence derived from the unionized molecule. Analysis of variance indicated no significant differences in assays performed on the same day. The mean recovery was 98.8 +/- 7.4% for plasma over a concentration range of 0.2-2.0 mug/ml. The method is convenient for routine clinical use and has sufficient sensitivity to quantify hydroflumethiazide levels after administration of therapeutic doses.

Animals↗
PubMed1979

Hypertension in the elderly: review of therapy with a hydroflumethiazide-reserpine combination.

A retrospective analysis revealed that 125 geriatric patients had been treated for mild to moderate essential hypertension with a combination drug, each tablet of which contained 50 mg of hydroflumethiazide and 0.125 mg of reserpine. The dosage schedule was one tablet once daily for most patients. The duration of treatment ranged from 1 to 93 months (mean, 22.1 months). After one month of therapy, the decreases in mean systolic (-18.3 mm Hg) and mean diastolic (-6.6 mm Hg) blood pressure were statistically significant and these initial reductions were well maintained over a 6-year period, without signs of tachyphylaxis. Side effects were reported by 53 patients, but these usually were mild and typical of those associated with antihypertensive therapy; discontinuation of treatment was required in only 3 patients. Use of the hydroflumethiazide-reserpine combination was associated with several significant advantages, including convenient once-daily dosing, improved compliance, and decreased cost.

Aged↗
PubMed1984

Amorphous spray-dried hydroflumethiazide-polyvinylpyrrolidone systems: physiochemical properties.

Hydroflumethiazide was spray-dried with polyvinylpyrrolidone (PVP) to produce products containing 0-30% PVP. These systems were amorphous and differed from previously prepared coprecipitates of similar composition. Differential scanning calorimetry (DSC) suggested that at low PVP weight fractions both amorphous drug and an amorphous drug-PVP complex can be present in spray-dried systems. The apparent solubility of hydroflumethiazide in spray-dried products increased with increasing PVP content reaching a plateau value approximately four times that of the pure crystalline drug. The estimated free energy and entropy of the spray-dried drug were greater than that of crystalline drug and also increased with increasing PVP content. Dissolution studies with compressed discs supported the apparent solubility data. The results suggest that amorphous phases having different orders of organization are formed in spray-dried systems with increasing PVP content.

Chemical Phenomena↗
PubMed1979

Distribution of elimination of hydroflumethiazide in man.

The pharmacokinetics of hydroflumethiazide (HFT) were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion, HFT behaved according to a three-compartment model. Two distribution phases were observed, with mean half-lives of 0.26 and 0.85 h, reflecting distribution to red blood cells and tissues. Mean biological half-life (t 1/2 beta) after infusion was 5.2 h. Renal blood and plasma clearance of HFT, as well as the ratio renal blood clearance/renal plasma clearance of HFT, were lower after infusion than during the infusion, due to the distribution characteristics of HFT. After a single oral dose of 2 micronmol/kg, t 1/2 beta was significantly shorter in all subjects than after a single oral dose of 6 micronmol/kg, with mean t 1/2 beta of 8.7 and 17.9 h, respectively. Due to lack of a sufficiently sensitive method for determination of HFT in plasma, it could not be established whether the observed dose-dependent difference in biological half-life of HFT was caused by variation in renal clearance and/or the volume of distribution.

Administration, Oral↗
PubMed1979

Excretion of hydroflumethiazide in bile and urine of man.

Biliary and urinary excretion of hydroflumethiazide (HFT) and its metabolite, 2,4-disulfamyl-5-trifluoromethylaniline (DTA), was investigated in 5 otherwise healthy patients with a T-drain in the common bile duct after cholecystectomy and choledochotomy. After a single oral dose of HFT 302--453 micromoles, a mean of 0.051% (range 0.028--0.075) of the dose was excreted in bile and 34.9% (range 23.7--45.4) in urine during the first 6 hours after administration. Biliary excretion appeared to be of minor importance in the elimination of HFT by man. DTA could not be detected in bile.

Adult↗
PubMed1981

Effects of hydroflumethiazide in congestive heart failure: renal electrolyte excretion related to urinary thiazide excretion and aldosterone.

