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PubMed1997

Identification of chlorothiazide and hydrochlorothiazide UV-A photolytic decomposition products.

Methanol solutions of hydrochlorothiazide and chlorothiazide were irradiated with fluorescent UV-A lamps in order to simulate degradation under normal conditions. The degradation products were identified by comparison to synthetic standards featuring electrospray ionization mass spectroscopy, ultraviolet spectroscopy, and high performance liquid chromatography. The standards were characterized by high resolution fast atom bombardment MS and 1H NMR. The photolysis of chlorothiazide resulted in photodehalogenation products exclusively, while the irradiation of hydrochlorothiazide primarily yielded photodehalogenation products with significant yields of photodehydrogenation products and minor amounts of thermal hydrolysis products.

Chlorothiazide↗
PubMed1976

Relative effectiveness of chlorothiazide, reserpine and hydrallazine in spontaneously hypertensive rats.

1. Previous studies in this laboratory indicated that a mixture of anti-hypertensive agents in the drinking water controlled the blood pressure of spontaneously hypertensive rats (SHR). The present study was designed to determine which of the agents exerted the greatest anti-hypertensive effect. 2. Treatment was begun at 12 weeks of age in groups of eleven to seventeen rats with one of the following drugs: reserpine, chlorothiazide or hydrallazine. Blood pressures were recorded by the tail method under light ether anaesthesia every 2 weeks until the rats were approximately 70 weeks of age. 3. At 50 weeks of age, blood pressure of chlorothiazaide-treated rats averaged 40 mmHg below untreated control SHR; reserpine-treated SHR were also 40 mmHg lower than control rats, and hydrallazine-treated SHR were 85 mmHg below the control rats. 4. Rats in all groups gained weight normally and appeared in good health. Although all drugs were active, hydrallazine was considerably more effective than chlorothiazide or reserpine in the SHR.

Animals↗
PubMed1976

Effects of furosemide and chlorothiazide on blood pressure and plasma renin activity.

Short (2 weeks) and long (12 weeks) term effects of furosemide and chlorothiazide on blood pressure, plasma renin activity, and uric acid concentration were studied in 69 hypertensive patients. Both treatments caused significant reductions in blood pressure and increases in plasma renin activity and uric acid at 2 and 12 weeks in 6) normal renin patients; there was no difference between the effects of furosemide and that of chlorothiazide. Reduction in blood pressure in eight low renin patients who showed smaller changes in plasma renin activity and uric acid was not significant at 2 weeks but significant after 12 weeks of treatment.

Adult↗
PubMed1977

Potentiation of the response to vasopressin (pitressin) by treatment with a combination of chlorpropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus.

1 The effect of a combination of chloropropamide and chlorothiazide in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI) treated with low doses of vasopressin (Pitressin tannate in oil) was investigated with particular reference to the time course of response from the initiation of treatment. 2 Analysis of the relationship between water intake and body weight indicated no real correlation and body weight accounted for only 4.4% of the variation in water intake. It was therefore decided to use whole body responses as the index in preference to the response per unit body weight. 3 The daily administration of 5 mg chlorpropamide combined with chlorothiazide in the drinking water (4 mg/1) to Pitressin-treated DI rats potentiated the response to small doses of vasopressin (25 and 50 mu Pitressin/24 hours). Water intake was reduced by the drug combination by an average of 12.35 ml/24 h, but only on the second day of treatment was the decrease of any real magnitude (30 ml/24 h but otherwise 9 ml/24 h or less). Analysis of urine volume measurements gave similar results to those obtained for water intake and the potency ratio measured in terms of free water clearance was 1.26 (agreeing closely with the ratio for water intake which was 1.24). 4 A reduction in the solute excretion was observed only in those DI rats treated with the higher dose of Pitressin (50 mu/24 h) combined with the two drugs. 5 Possible reasons for the discrepancy between the effect of the combination of chlorpropamide and chlorathiazide on water metabolism in the DI rat and the DI patient are discussed.

Animals↗
PubMed1985

Chlorothiazide absorption in humans--possible example of Michaelis-Menten kinetics.

Chlorothiazide absorption was studied in five healthy adult males at 1,000, 750, 500 and 250-mg dose levels. The 24-hour-absorbed fraction fell from a mean value of 20.15% of the orally administered dose at the 250-mg level to 8.38% at 1,000 mg. Analysis of data at the four dosage levels for each subject is suggestive of the fact that chlorothiazide absorption is possibly an example of Michaelis-Menten kinetics. Possible factors responsible for the saturable absorption are discussed.

