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Studies on interaction of timolol, hydrochlorothiazide and amiloride in the rat.

Scriabine A, Watson LS, Ludden CT, Russo HF, Bohidar NR.

1. The acute effects of hydrochlorothiazide, amiloride, timolol and their combinations on diuresis and arterial pressure were studied in rats. 2. Timolol did not modify the diuretic and saluretic effects of hydrochlorothiazide and/or amiloride and had no diuretic or antidiuretic effects alone. 3. At a single dose of 1.25 mg/kg, p.o., timolol alone had no antihypertensive effect in spontaneously hypertensive rats. 4. The antihypertensive effect of hydrochlorothiazide + amiloride + timolol was significantly greater than with any of the drugs alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7379349&dopt=Abstract hydrochlorothiazide Microzide



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Fenfluramine potentiation of antihypertensive effects of thiazides.

Lake CR, Ziegler MG, Coleman MD, Kopin IJ.

Hydrochlorothiazide, a drug which is often initially prescribed for mild to moderate hypertension, failed to lower blood pressures in 9 of 43 patients but concomitantly elevated plasma norepinephrine (NE) levels in all patients with hypertension. The 9 obese hydrochlorothiazide-resistant patients were then given fenfluramine, an anorectic, in addition to the thiazide. They were reevaluated after 2 and 5 wk, at which times there were reductions in blood pressures and marked reductions in the plasma NE levels which had been elevated by the hydrochlorothiazide. Since iatrogenic sympathetic activation seems undesirable in treating hypertension, fenfluramine may be useful in obese thiazide-resistant hypertensive patients when used in combination with a thiazide diuretic.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7389251&dopt=Abstract hydrochlorothiazide Microzide



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A novel approach to treatment of hypertension in diabetic patients - a multicenter, double-blind, randomized study comparing the efficacy of combination therapy of Eprosartan versus Ramipril with low-dose Hydrochlorothiazide and Moxonidine on blood pressure levels in patients with hypertension and associated diabetes mellitus type 2 - rationale and design [ISRCTN55725285].

Pater C, Bhatnagar D, Berrou JP, Luszick J, Beckmann K.

Department of Cardiovascular Clinical Development, Solvay Pharmaceuticals GmbH, Hannover, Germany. cornel.pater solvay.com.

Hypertension and diabetes mellitus are closely interrelated and coexist in as many as two-thirds of patients with type 2 diabetes. The consequent risk of such an association is an accelerated development of atherosclerotic cardiovascular disease and nephropathy complications.In choosing an antihypertensive agent, effectiveness needs to be accompanied by favourable metabolic, cardioprotective, and nephroprotective properties. Given the multifactorial nature of hypertension, the approach that has gained widespread agreement is treatment with more than one agent. Agents with different mechanisms of action increase antihypertensive efficacy because of synergistic impacts on the cardiovascular system. Combination therapy allows the use of lower doses of each antihypertensive agent which accounts for the excellent tolerability of combination products.The aim of the present study is to quantify the efficacy of combination therapy of Eprosartan 600 mg respectively Ramipril 5 mg with low-dose Hydrochlorothiazide and Moxonidine on blood pressure levels in patients with essential hypertension and associated diabetes mellitus type 2.The use of monotherapy (Eprosartan or Ramipril) followed by addition of low-dose Hydrochlorothiazide as second agent and of Moxonidine as a third agent will be individualized to the severity of hypertension in the particular patient and to his/her degree of response to current treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15461784&dopt=Abstract hydrochlorothiazide Microzide



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Changes in endothelium-derived hyperpolarizing factor in hypertension and ageing: response to chronic treatment with renin-angiotensin system inhibitors.

