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Bisoprolol and hydrochlorothiazide effects on cardiovascular remodeling in spontaneously hypertensive rats.

Mougenot N, Mediani O, Lechat P.

Service de Pharmacologie, CHU Pitie Salpetriere, 47, boulevard de l'Hopital, 75651 Paris cedex 13, France. nathalie.mougenot chups.jussieu.fr

Anti-hypertensive agents may differently stimulate compensatory neuro-hormonal mechanisms and induce different effects on the cardiovascular remodeling and function. The combination of low doses of the two synergistic drugs may lead to a lesser activation of counter regulatory mechanisms and could provide optimal therapeutic benefit. We evaluated on spontaneously hypertensive rats the effect of 3-week period of anti-hypertensive treatment. Rats were divided into four groups: control, bisoprolol (100 mg kg-1), hydrochlorothiazide (10 mg kg-1), and their combination with low doses (10 and 1 mg kg-1, respectively). The effects of treatment were evaluated on neuro-hormonal stimulation, cardiac and vascular structure and function. The combination had synergistic anti-hypertensive effects and significantly reduced heart rate and blood pressure but to a lower extent compared with bisoprolol 100 mg kg-1. Combination therapy was associated with a lower renin activation compared to hydrochlorothiazide alone and improved endothelial function. Cardiovascular remodeling differed between the groups: with bisoprolol, cardiac hypertrophy was reduced; with the combination therapy, the aortic media/lumen ratio was most increased. The consequent shear stress reduction may explain the associated endothelial function improvement. Such favourable cardiovascular remodeling with diuretic-beta-blockade combination may participate to the long-term cardiovascular protection during anti-hypertensive treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15683750&dopt=Abstract hydrochlorothiazide Microzide



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Stability study of losartan/hydrochlorothiazide tablets.

Lusina M, Cindric T, Tomaic J, Peko M, Pozaic L, Musulin N.

PLIVA-Research Institute Ltd., Analytics, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia.

The purpose of stability testing is to investigate how the quality of a drug product changes with time under the influence of environmental factors, to establish a shelf life for the product and to recommend storage conditions. Stability study of losartan/hydrochlorothiazide tablets is presented in this paper. Losartan (angiotensin II receptor antagonist) and hydrochlorothiazide (diuretic) are successfully used in association in the treatment of hypertension. Stability study of losartan/hydrochlorothiazide tablets consisted of three steps: stress test (forced degradation study), preliminary testing (selection of packaging) and formal stability testing. The results of stress test suggested that losartan/hydrochlorothiazide tablets are sensitive to moisture. It was demonstrated that the developed analytical methods are stability indicating. Additional preliminary testing was performed in order to select appropriate packaging for losartan/hydrochlorothiazide tablets. OPA/Al/PVC//Al blisters were found to provide adequate protection for the product. Based on the first 12 months of the formal stability study, a shelf life of 24 months was proposed. Losartan/hydrochlorothiazide tablets in OPA/Al/PVC//Al blisters are demonstrated to be chemically, physically and microbiologically stable.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15707739&dopt=Abstract hydrochlorothiazide Microzide



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Inhibition of carbonic anhydrase accounts for the direct vascular effects of hydrochlorothiazide.

Pickkers P, Garcha RS, Schachter M, Smits P, Hughes AD.

Department of Pharmacology, University Hospital Nijmegen, Nijmegen, The Netherlands.

Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (KCa) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because KCa channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pHi) were measured simultaneously with 2', 7'-bis(2-carboxyethyl)-5(6)'-carboxyfluorescein (BCECF-AM). Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16+/-8% relaxation) compared with hydrochlorothiazide (74+/-12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of KCa channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Hydrochlorothiazide and the inhibitors of carbonic anhydrase failed to relax tone induced by a depolarizing potassium solution. Acetazolamide and hydrochlorothiazide increased pHi by 0.27+/-0.07 and 0.21+/-0.04, respectively, whereas bendroflumethiazide had a much smaller effect: 0.06+/-0.03. The rise in pHi induced by any agent was not inhibited by charybdotoxin. The vasorelaxant effect of hydrochlorothiazide is shared by other inhibitors of carbonic anhydrase. Inhibitors of carbonic anhydrase, but not bendroflumethiazide, cause intracellular alkalinization, which is associated with KCa channel opening. These data suggest that the vasodilator effect of thiazide diuretics results primarily from inhibition of vascular smooth muscle cell carbonic anhydrase, which results in a rise in pHI, leading to KCa channel activation and vasorelaxation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10205245&dopt=Abstract hydrochlorothiazide Microzide



