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Renal tubular secretion and effects of chlorothiazide, hydrochlorothiazide and clopamide: a study in the avian kidney.

Odlind B, Lonnerholm G.

The relationship between renal tubular secretion and saluretic effects of two thiazides (chlorothiazide and hydrochlorothiazide) and clopamide was studied using a modified Sperber technique. The distribution of carbonic anhydrase in the avian kidney was studied by a histochemical method. The modified Sperber technique allows an absolute estimation of the tubular excretion efficiency of a substance, as determined by its True Tubular Excretion Fraction (TTEF). The TTEF values were for chlorothiazide 59%, hydrochlorothiazide 22% and clopamide 10%. Thus, they were all actively secreted by renal tubular cells; most likely through organic anion transport since novobiocin markedly reduced the TTEF values. After infusion of the diuretics into the renal portal system on one side there was only a small ipsilateral excess natriuresis and chloruresis, in spite of their different tubular excretion efficiencies. For hydrochlorothiazide, and especially for chlorothiazide the saluretic effect therefore appears to be largely independent of the tubular fluid concentration of the diuretic and primarily evoked from the peritubular side of the avian nephron. This is a sharp contrast to the primarily luminally induced saluretic effects of furosemide, ethacrynic acid and piretanide. Only chlorothiazide caused an ipsilateral excess excretion of potassium and bicarbonate, probably due to inhibition of carbonic anhydrase since similar effects were seen after acetazolamide. This effect was coupled to tubular secretion of the diuretic, and probably reflects an inhibition of carbonic anhydrase in cortical distal tubules, where the enzyme is present in the apical region of most cells and could be reached by chlorothiazide present in the tubular fluid.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6814186&dopt=Abstract hydrochlorothiazide Microzide



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Toxicology of the combination lofexidine/hydrochlorothiazide.

Friehe H, Fontaine R, Gibson JP, Larson EJ, Sells DM.

The toxicity and side-effects of the antihypertensive and diuretic combination 2-[1-(2,6-dichlorphenoxy)-ethyl-2-imidazoline-hydrochloride (lofexidine, Lofetensin and Loxacor) hydrochlorothiazide were studied in toxicity and teratogenicity tests and the possibility of interactions was investigated. In terms of lofexidine, there was no evidence of any adverse interactions with hydrochlorothiazide either following a single, oral administration to rats and mice or following short-term and long-term repeated oral dosing of rats and dogs. In the subchronic and chronic toxicity studies it was actually found that the familiar, unwanted sedative effect of lofexidine failed to occur when the combined preparation was given. With repeated oral administration to rats and dogs definite drug-related toxic findings, such as a reduction in serum potassium, mineralization of a few organs and crystal formation in the urine, only occurred at dose levels far above the therapeutic dose. The results of these studies along with historical data on the individual components would suggest a lack of carcinogenic potential for this combination. No teratogenic or embryotoxic effects were noted in rats or rabbits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6890371&dopt=Abstract hydrochlorothiazide Microzide



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Effect of hydrochlorothiazide on 1,25-dihydroxyvitamin D3-induced changes in calcium metabolism in experimental hypoparathyroidism in rats.

Rizzoli R, Hugi K, Fleisch H, Bonjour JP.

1. Chronic administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] can normalize plasma calcium in human hypoparathyroidism and in thyroparathyroidectomized animals. The effect of 1,25(OH)2D3 on plasma calcium is associated with an increase in urinary calcium excretion. In an attempt to prevent this increase thyroparathyroidectomized rats receiving 1,25(OH)2D3 were also treated with hydrochlorothiazide for 9-11 days. 2. Calcium clearance studies show that hydrochlorothiazide stimulated the tubular reabsorption of calcium in thyroparathyroidectomized rats treated with 1,25(OH)2D3. 3. Calcium balance and kinetic studies indicated that hydrochlorothiazide decreased 1,25(OH)2D3-induced hypercalciuria in thyroparathyroidectomized rats. Hydrochlorothiazide did not affect the 1,25(OH)2D3-induced increase in plasma calcium. The hypocalciuric effect of hydrochlorothiazide was not associated with significant changes in calcium deposition into or release from bone. 4. In thyroparathyroidectomized rats treated with 1,25(OH)2D3 the hypocalciuric effect of hydrochlorothiazide was associated with a fall in intestinal calcium absorption. Overall, the calcium balance was unaffected. 5. Thus it appears that hydrochlorothiazide reduces the 1,25(OH)2D3-induced hypercalciuria in parathyroid hormone-deficient animals by decreasing intestinal calcium absorption. Despite the decreased absorption, hydrochlorothiazide does not reduce the 1,25(OH)2D3-induced increase in plasma calcium.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6894567&dopt=Abstract hydrochlorothiazide Microzide



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Effect of chronic diuretic treatment on the plasma renin-angiotensin-aldosterone system in essential hypertension.

Lijnen P, Fagard R, Staessen J, Amery A.

1 Chronic treatment with a constant dose of hydrochlorothiazide or tienilic acid increases plasma renin activity (PRA) acutely to reach a maximum within the first week. 2 During chronic diuretic therapy from 1 month to 1 year, PRA remained elevated at a rather constant level, though this was somewhat lower than the maximum level reached after 1 week. 3 A significant (P less than 0.01) correlation (r = 0.74) between changes in plasma angiotensin II and renin activity provoked by chronic treatment for 3 months with hydrochlorothiazide and tienilic acid was found. 4 The increase in plasma aldosterone during chronic treatment with hydrochlorothiazide and tienilic acid (1000 mg) is related (r = 0.68; P less than 0.01) to the rise in plasma angiotensin II.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7028060&dopt=Abstract hydrochlorothiazide Microzide



Microzide
Development of solid-phase extraction method and its application for determination of hydrochlorothiazide in human plasma using HPLC.

Zendelovska D, Stafilov T, Milosevski P.

Institute of Preclinical and Clinical Pharmacology and Toxicology, St. Cyril and Methodius University, Medical Faculty, 50 Divizija bb, 1000 Skopje, Republic of Macedonia.

A high-performance liquid chromatographic method was developed, validated and applied for the determination of hydrochlorothiazide in human plasma. The effects of mobile phase composition, buffer concentration, mobile phase pH and concentration of organic modifiers on retention of hydrochlorothiazide and internal standard were investigated. The method involves solid-phase extraction on RP-select B cartridges followed by isocratic reversed-phase chromatography on a Hibar Lichrospher 100 RP-8 column with UV detection at 230 nm. The recovery, selectivity, linearity, precision and accuracy of the method were evaluated from spiked human plasma samples. Limit of quantification was 10 ng mL(-1). The method has been implemented to monitor hydrochlorothiazide levels in patient samples. Copyright 2004 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15039957&dopt=Abstract hydrochlorothiazide Microzide