Goto K, Fujii K, Kansui Y, Iida M.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kenichi.goto anu.edu.au

1. Endothelial function is impaired in hypertension and ageing and this may be associated with an increase in cardiovascular disease. Several clinical studies have shown that blocking the renin-angiotensin system (RAS) improves endothelial function not only in hypertensive patients, but also in normotensive patients with cardiovascular disease. 2. The aim of the present study was to test whether endothelium-derived hyperpolarizing factor (EDHF)-mediated smooth muscle hyperpolarization and relaxation are altered in hypertension and ageing and, if so, whether chronic treatment with RAS inhibitors (the angiotensin-converting enzyme inhibitor enalapril and the angiotensin AT1 receptor antagonist candesartan) would correct such changes. 3. Endothelium-derived hyperpolarizing factor-mediated responses were examined in mesenteric arteries from 12-month-old spontaneously hypertensive rats (SHR) and 3-, 6-, 12- and 24-month-old normotensive Wistar-Kyoto (WKY) rats. Furthermore, both strains were treated for 3 months with either RAS blockers or a conventional therapy with hydralazine and hydrochlorothiazide from 9 to 12 months of age. 4. In arteries of 12-month-old SHR, EDHF-mediated responses were impaired compared with age-matched WKY rats. In SHR, all antihypertensive treatments improved the impairment of EDHF-mediated responses; however, RAS inhibitors tended to improve these responses to a greater extent compared with conventional therapy with hydralazine and hydrochlorothiazide. 5. In arteries of WKY rats, EDHF-mediated responses were impaired at the age of 12 and 24 months compared with 3- and 6-month-old rats, with the response tending to be impaired to a greater extent in 24-month-old rats. 6. Three months of treatment of WKY rats, until 12 months of age, with RAS inhibitors, but not with conventional therapy with hydralazine and hydrochlorothiazide, improved the age-related impairment of EDHF-mediated responses, despite a similar reduction in blood pressure by both treatments. 7. These findings suggest that: (i) EDHF-mediated hyperpolarization and relaxation decline with hypertension and ageing in rat mesenteric arteries; (ii) antihypertensive treatment restores the impaired EDHF-mediated responses in hypertension; (iii) RAS inhibitors may be more efficacious in improving endothelial dysfunction associated with hypertension; and (iv) chronic treatment with RAS inhibitors improves the age-related impairment of EDHF-mediated responses, presumably through the blockade of RAS but not blood pressure lowering alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15479174&dopt=Abstract hydrochlorothiazide Microzide



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Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: principal results of PHYLLIS--a randomized double-blind trial.

Zanchetti A, Crepaldi G, Bond MG, Gallus G, Veglia F, Mancia G, Ventura A, Baggio G, Sampieri L, Rubba P, Sperti G, Magni A; PHYLLIS Investigators.

Istituto Auxologico Italiano, Ospedale Maggiore, University of Milan, Italy. alberto.zanchetti unimi.it

BACKGROUND AND PURPOSE: The Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) tested whether (1) the angiotensin-converting enzyme (ACE) inhibitor fosinopril (20 mg per day) was more effective on carotid atherosclerosis progression than the diuretic hydrochlorothiazide (25 mg per day), (2) pravastatin (40 mg per day) was more effective than placebo when added to either hydrochlorothiazide or fosinopril, and (3) there were additive effects of ACE inhibitor and lipid-lowering therapies. METHODS: A total of 508 hypertensive, hypercholesterolemic patients with asymptomatic carotid atherosclerosis were randomized to: (A) hydrochlorothiazide; (B) fosinopril; (C) hydrochlorothiazide plus pravastatin; and (D) fosinopril plus pravastatin, and followed up blindly for 2.6 years. B-Mode carotid scans were performed yearly by certified sonographers in 13 hospitals and read centrally. Corrections for drift were calculated from readings repeated at study end. Primary outcome was change in mean maximum intima-media thickness of far and near walls of common carotids and bifurcations bilaterally (CBM(max)). RESULTS: CBM(max) significantly progressed (0.010+/-0.004 mm per year; P=0.01) in group A (hydrochlorothiazide alone) but not in groups B, C, and D. CBM(max) changes in groups B, C, and D were significantly different from changes in group A. Changes in group A were concentrated at the bifurcations. "Clinic" and "ambulatory" blood pressure reductions were not significantly different between groups, but total and low-density lipoprotein cholesterol decreased by approximately 1 mmol/L in groups C and D. CONCLUSIONS: Progression of carotid atherosclerosis occurred with hydrochlorothiazide but not with fosinopril. Progression could also be avoided by associating pravastatin with hydrochlorothiazide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15514192&dopt=Abstract hydrochlorothiazide Microzide