Adult↗
PubMedDate not supplied

Effects of frusemide, ethacrynic acid and chlorothiazide on the portal vein of normotensive and spontaneously hypertensive rats.

The effects of frusemide, ethacrynic acid and chlorothiazide were studied in the Wistar Kyoto (WKY) rats and spontaneously hypertensive rat (SHR) portal veins in vitro. Frusemide produced concentration-dependent contractions of the portal vein from both WKY control and SHR. The WKY were more sensitive (as judged by the EC50) whilst a greater maximal response was generated in the SHR. The contractile response to frusemide in WKY rats was attenuated reversibly by phenoxybenzamine whereas the latter was ineffective in the SHR. Ethacrynic acid produced reductions of the myogenic rhythmic contractions of the portal vein in a concentration-related manner in both WKY and SHR. The inhibitory action of ethacrynic acid was greater in the SHR than in the WKY control rats. The inhibitory action of ethacrynic acid was blocked by propranolol suggesting the involvement of beta adrenoceptors. Chlorothiazide, on its own, had no observable effect on the portal vein. However, it reduced the sensitivity of the vein to noradrenaline and K+. This reduction was greater in the SHR than in the WKY. It is concluded that some of the observed effects of these diuretics may contribute beneficially to their anti-hypertensive actions.

Animals↗
PubMed1980

Comparison of piretanide and chlorothiazide in the treatment of cardiac failure.

Piretanide, a diuretic that acts on the loop of Henle, was used to treat patients with cardiac failure. Over a three-day period it caused a significant dose related diuresis and weight loss. It was as effective as chlorothiazide in the control of cardiac failure and was well tolerated by the patients. Potassium loss was less than occurred with chlorothiazide. Its role in the treatment of cardiac failure requires further study and warrants further investigation. The study also showed that many patients with cardiac failure receive diuretic drugs which are not necessary.

Adult↗
PubMed1981

Dissociation of antipolyuric action and increase in plasma renin activity caused by chlorothiazide in Brattleboro rats.

The previous finding that chlorothiazide (about 250 mg/day) induces a sustained reduction in the polyuria of homozygous Brattleboro (BB) female rats, as well as an increase to about 250% of plasma renin activity was confirmed. Disruption of the renin-angiotensin system by either the angiotensin antagonist saralasin or the beta-blocking agent propranolol does not interfere with chlorothiazide antidiuresis. Each inhibitor reduces BB polyuria on its own, an effect which, however, may be explained by a possible interference with thirst.

Animals↗
PubMedDate not supplied

Determination of reserpine and chlorothiazide in commercial tablets by liquid chromatography with fluorescence and UV absorbance detectors in series.

A procedure is presented for determination of reserpine and chlorothiazide in commercial tablets by liquid chromatography (LC). Powdered sample, equivalent to the weight of one tablet, is dissolved in 10.0 mL dimethyl sulfoxide, the mixture is diluted to 100.0 mL with methanol, and the solution is filtered; 10 mL of the filtrate is then diluted to 100.0 mL with methanol. The standard solution is prepared in the same solvent mixture and contains the 2 ingredients in approximately the same quantities as in the diluted sample solution. For LC, a 7.5 cm long normal-phase column is used; mobile phase consists of methanol containing a small volume of an aqueous solution of 1-pentanesulfonic acid, sodium salt. Two detectors are arranged in series: a fluorescence detector set at 280 nm excitation and 360 nm emission quantitates reserpine and a UV absorbance detector set at 300 nm determines chlorothiazide. Several synthetic mixtures containing the 2 ingredients in amounts ranging from 80 to 120% of quantities declared in commercial tablets were analyzed by the proposed method. Two samples of commercial tablets were also analyzed; for each sample, 5 determinations were made on a ground composite of 20 tablets; 10 individual tablets were also analyzed. The composites were also analyzed by the current U.S. Pharmacopeia method for this product.

Antihypertensive Agents↗
PubMed1979

Double-blind trial of antihypertensive effect of chlorothiazide in severe renal failure.

A randomised double-blind crossover trial was done to assess the efficacy of chlorothiazide as an antihypertensive drug in patients with severe renal failure. There was a significant reduction in standing (mean drop 13/6 mm Hg) and supine (mean drop 13/5 mm Hg) blood-pressure, without postural hypotension. Chlorothiazide has a place in the management of hypertension in patients with severe renal failure and its antihypertensive effect is probably due to a change in peripheral vascular resistance and not to volume contraction.

Adult↗
PubMed1978

Increase in diuretic effect of chlorothiazide by probenecid.

