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Hemodynamic and neurohumoral factors in the response of hypertensives to hydrochlorothiazide therapy.

Fernandez PG, Snedden W, Nath C, Vasdev S, Lee C, Darke A.

Department of Medicine, Memorial University of Newfoundland, St John's, Canada.

We investigated the roles of the renin-angiotensin-aldosterone axis, the sympathetic nervous system, and the responses of the forearm vascular bed in the antihypertensive action of hydrochlorothiazide. Plasma renin activity, aldosterone, catecholamines, blood pressure, and forearm blood flow were measured before and after 8 weeks of hydrochlorothiazide therapy in 21 hypertensive patients whose blood pressures responded to the diuretic, and were then compared to a similar group of 19 hypertensives who did not respond to the thiazide therapy. Dietary salt intake was stable and comparable for the two groups. In the responsive patients, administration of the diuretic caused a significant fall in supine systolic and diastolic blood pressure and forearm vascular resistance, with constant forearm blood flow. No significant changes were noted in these parameters in the non-responsive group. Plasma renin activity and aldosterone concentration was increased in both groups to a comparable extent but plasma norepinephrine and epinephrine concentrations were increased to a greater extent (p less than 0.01) in the responsive group. Heart rate did not change significantly in either group in spite of significant increases in circulating epinephrine. The results are consistent with minimal thiazide-induced volume and salt depletion in either study group. The reduction in blood pressure and forearm vascular resistance observed in the responsive group appears to be the result of diminished target-organ sensitivity towards catecholamines and possibly angiotensin II.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3326694&dopt=Abstract hydrochlorothiazide Microzide



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Effect of antihypertensive therapy on a vascular change in genetically hypertensive rats.

Bruner CA, Webb RC.

Department of Physiology, University of Michigan Medical School, Ann Arbor 48109-0622.

Isolated tail arteries from stroke-prone spontaneously hypertensive rats (SHRSP), but not normotensive Wistar-Kyoto (WKY) rats, exhibit oscillatory contractions in response to norepinephrine. To establish whether this vascular abnormality is secondary to elevated arterial pressure, SHRSP and WKY were treated with hydralazine and hydrochlorothiazide from weaning to 4 months of age. Hydralazine and hydrochlorothiazide treatment significantly attenuated hypertension development in SHRSP (systolic blood pressure: control SHRSP = 219 +/- 9 mmHg; treated SHRSP = 143 +/- 5 mmHg at 15 weeks of age). Helically-cut tail artery strips from all rats were mounted in tissue baths for isometric force recording and exposed to norepinephrine (6 x 10(-10)-6 x 10(-6) M) for 20 min at each concentration. Oscillatory activity was defined as the sum of the magnitudes of all phasic contractions occurring during the final 10 min of NE incubation. There was no significant difference in the magnitude of oscillatory activity between hydralazine/hydrochlorothiazide-treated SHRSP and control SHRSP. From these results we conclude that norepinephrine-induced oscillatory activity in SHRSP is a primary vascular abnormality that is not secondary to high blood pressure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3436074&dopt=Abstract hydrochlorothiazide Microzide



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[The effect of selected disintegrants on the properties of three hydrochlorothiazide tablet formulations]

[Article in German]

Hennig D, Schubert E.

Sektion Pharmazie, Martin-Luther-Universitat Halle-Wittenberg.

The admixture of disintegrants was investigated in three different hydrochlorothiazide formulations with respect to tablet properties. Sodiumcarboxymethyl starchs, Na-CMS (Explotab, Primojel, Na-CMS AB-G.D.R.), cross-linked polyvinylpyrrolidone, CL PVP (Polyplasdone) and potato starch were applied. The investigations were especially aimed at the alteration of tablet properties in dependence on compressive force. Considering the values of decomposition and compressive strength Polyplasdone XL has been proved to be the most effective disintegrant for the hydrochlorothiazide formulations investigated. Potato starch shows the worst results. There are only slight differences between the three Na-CMS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3438336&dopt=Abstract hydrochlorothiazide Microzide



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Antihypertensive properties of tiapamil (RO 11-1781)--a new calcium antagonist--in patients with mild and moderate essential hypertension.

