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Simultaneous determination of losartan and hydrochlorothiazide in tablets by high-performance liquid chromatography.

Carlucci G, Palumbo G, Mazzeo P, Quaglia MG.

Dipartimeto di Chimica, Ingegneria Chimica e Materiali, Universita dell'Aquila, Coppito (L'Aquila), Italy. carlucci aquila.infn.it

A method for the simultaneous determination of losartan potassium and hydrochlorothiazide in tablets is described. The procedure, based on the use of reversed-phase high-performance liquid chromatography, is linear in the concentration range 3.0-7.0 microg ml(-1) for losartan and 0.5-2.0 microg ml(-1) for hydrochlorothiazide, is simple and rapid and allows accurate and precise results. The limit of detection was 0.08 microg ml(-1) for losartan and 0.05 microg ml(-1) for hydrochlorothiazide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10898169&dopt=Abstract hydrochlorothiazide Microzide



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The Interaction of Hydrochlorothiazide with Spirapril: A Novel Ace Inhibitor.

Johnson BF, Johnson J, Surve A, Smith H.

University of Massachusetts Medical Center, Worcester, USA, and Sandoz Research Institute.

In an open-label, randomized trial using a 3 x 3 Latin square design, single doses of 24 mg of the ACE inhibitor spirapril, or 50 mg hydrochlorothiazide, or their combination were given to 18 healthy male volunteers. No alteration in the area under plasma drug concentration curve (AUC), peak plasma level, time to peak level, or elimination half-life was detected for hydrochlorothiazide, spirapril, or its active metabolite, spiraprilat, during combination therapy. It was concluded that there was no significant effect of spirapril on single-dose kinetics of hydrochlorothiazide, nor of hydrochlorothiazide on single-dose kinetics of spirapril. Significant reductions in systolic blood pressure were noted 2--6 h after either spirapril or combination treatment, but no evidence of any synergistic effect of single-dose effects on blood pressure was seen during combination therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11835060&dopt=Abstract hydrochlorothiazide Microzide



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Protective effects of delapril combined with indapamide or hydrochlorothiazide in spontaneously hypertensive stroke-prone rats: a comparative dose-response analysis.

Boschi S, Vantaggiato G, Torri C, Zini I, Agnati LF, Zoli M, Biagini G.

Department of Biomedical Sciences, and Centre of Clinical Nutrition and Metabolic Diseases, University of Modena and Reggio Emilia, Italy.

In previous articles, we have shown that the combination of the angiotensin-converting enzyme (ACE) inhibitor delapril (12 mg/kg/day) and the diuretic indapamide (1 mg/kg/ day) was able to prolong the life span significantly in salt-loaded stroke-prone spontaneously hypertensive rats (SHRsp). Because this finding was partly dependent on the antagonism of salt-loading effects by pharmacologic induction of diuresis, which prevented any increase in blood pressure values, we decided to evaluate whether lower doses of the combination could be equally protective without changing the progression of hypertension. Thus, we studied several treatments with progressively lower doses of delapril (6, 3, or 1.5 mg/kg/day) combined with indapamide (0.5, 0.25, or 0.125 mg/kg/day) or hydrochlorothiazide (2.5, 1.25, or 0.625 mg/kg/day) in salt-loaded SHRsp. Salt-loaded untreated animals were considered to be the control group. In agreement with previous experiments, control rats reached 50% mortality approximately 7 weeks after the beginning of salt loading. The combination of delapril and hydrochlorothiazide at the two lowest doses was not able to delay animal death significantly, whereas treatment with delapril and indapamide at the lowest dose was effective (50% survival rate, 15 weeks). The groups treated with the highest dose of delapril and hydrochlorothiazide or with the intermediate or highest dose of delapril and indapamide did not reach 50% mortality by the end of the experiment, at 44 weeks of treatment (i.e., when animals reached age 1 year). Only the highest delapril and indapamide doses were able to increase diuresis, but for a relatively short period. None of the treatments was able to lower or control blood pressure levels adequately. Therefore, blood pressure levels by themselves were not predictive of rat mortality. In contrast, the maximal value of proteinuria in the weeks preceding death was inversely correlated with the survival time. In conclusion, this study shows that low doses of an ACE inhibitor in combination with a diuretic can be effectively protective in a model of severe hypertension, independent of any change in blood pressure levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10975589&dopt=Abstract hydrochlorothiazide Microzide



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Perindopril/Hydrochlorothiazide Combination in Hypertensive Patients Unresponsive to Hydrochlorothiazide Alone: A Double-Blind, Multicenter Study.