Thiazide diuretics reach their presumed intraluminal site of action by active transport at the organic acid secretory site of the proximal tubule. Probenecid competes for this transport and might therefore affect the diuresis induced by thiazide at that site. Doses of 500 mg and 1 gm of chlorothiazide (CTZ) intravenously to 5 volunteers with probenecid pretreatment increased 8-hr rates of excretion of sodium and urine over that without probenecid. Eight-hour excretion of sodium after administering 500 mg of CTZ was 147 +/- 7.5 mEq and 257.9 +/- 16.4 mEq after CTZ with probenecid (p less than 0.0005). The volume of urine after CTZ was 728 +/- 37 ml and 1,886 +/- 301 ml after CTZ with probenecid (p less than 0.001). This increase was associated with prolongation of CTZ diuresis rather than increase in intensity. These results are consistent with CTZ reaching its site of action from the peritubular side or that prolonged exposure of the lumen to lesser amounts of filtered CTZ causes a greater overall effect.

Adult↗
PubMed1981

In vitro and in vivo release of microencapsulated chlorothiazide.

Microcapsules of chlorothiazide were prepared by the complex coacervate technique using gelatin and acacia as the wall-forming materials. The release of drug from the microcapsules and compressed tablets of microcapsules were studied in vitro and in vivo. In vitro dissolution was characterized by a rapid release of drug followed by a slower, more sustained release. The effects of pH and concentration are discussed. In vivo release of drug was determined from urine, and the volume of urine passed was studied.

Capsules↗
PubMed1985

Bioadhesive polymers as platforms for oral controlled drug delivery III: oral delivery of chlorothiazide using a bioadhesive polymer.

Bioadhesive polymers that bind to the gastric mucin or epithelial cell surface are useful in drug delivery for the purposes of (a) retaining a dosage from in the GI tract and (b) increasing the intimacy and duration of contact of drug with the absorbing membrane. Polycarbophil has previously been shown to have bioadhesive properties in the rat stomach and small intestine and was employed in the present study with a sustained-release delivery system to demonstrate improved drug delivery. Using chlorothiazide as the model drug, drug containing albumin beads were prepared and used as the sustained-release system. The beads were physically mixed with equally sized particles of polycarbophil and placed in a capsule to produce a bioadhesive dosage form. When the dosage form contacts the stomach, the gelatin capsule dissolves, exposing the polycarbophil to the bathing fluid. The bioadhesive polymer rapidly hydrates, retaining the albumin beads and attaching to the mucin coating of the stomach. Plasma drug levels in rats showed a longer duration of action and greater bioavailability for the bioadhesive dosage form than for either albumin beads or drug powder alone. The results suggest that the principle of bioadhesion can significantly improve therapy, due to a reduced rate of gastric emptying, an increase in contact time, and the intimacy of contact of the drug with the absorbing membrane.

Acrylic Resins↗
PubMed1988

Effect of temperature and fat content on the binding of hydrochlorothiazide and chlorothiazide to milk.

The binding of hydrochlorothiazide and chlorothiazide to milk has been measured. Experiments were carried out at 5, 15, 25, and 37 degrees C on bovine milk samples with fat contents of 0.75, 1.70, and 3.50%, using a wide range of drug concentrations to mimic concentrations encountered when a drug-milk freeze-dried system is utilized. Binding experiments with a 2.6% solution of casein were also carried out at the same temperature and concentration range of drugs. The binding to milk and casein was found to be not dependent on the concentration of drugs. The fat content of milk had no significant effect on the binding of both drugs. Higher binding was observed at lower temperatures than at higher temperatures for both drugs examined. The binding of both drugs to casein at 37 degrees C agrees fairly well with the corresponding binding to all types of milk at 37 degrees C. The potential significance of the findings in respect to preparation and in vivo delivery of drugs from drug-milk formulations is discussed.

Animals↗
PubMed1987

The phenomenon and cause of the dose-dependent oral absorption of chlorothiazide in rats: extrapolation to human data based on the body surface area concept.

