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PubMed1990

High-performance liquid chromatographic method for studies on the photodecomposition kinetics of chlorothiazide.

A simple isocratic high-performance liquid chromatographic method for monitoring the photodecomposition of chlorothiazide in ethanolic solution is described. A 125-mm RP-18 column and an aqueous mobile phase containing 10% methanol and 2% acetic acid were used. The flow-rate was 1.0 ml/min and the UV detector wavelength 265 nm. Samples of 0.2 ml were taken from the reaction vessel and diluted 10-fold. The external standard method was used in the quantitative determinations. The decomposition appeared to proceed according to first-order kinetics. When the solutions were saturated with oxygen, the decomposition was greatly inhibited.

Chlorothiazide↗
PubMed1988

Renal effects of nifedipine in healthy normotensive volunteers. Effects of dose, formulation, duration of treatment, and chlorothiazide coadministration.

Renal effects of nifedipine were assessed in 3 groups of healthy normotensive volunteers. In the first group (N = 10), a single 20-mg dose of the slow-release formulation caused an increase in 8-h sodium excretion (P less than 0.025) and urine volume (P less than 0.005). Natriuresis (P less than 0.05) and diuresis (P less than 0.05) were still evident after 1 wk of pretreatment, but were significantly attenuated (P less than 0.05), in each case, compared to levels after a single dose. Natriuresis and diuresis after 2 wk of intake were indistinguishable from control levels. In another group of 8, a single 10 mg dose of the conventional formulation (capsule) effected natriuresis (P less than 0.01) and diuresis (P less than 0.001) similar to those associated with intake of a single 20-mg dose of the slow-release formulation. Natriuresis and diuresis associated with a 20-mg single dose of the conventional formulation were not different from control but were less than those following intake of the 10-mg dose (P less than 0.025 in each case). In the third group of 6, nifedipine, though weaker than chlorothiazide, promoted natriuresis (P less than 0.025) and diuresis (P less than 0.025) of the thiazide without augmenting its kaliuresis. In all the groups, there were no changes in creatinine clearance, and nifedipine did not alter kaliuresis. It is suggested that natriuretic and diuretic effects of nifedipine in healthy normotensive individuals are dependent on the dose employed, the formulation used, and the duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1980

The effect of dosage on the bioavailability of chlorothiazide administered in solution.

Chlorothiazide in solution was administered at four dose levels to three healthy male volunteers under controlled conditions. Excretion data indicated that the drug was poorly absorbed from the gastrointestinal tract. The 24 h recovery of the drug from urine fell from 33 to 6% as the dose was increased from 0.21 to 1.75 g per 70 kg of body weight. The cumulative amount of sodium excreted could be correlated with the cumulative amount of drug excreted, rather than with the dose administered. The electrolyte excretion response intensity could also be correlated with the amount of drug excreted. There was a poor linear relationship between response intensity and drug excretion rate. After higher doses the data suggested that the response was in the non-linear section of the dose response curve.

Biological Availability↗
PubMed1991

Regulation of cellular volume in rabbit ventricular myocytes: bumetanide, chlorothiazide, and ouabain.

Video microscopy was used to study the regulation of cell volume in isolated rabbit ventricular myocytes. Myocytes rapidly (less than or equal to 2 min) swelled and shrank in hyposmotic and hyperosmotic solutions, respectively, and this initial volume response was maintained without a regulatory volume decrease or increase for 20 min. Relative cell volumes (normalized to isosmotic solution, 1T) were as follows: 1.41 +/- 0.01 in 0.6T, 1.20 +/- 0.04 in 0.8T, 0.71 +/- 0.04 in 1.8T, and 0.57 +/- 0.03 in 2.6T. These volume changes were significantly less than expected if all of the measured volume was osmotically active water. Changes in width and thickness were significantly greater than changes in cell length. The idea that cotransport contributes to cell volume regulation was tested by inhibiting Na(+)-K(+)-2Cl- cotransport with bumetanide (BUM) and Na(+)-Cl- cotransport with chlorothiazide (CTZ). Under isotonic conditions, a 10-min exposure to BUM (1 microM), CTZ (100 microM), or BUM (10 microM) plus CTZ (100 microM) decreased relative cell volume to 0.87 +/- 0.01, 0.86 +/- 0.02, and 0.82 +/- 0.04, respectively. BUM plus CTZ also modified the response to osmotic stress. Swelling in 2.6T medium was 76% greater and shrinkage in 0.6T medium was 29% less than in the absence of diuretics. In contrast to the rapid effects of diuretics, inhibition of the Na(+)-K+ pump with 10 microM ouabain for 20 min did not affect cell volume in 1T solution. Nevertheless, ouabain decreased swelling in 0.6T medium by 52% and increased shrinkage in 1.8T medium by 34%. These data suggest that under isotonic conditions Na(+)-K(+)-2Cl- and Na(+)-Cl- cotransport are critical in establishing cell volume, but osmoregulation can compensate for Na(+)-K+ pump inhibition for at least 20 min. Under anisotonic conditions, the Na(+)-K+ pump and Na(+)-K(+)-2Cl- and/or Na(+)-Cl- cotransport are important in myocyte volume regulation.

Animals↗
PubMed1982

Effects of chlorothiazide on 1,25-dihydroxyvitamin D3, parathyroid hormone, and intestinal calcium absorption in the rat.