Weiss RJ, Sandall PG, Chrysant SG.

This study evaluated the efficacy and tolerability of perindopril erbumine, a long-acting ACE inhibitor, added to continuing hydrochlorothiazide (HCTZ) therapy in hypertensive patients (DBP of 95 to 114 mmHg) whose blood pressure did not normalize (supine DBP <90 mmHg) with HCTZ therapy alone. In this multicenter study, 252 patients received HCTZ 25 mg/day for 4 weeks; the 208 whose blood pressure did not normalize entered a 12-week, double-blind segment. These patients continued to receive HCTZ and were randomly assigned to perindopril (2, 4, or 8 mg) or placebo once daily. Mean supine SBP/DBP reductions from baseline for all HCTZ plus perindopril groups were significantly (p less-than-or-equal 0.05) greater than for HCTZ plus placebo. At the start of double-blind treatment, mean supine SBP/DBP readings were 146.1/97.0, 145.4/98.2 and 146.4/98.2 mmHg for the HCTZ plus perindopril 2-, 4-, and 8-mg groups, respectively, and 143.9/96.9 mmHg for HCTZ plus placebo group. At the final visit, mean reductions in supine SBP/DBP were 10.3/6.7, 9.6/8.0, and 9.3/6.3 mmHg for HCTZ plus perindopril 2, 4, and 8 mg, respectively, and 1.6/2.0 mmHg for HCTZ plus placebo. Significantly (p less-than-or-equal 0.05) more HCTZ plus perindopril patients (53.2%) than HCTZ plus placebo patients (24.5%) achieved an adequate response to therapy (supine DBP <90 mmHg or decrease by >10 mmHg). Incidences of adverse experiences were similar among treatment groups. There were no reports of first-dose hypotension. In patients unresponsive to HCTZ alone, the addition of perindopril at doses of 2--8 mg once daily provided safe and effective blood pressure reduction with no added side-effect liability.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11835076&dopt=Abstract hydrochlorothiazide Microzide



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Interaction and transport of thiazide diuretics, loop diuretics, and acetazolamide via rat renal organic anion transporter rOAT1.

Uwai Y, Saito H, Hashimoto Y, Inui KI.

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.

The renal tubular secretion of thiazides and loop diuretics via the organic anion transport system in renal tubules is required for them to reach their principal sites of action. Similarly, acetazolamide, a diuretic clinically administered for glaucoma, is excreted from the kidney by glomerular filtration and tubular secretion. In this study, we investigated the interaction and transport of these diuretics via the rat renal organic anion transporter rOAT1 by using Xenopus laevis oocyte expression system. p-[(14)C]Aminohippurate (PAH) uptake by rOAT1-expressing oocytes was inhibited in the presence of a thiazide (chlorothiazide, cyclothiazide, hydrochlorothiazide), a loop diuretic (bumetanide, ethacrynic acid, furosemide), or a carbonic anhydrase inhibitor (acetazolamide, ethoxzolamide, methazolamide). Dixon plot analysis demonstrated that the inhibition constant (K(i)) value was 1.1 mM for acetazolamide, 150 microM for hydrochlorothiazide, 9.5 microM for furosemide, and 5. 5 microM for bumetanide. Kinetic analysis revealed that acetazolamide inhibited rOAT1 competitively and that inhibition style of furosemide was a mixture of competitive and noncompetitive. [(14)C]PAH efflux was significantly enhanced when the rOAT1-expressing oocytes were incubated in the presence of unlabeled PAH, alpha-ketoglutarate, acetazolamide, chlorothiazide, or hydrochlorothiazide. rOAT1 stimulated acetazolamide uptake, which was inhibited by probenecid. Although the loop diuretics had little trans-stimulation effect on [(14)C]PAH efflux via rOAT1, the rOAT1-mediated furosemide uptake was observed. These findings suggest that rOAT1 contributes, at least in part, to the renal tubular secretion of acetazolamide, thiazides, and loop diuretics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10991988&dopt=Abstract hydrochlorothiazide Microzide