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Rapid recovery of bone mass in hypercalciuric, osteoporotic men treated with hydrochlorothiazide.

Adams JS, Song CF, Kantorovich V.

Burns and Allen Research Institute and Cedars-Sinai Medical Center, University of California, Los Angeles, School of Medicine 90048, USA. adamsj cshs.org

BACKGROUND: Chronic hypercalciuria can contribute to osteoporosis, particularly in men. OBJECTIVE: To ascertain the effects of resolution of hypercalciuria on bone mineral density. DESIGN: Case series. SETTING: Referral service for metabolic bone disease in a tertiary-care teaching hospital. PATIENTS: Five male patients (42 to 66 years of age) with hypercalciuria and osteoporosis. INTERVENTION: Hydrochlorothiazide, 25 mg twice daily, for a mean (+/- SD) of 7.8 +/- 3.6 months. MEASUREMENTS: Fasting urinary calcium:creatinine ratio, serum calciotropic hormone levels, and bone mineral density before and after hydrochlorothiazide administration. RESULTS: Hydrochlorothiazide resolved hypercalciuria and increased bone mineral density at a rate of 8% and 3% per year at the spine and hip, respectively. CONCLUSIONS: Hydrochlorothiazide treatment in hypercalciuric and osteoporotic men was associated with a rapid rebound increase in bone mineral density.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10215562&dopt=Abstract hydrochlorothiazide Microzide



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Optimization of urinary FDG excretion during PET imaging.

Moran JK, Lee HB, Blaufox MD.

Department of Nuclear Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.

Accumulation of fluorodeoxyglucose (FDG) activity in the urine interferes with the visualization of pelvic and, sometimes, abdominal abnormalities. Although this is a major problem, there are few data on the physiological variables affecting FDG urinary excretion that are critical to minimizing urinary FDG interference during PET imaging. METHODS: The excretion of FDG in urine was determined during 90 min in four groups of rats (n = 24) under the following conditions: normal, hydrated, hydrochlorothiazide treated and phlorizin treated. FDG clearance rates were measured in both normal and phlorizin-treated animals and compared with the glomeruler filtration rate measured with 99mTc-diethylenetriamine pentaacetic acid. We measured FDG excretion in 10 patients who had no known renal disease and were undergoing PET scanning (divided into two groups: hydrated and dehydrated) to relate the animal data to humans. RESULTS: The hydrated and phlorizin-treated animals had the highest excretion of FDG (39.68+/-5.00 % injected dose (%ID) and 45.64+/-9.77 %ID, respectively). Animals given the hydrochlorothiazide had the highest urinary volume, but the percentage excreted was comparable with the normal rats. Measurement of the clearance of FDG in animals before and after the administration of phlorizin determined the amount of FDG reabsorbed in the proximal tubules to be 56%+/-9.15%. The hydrated patients had a higher excretion of FDG than dehydrated patients (16.98+/-1.99 %ID versus 14.27+/-1.00 %ID, P < 0.021), and the volume of urine voided was significantly higher (P < 0.020). CONCLUSION: Hydrochlorothiazide increases urine volume without enhancing FDG excretion. The hydration of patients before PET scanning may lead to more FDG reaching the bladder. Reduction of bladder activity by more frequent voiding facilitated by increased urine volume in hydrated patients may be offset by increased delivery of FDG to the bladder. A preferable means of increasing urinary volume without increasing delivery of FDG to the bladder may be the use of a diuretic.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10450688&dopt=Abstract hydrochlorothiazide Microzide