The effect of hydroflumethiazide (HFT) on renal excretion of sodium, chloride, and potassium was studied in congestive heart failure and related to urinary excretion of thiazide and aldosterone. HFT 75 or 150 mg was administered orally once daily for 4 days to 8 male patients with roentgenological evidence of enlarged heart and slight or no peripheral oedema receiving digitalis and controlled diet. Urinary excretion of HFT did not change after repeated doses, whereas urinary excretion of a metabolite increased significantly. Initially, HFT induced a significant increase in the urinary excretion of sodium and potassium. After repeated doses, the natriuretic effect declined gradually in 6 of the patients. There was consistently a small natriuretic effect and a large kaliuretic effect at high serum aldosterone concentrations and high urine aldosterone excretion rates, whereas at low aldosterone levels, there was a wide range in magnitude of these effects. Relationships of the log urinary excretion rate of HFT to the increase in urinary excretion rate of sodium, chloride, and potassium showed positive and significant correlations. It was concluded that reduced natriuretic effect of HFT in congestive heart failure is not due to reduced delivery of thiazide to renal tubular cells but to compensatory adjustments of the kidney in part induced by aldosterone.

Aged↗
PubMed1981

Effect of repeated doses of hydroflumethiazide on renal excretion of electrolytes and uric acid in healthy subjects.

Urinary excretion of electrolytes and uric acid was investigated in six healthy subjects during repeated oral administration of 100 mg hydroflumethiazide (HFT) daily for seven days, and related to urinary thiazide excretion. Mean 24 hr-urinary excretion of sodium and chloride increased 100% (P less than 0.02) after the first HFT-dose, whereas 24 hr-excretion values were at control level after the fourth and seventh doses. Mean 24 hr-urinary excretion of potassium was increased by 31% after the first HFT-dose (P less than 0.05) and by 47% after the fourth dose (P less than 0.05). After HFT was discontinued, mean urinary excretion rates of sodium and chloride dropped to 30% and that of potassium to 70% of control. In the state of fluid deficiency and elevated aldosterone concentration, there was a significant positive correlation between log excretion rate of HFT and excretion rate of sodium (r=0.68, P less than 0.002) calculated from excretion data 0-67, 6-12, and 12-14 hrs after the seventh dose. After the first dose of HFT, sodium excretion was also significantly correlated to log excretion rate of HFT (r=0.86, P less than 0.001) but was probably influenced by other factors as well. Mean serum concentration of uric acid increased significantly, but mean 24 hr-urinary excretion of uric acid was constant during HFT-treatment.

Adult↗
PubMed1982

Pharmacokinetics of hydroflumethiazide during repeated administration in congestive heart failure.

The renal elimination and accumulation of hydroflumethiazide (HFT) during repeated oral administration was investigated in patients with congestive heart failure (CHF). When four doses of HFT wee given with 24 hr intervals, the mean 24 hr urinary excretion of HFT was 55-65% of the dose after 75 mg and 53-57% after 150 mg. 24 hr excretion of HFT was not significantly higher after the fourth dose as compared with the first. The renal plasma clearance of HFT was significantly correlated with creatinine clearance (P less than 0.01). The biological half-life (t1/2 beta) of HFT ranged from 6.5-27.9 hrs. Mean t1/2 beta was shorter (P less than 0.05) after 75 mg (9.2 hrs) than after 150 mg doses (14.1 hrs). The disposition rate constant of HFT was not significantly correlated with creatinine clearance or with renal plasma clearance of HFT, indicating that the volume of distribution was reduced at reduced renal function.

Aged↗
PubMed1982

Interaction of hydroflumethiazide and 2,4-disulfamyl-5-trifluoromethylaniline with cyclic AMP phosphodiesterase and carbonic anhydrase.

