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Analysis of captopril and hydrochlorothiazide combination tablet formulations by liquid chromatography.

Kirschbaum J, Perlman S.

A reverse-phase, high-performance liquid chromatographic (HPLC) procedure was developed for the simultaneous assay of captopril and hydrochlorothiazide in a combination tablet formulation. Gradient elution was used to quantify these two drugs, as well as the oxidized form of captopril, the disulfide. Tablets were extracted with methanol and, after centrifugation, were chromatographed. Initially, a methanol-0.05% aqueous phosphoric acid (25:75, v/v) solution was pumped at 2 mL/min into a phenyl column. After 8 min, the flow rate was increased to 4.5 mL/min and the methanol content of the mobile phase was increased to 45% to elute the disulfide. Detection was at 210 nm. Linearity and repeatability of all constituents were satisfactory. The hydrolytic degradation product of hydrochlorothiazide, 4-amino-6-chloro-1,3-benzene disulfonamide (also called the disulfonamide ), could be resolved in test solutions but was not visible in chromatograms of tablets carried through the gradient procedure even after storage at elevated temperatures for prolonged time periods prior to assay. The method can be automated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6376768&dopt=Abstract hydrochlorothiazide Microzide



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The effect of captopril on renal hemodynamics in hypertensive patients.

Duchin KL, Willard DA.

The effects of captopril (50 or 100 mg t.i.d.) with and without hydrochlorothiazide (25 or 50 mg/day) on renal blood flow, glomerular filtration rate, and the renin-angiotensin system were determined in 20 patients with mild to moderate essential hypertension. Normalization of blood pressure (supine diastolic blood pressure less than 90 mm Hg) was achieved in 12 patients after four or six weeks of captopril alone (147 +/- 3/100 +/- 3 mm Hg after a two-week placebo lead-in vs. 135 +/- 4/83 +/- 1 mm Hg after captopril, P less than 0.01/P less than 0.001). In these 12 patients, no significant alterations in renal blood flow or glomerular filtration rate were observed. Plasma renin activity increased two- to threefold above baseline levels, whereas serum and urinary aldosterone decreased by 23 and 35 per cent, respectively. Eight other patients remained hypertensive after four weeks of captopril alone (165 +/- 6/110 +/- 3 vs. 156 +/- 8/102 +/- 4 mmHg, P greater than 0.05/P less than 0.05). With addition of hydrochlorothiazide, blood pressure fell (P less than 0.001) to 129 +/- 7/84 +/- 3 mm Hg. Captopril alone or in combination with diuretic had no significant effect on renal hemodynamics. In the eight patients requiring diuretic, plasma renin activity remained constant after captopril monotherapy, but rose threefold after hydrochlorothiazide was added. The combination of these two antihypertensive agents significantly lowered serum aldosterone levels and urinary aldosterone excretion by 53 and 50 per cent, respectively. In summary, captopril with and without a thiazide diuretic reduced blood pressure without altering renal hemodynamics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6384279&dopt=Abstract hydrochlorothiazide Microzide



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Metabolic parameters after changing from hydrochlorothiazide to verapamil treatment in hypertension.

Lehtonen A, Gordin A.