The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when the doses were related to unit body surface area (BSA) but not on unit body weight, indicating similar interspecies absorptive capacity in terms of unit BSA. This finding may be partly rationalized by marked similarities in the reported solution transit time (2-3 hr) in the small intestine as well as in the calculated gross surface area of the small intestine per unit BSA (0.163 for rat and 0.132 for human). Contrary to the previous postulation of a specific absorption site, the drug was absorbed from different regions of the GI tract with apparent 1-hr absorption rates, studied by the in situ closed-loop method, in the following rank order: jejunum (34.6%) greater than duodenum (32.7%) greater than large intestine (20.1%) greater than ileum (18.0%) greater than stomach (12.4%). Different from the commonly assumed first-order absorption process, the intestinal loop absorption was concentration-dependent, suggesting a saturable mechanism. For example, the absorption rate at 0.008 mg/mL was higher than that at 0.2 mg/mL in ileal loops (61%, p less than 0.01) and jejunal loops (22%, p less than 0.1). In addition, the absorption rates at pH 6 and 7.4 were statistically identical, indicating a lack of ionization effect that is important in the passive absorption process. The solubility-limited absorption could probably be ruled out at doses below 2.55 mg/kg for rat and 125 mg for human in view of higher aqueous solubilities at 37 degrees C (e.g., 1.3 mg/mL at pH 7) found in the present study. Contrary to the previous hypothesis of low membrane permeability as a limiting factor for absorption, the "intrinsic" partition coefficient in 1-octanol/aqueous buffer was moderate, 0.6. Furthermore, the absorption in ileal and jejunal loops was enhanced by an apparent increase in mesenteric blood flow by caffeine. The existence of prolonged oral absorption in rats and humans is discussed.

Animals↗
PubMed1998

Distinct calcium channel isoforms mediate parathyroid hormone and chlorothiazide-stimulated calcium entry in transporting epithelial cells.

Some cells express multiple calcium channel isoforms that are likely to have distinct functions. The present study used molecular cloning and antisense techniques to identify calcium channel isoforms mediating calcium entry in mouse distal convoluted tubule (DCT) cells. The DCT is the major site of hormone- and diuretic-regulated calcium transport in the kidney. Cellular calcium absorption involves entry through apical membrane calcium channels that are sensitive to dihydropyridine-type calcium channel antagonists. Partial cDNA clones corresponding to one isoform of the calcium channel alpha1 pore-forming subunit, alpha1C, and one isoform of the calcium channel beta accessory subunit, beta3, were isolated by RT-PCR. Full-length transcripts were detected by Northern blot analysis in immortalized DCT cells. Antisense oligonucleotides complementary to the alpha1C sequence inhibited the rise of intracellular calcium ([Ca2+]i) induced by the thiazide diuretic, chlorothiazide (CTZ), but not that induced by parathyroid hormone (PTH). However, antisense oligonucleotides complementary to the beta3 sequence inhibited both CTZ- and PTH-induced rises of [Ca2+]i. beta3 antisense oligonucleotides also inhibited the membrane hyperpolarization induced by CTZ but not that triggered by PTH. Thus, members of the voltage-gated calcium channel family are expressed in DCT cells, where they are responsible for hormone- and drug-induced calcium uptake. The results suggest that DCT cells contain multiple calcium channels with distinct roles in the regulation of cellular calcium.

Animals↗
PubMed1994

Validated micellar electrokinetic capillary chromatography method for quality control of the drug substances hydrochlorothiazide and chlorothiazide.

A stability-indicating, quality control analysis method was developed and validated for the diuretic drug substances hydrochlorothiazide (HCTZ) and chlorothiazide (CTZ). Micellar electrokinetic capillary chromatography employing the anionic detergent sodium dodecyl sulfate at 30 mM in 20 mM sodium borate buffer pH 9.5 was utilized to separate and quantify the active drug substance HCTZ from CTZ and the common impurity, 4-amino-6-chloro-1,3-benzenedisulfonamide (DSA). A 100 microns I.D. uncoated fused-silica capillary was necessary to provide the sensitivity, i.e. 1 microgram/ml, for quantification of the DSA impurity. In this study, the linearity, precision, selectivity, accuracy, reproducibility and limit of quantitation for the method were investigated for HCTZ, CTZ and DSA. As the first validation of a drug substance method by capillary electrophoresis in this laboratory, unusual care was taken to insure reliability and ruggedness with multiple instruments, capillaries and analysts. Precision and reproducibility in the range of 1% R.S.D. was achieved by controlling subtle injection factors. These included minimizing the time in which the capillary ends were not immersed in buffer or sample during the injection process and minimizing the number of assays for each anode or inlet buffer vial. Stacking induced by differences in ionic strength between sample and capillary buffer was reduced by using a sample buffer concentration similar to that of the capillary buffer. Although stacking accomplished by using lower sample buffer concentrations increased sensitivity, reproducibility was decreased. Achievement of the 1% R.S.D. precision level means that many quality control assays for drugs with good absorbance characteristics can be validated with HPLC reproducibility and CE efficiency. These micellar electrokinetic capillary chromatography methods conform to the USA and European Pharmacopoeial validation guidelines.

Chlorothiazide↗