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Clinical efficacy and safety of indapamide in the treatment of edema.

Slotkoff L.

Whether edema is caused by "overflow" or "underfill," the excess retention of salt and water is common to virtually all forms. The use of natriuretic agents has been shown to be effective in most cases of edema. The present study compares the efficacy of a new long-acting indoline compound, indapamide, with that of hydrochlorothiazide, both given once daily, in the treatment of edema. This double-blind study was conducted in 17 centers. Edema was evaluated by weight change and pitting of the lower extremities. Indapamide was given in doses of 2.5, 5.0, and 10.0 mg and was compared with 100 mg of hydrochlorothiazide. Active treatment was continued up to 12 weeks. Weight change efficacy evaluation was done on 219 patients, and efficacy analysis for pitting edema was done on 214 patients. Of the 219 subjects, 90 were men and 129 were women. Mean age was 57.4 years, and mean body weight was 88.5 kg. By the end of 2 weeks of active treatment, the percentages of patients with no edema were 26%, 44%, and 31% for the indapamide groups (2.5, 5.0, and 10.0 mg), respectively, and 40% for the hydrochlorothiazide group (100 mg). Early response to treatment as measured by weight loss was demonstrated by all patients in the study regardless of treatment group. Hypokalemia was the most frequently reported adverse reaction. Other adverse reactions were infrequent, with no significant difference among the treatment groups. This study concluded that indapamide in once-daily oral doses of 2.5, 5.0, or 10.0 mg was as safe and effective as a once-daily 100 mg dose of hydrochlorothiazide for the treatment of 219 patients with edema from various causes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6869205&dopt=Abstract hydrochlorothiazide Microzide



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Sodium balance and antidiuresis in thiazide-treated rats with diabetes insipidus.

Walter SJ, Shirley DG.

A sodium deficit was induced in Brattleboro rats by lowering the dietary sodium content. Urine volume was only slightly reduced. Addition of hydrochlorothiazide to the food caused a small, transient sodium deficit but led to a marked, sustained antidiuresis. The acute administration of a large dose of hydrochlorothiazide produced a larger, sustained sodium deficit but no lasting antidiuresis. These results indicate that sodium depletion cannot account for the antidiuresis of hydrochlorothiazide treatment in diabetes insipidus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6873164&dopt=Abstract hydrochlorothiazide Microzide



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Thiazide diuretic effect on medullary collecting duct function in the rat.

Wilson DR, Honrath U, Sonnenberg H.

The distal convoluted tubule is thought to be the principal site of action of thiazide diuretics, but, to our knowledge, there are no studies of their possible effects on collecting duct transport. Microcatheterization of the inner medullary collecting duct (IMCD) was carried out in rats undergoing a modest diuresis, natriuresis, and chloriuresis from hydro-chlorothiazide (2 mg/kg/hr) and in normal controls. Delivery of fluid, sodium, and chloride to the beginning of the IMCD was increased, but not significantly, while the load remaining at the papillary tip (end) of the duct was increased markedly by hydrochlorothiazide. Chloride reabsorption in the IMCD was affected most markedly; the chloride reabsorption between the beginning and end of the duct, as a fraction of the delivered load, was reduced from 70.4 +/- 5.4% in controls to insignificant amounts with hydrochlorothiazide (8.2 +/- 11.5%, P less than 0.001). The fraction of delivered sodium reabsorbed along the collecting duct was decreased from 78.5 +/- 4.9% in controls to 37.2 +/- 12.4% (P less than 0.005) in thiazide-treated rats and fluid reabsorption was decreased from 59.4 +/- 4.0% in controls to 31.9 +/- 5.1% (P less than 0.005). Small but significant potassium secretion into the IMCD occurred with hydrochlorothiazide, probably secondary to the marked increase in potassium delivery to the duct. Increased potassium excretion could account for a maximum of 50% of chloriuresis with hydrochlorothiazide. The observation that thiazide diuretics decrease chloride, sodium, and fluid reabsorption in the medullary collecting duct, like the recently demonstrated inhibitory effect of furosemide on this nephron segment, has significant implications for the rationale for diuretic use.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6876566&dopt=Abstract hydrochlorothiazide Microzide



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Pharmacokinetics in man of acebutolol and hydrochlorothiazide as single agents and in combination.

Roux A, Le Liboux A, Delhotal B, Gaillot J, Flouvat B.

The pharmacokinetics of acebutolol and hydrochlorothiazide (HCT) alone or in combination were studied in 12 healthy subjects in a cross over study. Acebutolol and diacetolol (the main metabolite) in plasma and urine were determined by HPLC and hydrochlorothiazide by GLC. The main pharmacokinetic parameters of acebutolol did not differ significantly: AUC 4492 +/- 272 micrograms l-1h given alone versus 4118 +/- 354 micrograms l-1h with HCT, half-life (7,69 +/- 0,32 h vs 8,10 +/- 0,72 h) and renal clearance (13,1 +/- 0,5 lh-1 vs 13,8 +/- 0,9 lh-1), respectively. There was no difference in diacetolol pharmacokinetics. HCT values were not significantly different: AUC 784 +/- 48 micrograms l-1h given alone and 720 +/- 42 micrograms l-1h with acebutolol, t 1/2 (4,79 +/- 0,37 h vs 4,73 +/- 0,43 h). The renal clearance was slightly higher when HCT was given with acebutolol (26,2 +/- 2,6 vs 20,3 +/- 2,1 lh-1, p less than 0,05). This increase, observed during the first four hours, was probably due to competition between the drugs for binding to red blood cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6884417&dopt=Abstract hydrochlorothiazide Microzide



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The antidiuretic effect of chronic hydrochlorothiazide treatment in rats with diabetes insipidus: water and electrolyte balance.

Walter SJ, Skinner J, Laycock JF, Shirley DG.

1. The antidiuretic effect of hydrochlorothiazide in diabetes insipidus was investigated in rats with the hereditary hypothalamic form of the disease (Brattleboro rats). 2. Administration of hydrochlorothiazide in the food resulted in a marked fall in urine volume and a corresponding rise in osmolality. These effects persisted throughout the period of treatment (6-7 days). 3. Body weight and extracellular volume were significantly reduced in the thiazide-treated rats. 4. Hydrochlorothiazide caused an increase in urinary sodium excretion only on the first day of treatment. The resulting small negative sodium balance (in comparison with untreated rats) remained statistically significant for 2 days only. Thiazide-treated rats gradually developed a potassium deficit which was statistically significant from the fourth day of treatment. 5. Total exchangeable sodium, measured after 7 days of thiazide treatment, was not significantly different from that of untreated rats. However, plasma sodium was reduced in thiazide-treated animals, whereas erythrocyte sodium concentration was elevated. 6. It is concluded that the antidiuresis resulting from chronic hydrochlorothiazide administration is associated with a reduction in extracellular volume, but not with a significant overall sodium deficit. Hydrochlorothiazide appears to cause a redistribution of the body's sodium such that the amount of sodium in the extracellular fluid compartment is reduced.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7128020&dopt=Abstract hydrochlorothiazide Microzide