The effect of verapamil on different metabolic parameters has been studied after changing the treatment of hypertension from hydrochlorothiazide to verapamil monotherapy. Verapamil 80 to 160 mg b.i.d. was continued for 6 months. The antihypertensive efficacy of verapamil was comparable to that of hydrochlorothiazide. Plasma total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and free fatty acids did not change significantly after the change in treatment; serum total cholesterol, LDL-cholesterol and HDL-cholesterol were 7.28 +/- 1.80 (m +/- SD), 5.11 +/- 1.59 and 1.65 +/- 0.39 mmol/l at the end of the hydrochlorothiazide period and 7.10 +/- 1.92, 5.09 +/- 1.70 and 1.56 +/- 0.35 mmol/l at the end of the verapamil period, respectively. The only statistically significant differences were the increases in total and LDL-cholesterol after three months on verapamil as compared to the basal values before diuretic therapy. Marked changes were not observed in fasting blood glucose, insulin or C-peptide values. Serum uric acid concentration decreased significantly (p less than 0.001) from 326 +/- 66 to 252 +/- 53 mmol/l, and serum potassium level increased significantly (p less than 0.01) from 3.5 +/- 0.4 to 3.9 +/- 0.3 mmol/l, on verapamil as compared to the diuretic period. Serum calcium decreased from 2.45 +/- 0.10 to 2.37 +/- 0.08 mmol/l (p less than 0.01) and calcium excretion increased significantly (p less than 0.01) to 5.43 +/- 2.55 mmol/24 h during verapamil administration from the level of 3.56 +/- 2.78 mmol/24 h whilst on the diuretic.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6389153&dopt=Abstract hydrochlorothiazide Microzide



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Comparative effects of hydralazine and captopril on the cardiovascular changes in spontaneously hypertensive rats.

Limas C, Westrum B, Limas CJ.

Vascular changes that develop during the course of blood pressure rise in spontaneously hypertensive rats (SHRs) can be modified by antihypertensive therapy. It is not known, however, whether there is selectivity in the structural response to specific antihypertensive drugs. This issue was examined by comparing the effects of a direct vasodilator (hydralazine) and a converting enzyme inhibitor (captopril) on morphologic aspects of the cardiovascular system. Male SHRs, 21 weeks of age, were given either hydralazine (HCl plus hydrochlorothiazide, captopril plus hydrochlorothiazide, or hydrochlorothiazide alone. Untreated age-matched SHRs and Wistar-Kyoto normotensive rats (WKYs) were used as controls. Animals were sacrificed at 27-28 weeks of age. Both hydralazine and captopril lowered significantly the blood pressure of SHRs, whereas hydrochlorothiazide alone was ineffective. The heart/body weight ratios were dramatically reduced in captopril-treated SHRs to below the level of WKYs; hydralazine induced only a very modest (5%) reduction, whereas the diuretic alone was ineffective. The morphology of the aortic intima improved dramatically in response to captopril and hydralazine and, to a lesser extent, hydrochlorothiazide alone. This effect becomes apparent within 6 weeks of treatment, and the only evidence of preexisting disease is the persistence of collagen in the subendothelium. Captopril and hydralazine, but not hydrochlorothiazide alone, reduce the thickness of the aortic media below that of normotensive controls. In addition, captopril and hydralazine improve the structure of small intrarenal vessels. There was a strong correlation between the relative effectiveness of the three pharmacologic agents in lowering blood pressure and in improving the changes of intrarenal vessels. These results highlight the capacity of antihypertensive therapy to arrest or reverse the structural sequelae of hypertension. In addition, they underscore the heterogeneity in the response of different components of the cardiovascular system, which, in part, reflects selectivity in the action of antihypertensive agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6391187&dopt=Abstract hydrochlorothiazide Microzide



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Mechanism for the high bias in the USP colorimetric assay for diazotizable substances in hydrochlorothiazide.

Sieh DH, Perlman S.

The USP XX colorimetric assay for the determination of diazotizable substances in hydrochlorothiazide was studied. Colorimetric assay results of hydrochlorothiazide bulk powder and captopril-hydrochlorothiazide combination tablets were found to have a high bias when compared with HPLC. A kinetic study of the diazotization step in the colorimetric assay and extrapolation of the free amine content, i.e., 4-amino-6-chloro-1, 3-benzenedisulfonamide, to time zero provided results which correlated favorably with those obtained by HPLC. The high bias of the colorimetric assay was shown to result from the formation of 4-nitroso derivative of hydrochlorothiazide, which is formed by acid hydrolysis during the diazotization step. Bendroflumethiazide and flumethiazide also showed increasing free amine content when the time of diazotization was increased.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6394743&dopt=Abstract hydrochlorothiazide Microzide