The inhibitory effect of hydroflumethiazide (HFT) and its metabolite, 2,4-disulfamyl-5-trifluoromethylaniline (DTA) on cyclic AMP phosphodiesterase and the binding of HFT and DTA to carbonic anhydrase was studied in vitro. Significant inhibition of rat kidney low-Km cyclic AMP phosphodiesterase was observed with DTA concentration above 2.5 X 10(-4) mol/l and with HFT concentration above 1 X 10(-4) mol/l. 50% inhibition was observed at a DTA concentration of 1 X 10(-3) mol/l. Binding of DTA and HFT to commercially obtained bovine erythrocyte carbonic anhydrase was demonstrated by equilibrium dialysis. Data were consistent with one class of binding sites. The product of n (number of binding sites) and Kass (association constant) was 5 X 10(5) M for DTA and 3.3 X 10(4) M for HFT at 2 degrees. In human blood in vitro at 37 degrees, the equilibrium erythrocyte/plasma concentration ratio was 18 for DTA and 1.6 for HFT. It is concluded that HFT and DTA have approximately the same potency as cyclic AMP phosphodiesterase inhibitors, whereas DTA is more extensively bound by erythrocyte carbonic anhydrase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

Randomised double-blind comparative study of efficacy and safety of hydroflumethiazide and reserpine and chlortalidone and atenolol in the treatment of mild to moderate hypertension in black patients.

This randomised, double-blind study compared the efficacy and safety of a fixed combination of hydroflumethiazide 50 mg and reserpine 0.125 mg (H-R) and chlortalidone 12.5 mg and atenolol 50 mg (C-A) in adult black patients with mild to moderate hypertension (a resting supine diastolic blood pressure (DBP) between 95 and 115 mmHg after a two week placebo washout period). If the DBP did not reach 90 mmHg after four weeks, the dosage was doubled. There were 27 patients in the H-R group and 22 in the C-A group who completed the study. In the H-R group, supine systolic and diastolic BP were reduced from 156.5 (95% confidence intervals 150.1-162.9) and 102.0 (97.5-106.5) mmHg to 137.0 (130.6-143.4) and 87.4 (83.0-91.9) mmHg, respectively. The corresponding values in the C-A group were 154.1 (147.0-161.2) and 103.4 (98.5-108.4) mmHg to 136.4 (129.3-143.5) and 91.2 (86.2-96.1) mmHg, respectively. Normalisation, response and control of DBP was achieved in 88.9, 92.6 and 100% of patients, respectively, in the H-R group, and in 81.8, 95.5 and 95.5% of patients in the C-A group, respectively. The dose was doubled in 14.8% of patients on H-R and 40.1% on C-A. No clinically significant abnormalities in laboratory variables and no serious adverse effects were encountered. Both drugs have been shown to be efficacious and safe in the treatment of mild to moderate hypertension in black patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Comparative study of the efficacy and tolerability of hydroflumethiazide versus propranolol in Africans with mild to moderate hypertension.

Sixty patients with Diastolic Blood Pressure (DBP) of 100-110mmHg matched for age, sex and Bp levels were randomly assigned to propranolol 80mg daily or Hydroflumethiazide (HFM) 50mg daily. HFM causes a significant reduction in systolic blood pressure (SBP) and DBP within 4 weeks compared both with baseline and propranolol (SBP 143.7 +/- 12.3 vs 158.1 +/- 10.9mmHg, P < 0.05; DBP 92.0 +/- 4.5 vs 102.4 +/- 5.1mmHg, P < 0.05), (SBP 143.7 +/- 12.2 vs 152 +/- 11.0mmHg P < 0.05; DBP 92.0 +/- 4.5 vs 101.1 +/- 6.1mmHg, P < 0.05), respectively. Propranolol produced no significant difference from the baseline at 4 weeks (SBP 152.0 +/- H.0 vs 154.1 +/- 11.5mmHg NS; DBP 101.1 +/- 6.1 vs 102.2 +/- 5.6mmHg, NS). Reduction in BP by HFM was maintained after 8 and 12 weeks with further reduction but which did not achieve statistical significance. Increased dose of propranolol (160mg daily) after 4 weeks caused significant reduction in BP by 8 week (SBP 146.8 +/- 11.8 vs 152.0 +/- 11.0mmHg, P < 0.05; DBP 95.9 +/- 4.4 vs 101.1 +/- 6.1mmHg P < 0.05), which was maintained upto 12 weeks. The values however remained higher than in the HFM group. More patients in the HFM group achieved target BP (< 140/90), SBP 53.8% vs 29.6% P < 0.05, DBP 69.2% vs 14.8% P < 0.01. Incidence of side effects was similar and will be discussed. Thiazides are superior to B'blockers as initial monotherapy in black hypertensives.

Adult↗