Velasco M, Morillo J, Urbina A, Kogler P, Leishman B, Pasquier M, Hernandez-Pieretti O.

Clinical Pharmacology Unit, Vargas Hospital, Caracas, Venezuela.

An open, non-comparative study, with a new calcium antagonist-tiapamil, was undertaken in 22 patients with mild and moderate essential hypertension (stage I-II WHO). After a two-week placebo period, patients were treated with tiapamil, 300-600 mg twice daily during a period of six weeks (Dose-finding period). Thereafter patients were continued on tiapamil during a 54 week period (Long-term follow-up). In some patients it was necessary to add the diuretic hydrochlorothiazide to obtain adequate control of the arterial hypertension. Monotherapy with tiapamil normalized supine diastolic blood pressure after the first six weeks in 17 of the 21 evaluable patients, and reduced it by greater than or equal to 10 mmHg (1.3 kPa) from baseline without normalization in two patients. In the two remaining cases the decrease was less than 10 mmHg. The optimal dose administered at six weeks in those patients who responded to treatment (normalization or decrease by greater than or equal to 10 mmHg.) was 600 mg/day in 32% of the cases, 750-900 mg/day in 47% and more than 900 mg/day in 21%. After completion of the dose-finding part, 19 patients continued treatment for a further 54 weeks. In 16 out of 19 patients hydrochlorothiazide was added to enhance the antihypertensive effect. All three patients who received tiapamil monotherapy throughout the trial, had normalized supine diastolic blood pressure on completing the study. In the 16 patients with the combination therapy, the addition of hydrochlorothiazide led in two patients to no further decrease in supine diastolic blood pressure, to an additional decrease by less than 10 mmHg in ten patients and by greater than or equal to 10 mmHg in four in comparison with the values obtained before starting combination therapy. At the end of the study 11 of these 16 patients had normalized supine diastolic blood pressure. The mean daily dose was 900 +/- 45 mg of tiapamil and 39 +/- 4 mg of hydrochlorothiazide. Both monotherapy and the combination regimen were well tolerated, and no effects attributable to drug interactions were observed. It may be concluded that tiapamil in oral doses of 300-600 mg twice daily is an effective antihypertensive agent with an excellent tolerance when administered for a period of 54 weeks.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3440635&dopt=Abstract hydrochlorothiazide Microzide



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Effects of formulation and food on the absorption of hydrochlorothiazide and triamterene or amiloride from combination diuretic products.

Williams RL, Mordenti J, Upton RA, Lin ET, Gee WL, Blume CD, Benet LZ.

Drug Studies Unit, University of California, San Francisco 94143-0446.

The absorption of three combination formulations of hydrochlorothiazide and either triamterene or amiloride was studied over a 5-year period in seven separate investigations under varying conditions of food and fasting. The most widely prescribed combination, containing 25 mg of hydrochlorothiazide and 50 mg of triamterene, demonstrated impaired absorption in the fasting state that was partially corrected by the addition of a breakfast high in fat. The increase in the fat content of the food appeared to correlate directly with the amount of both drugs absorbed from this formulation. The second formulation studied, a new combination formulation of 50 mg of hydrochlorothiazide and 75 mg of triamterene, demonstrated acceptable absorption in the fasting state that was not altered by the concurrent administration of a high-fat breakfast. The absorption of the third formulation, a combination of 50 mg hydrochlorothiazide and 5 mg amiloride, was acceptable in the fasting state and demonstrated a slight reduction in the absorption of the amiloride component when administered concurrently with a high-fat meal. The clinical and biopharmaceutic implications of these observations are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3508542&dopt=Abstract hydrochlorothiazide Microzide