Methyclothiazide

To determine whether thiazides have a chronic antihypertensive effect, in the absence of diuresis, in patients with severe renal disease (creatinine clearance <30 mL/min) or in those receiving dialysis.

A search was performed in PubMed, CENTRAL, and International Pharmaceutical Abstracts, using MeSH terms and/or key words. MeSH terms included kidney failure, chronic and exploded terms hydrochlorothiazide, renal dialysis, and thiazides. Key words included thiazide*, hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, metolazone, methyclothiazide, bendroflumethiazide, hemodialysis, dialysis, kidney failure, renal failure, renal insufficiency, hypertension, vasodilation, vascular, and diuretics.

All relevant English-language publications were evaluated. Studies evaluating the efficacy of thiazides in renal insufficiency or dialysis were limited to those that included blood pressure measurements. Studies were included only if treatment duration was at least 4 weeks to evaluate chronic antihypertensive effects.

Thiazide diuretics are associated with a chronic reduction in peripheral vascular resistance secondary to a purported vasodilatory effect. However, few clinical studies have evaluated the chronic antihypertensive efficacy of thiazide and thiazide-like diuretics in patients with severe renal disease or those on dialysis. Agents studied include hydrochlorothiazide, chlorothiazide, indapamide, and metolazone, with results varying by drug and patient population. Hydrochlorothiazide 25–200 mg daily, chlorothiazide 500 mg twice daily, and indapamide 2.5 mg daily provided long-term blood pressure reduction in patients with severe renal disease who were not on dialysis. In studies involving patients on dialysis, hydrochlorothiazide 50 mg daily and metolazone 5 mg daily did not affect blood pressure; however, 1 study suggested that indapamide 2.5 mg daily may confer an antihypertensive effect. All studies were small (≤12 subjects) and had methodological limitations.

Thiazide diuretics may decrease peripheral vascular resistance independent of natriuresis. However, because current clinical data are inconclusive as to the efficacy of these agents at chronically lowering blood pressure in patients with severe renal disease or in those on dialysis, thiazide diuretics cannot be routinely recommended for this indication.

To study the drug-drug interaction of morinidazole and warfarin and its application, a sensitive and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of R-warfarin/S-warfarin in human plasma. In a random, two-period crossover study, 12 healthy volunteers received a single oral dose of 5 mg racemic warfarin in the absence and presence of morinidazole. Blood samples were collected according to a pre-designed time schedule. R-warfarin, S-warfarin and methyclothiazide were extracted with ethylether : methylenechloride (3 : 2), then separated on a Astec Chirobiotic V (150 mm x 4.6 mm ID, 5 microm) column using 5 mmol x L(-1) ammonium acetate (pH 4.0) - acetonitrile as mobile phase at a flow-rate of 1.5 mL x min(-1). The mobile phase was splitted and 0.5 mL x min(-1) was introduced into MS. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the negative ion mode. Quantification was performed using multiple reaction monitoring (MRM). The resolution of warfarin enantiomers is 1.56. The linear calibration curves for R-warfarin and S-warfarin both were obtained in the concentration range of 5 - 1 000 ng x mL(-1). Intra- and inter-day relative standard deviation (RSD) for R-warfarin and S-warfarin over the entire concentration range across three validation runs was both less than 10%, and relative error (RE) ranged from -4.9% to 0.7%, separately. The method herein described is effective and convenient, and suitable for the study of metabolic interaction between morinidazole and warfarin. The results showed that coadministration of warfarin with morinidazole did not affect the pharmacokinetics of either R-warfarin or S-warfarin.