Previous studies have shown that thiazide diuretic agents reverse secondary hyperparathyroidism and reduce circulating 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and intestinal calcium absorption rates in patients with idiopathic hypercalciuria of the renal-leak variety. We have investigated whether thiazides can reverse the secondary increase in serum parathyroid hormone (PTH) and 1,25(OH)2D3 levels or intestinal calcium absorption induced by feeding rats a diet low in calcium (LCD, 0.02% calcium) but adequate in phosphorus and vitamin D. We found that LCD increased circulating immunoreactive PTH [chow vs. LCD, 0.52 +/- 0.06 vs. 1.06 +2- 0.1 (SE) ng/ml, P less than 0.001], 1,25(OH)2D3 (chow vs. LCD, 101 +/- 15 vs. 325 +/- 38 pg/ml, P less than 0.001), calcium uptake by everted gut sacs from duodenum, ileum, and descending colon, and net calcium absorption by descending colon studied in Ussing chambers in vitro. Chlorothiazide (CTZ) prevented the increase in PTH during LCD (chow + CTZ vs. LCD + CTZ, 0.69 +/- 0.07 vs. 0.73 +/- 0.06, NS) but not the increase in 1,25(OH)2D3 (chow + CTZ vs. LCD + CTZ, 88 +/- 10 vs. 277 +/- 31, P less than 0.002) or intestinal calcium transport. The drug caused no change in serum 1,25(OH)2D3 or intestinal calcium absorption in rats fed normal chow. In rats given exogenous 1,25(OH)2D3 to stimulate intestinal calcium absorption, CTZ reduced urine calcium excretion greatly but did not alter intestinal calcium absorption.

Administration, Oral↗
PubMed1989

Chlorothiazide effect on feedback-mediated control of glomerular filtration rate.

We examined the effect of chlorothiazide (CTZ) on the tubuloglomerular (TG) feedback system in anesthetized Sprague-Dawley rats. During infusion of CTZ (0.25 mg.kg body wt-1.min-1) we found that whole kidney glomerular filtration rate (GFR) decreased by 19% (1.0 +/- 0.1 vs. 0.8 +/- 0.1 ml/min; P less than 0.005). To asses the activity of the TG feedback system during CTZ administration we compared measurements of single-nephron (SN)GFR from tubule fluid sampled separately at proximal and distal sites. During CTZ administration, distally measured SNGFR decreased significantly by 16% (27.3 +/- 1.3 vs. 22.9 +/- 1.1 nl/min; P less than 0.025), whereas proximally measured SNGFR was unchanged. Thus the difference in SNGFR between proximal and distal determination increased during CTZ infusion (4.7 +/- 0.7 vs. 7.7 +/- 0.7 nl/min; P less than 0.025), indicating that CTZ suppresses GFR by TG feedback. Na, K, and Cl concentrations measured in the late proximal tubule fluid during control and CTZ infusions were similar. In early distal tubule fluid samples K and Cl concentrations were unaffected by CTZ infusion, whereas Na concentrations increased by 32% (47.9 +/- 2.7 vs. 63.1 +/- 2.4 mM; P less than 0.001). Proximal tubule microperfusion with 1.0 mM CTZ decreased transport rates of Na and water by approximately 40%, whereas the transport rate of Cl was not affected. In conclusion our results indicate that CTZ reduces GFR by activating TG feedback. The mechanism by which this occurs is in part due to an increase in the strength of the signal.

Absorption↗
PubMed1992

The effect of chlorothiazide on neurally mediated contraction of rabbit bronchial smooth muscle.

The neuromodulatory action of chlorothiazide (CTZ) was investigated in isolated rabbit bronchial smooth muscle (BSM) segments contracted with electrical field stimulation (ES). The tissues were placed in organ baths and stimulated with ES frequencies ranging from 1 to 75 Hz. CTZ (10(-4) to 10(-3) M) produced dose-dependent increases in ES-induced contractions. In the presence of 10(-3) M CTZ, the mean +/- SEM maximal tension (Tmax) induced by ES increased significantly (p less than 0.03) from 292.8 +/- 39.5 to 363.0 +/- 58.5 g/g tissue. BSM sensitivity to ES, expressed as the log ES frequency producing 50% of Tmax (i.e., log ES50) was also increased (p less than 0.001) in the presence of CTZ as indicated by a fall in the mean +/- SEM log ES50 from 1.05 +/- 0.05 to 0.804 +/- 0.09 Hz. The potentiating effect of CTZ on ES-induced contractions was independently blocked by either the neurotoxin, tetrodotoxin (4 x 10(-6) M), or the cholinergic antagonist, atropine (10(-5) M). In the presence of CTZ, the mean Tmax response to acetylcholine (ACh) was unaffected, whereas BSM sensitivity to the agonist increased significantly (p less than 0.001). On the other hand, the dose-response relationship to carbachol, a cholinergic agonist resistant to cholinesterase degradation, was unaffected by CTZ. In tissues pretreated with 10(-5) M neostigmine, an acetylcholinesterase (AChase) inhibitor, CTZ did not further augment either ES- or ACh-induced contractions. Taken together, these findings suggested that CTZ might be acting as an AChase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1974

On the hypocalciuric action of chlorothiazide.

Clearance experiments were performed in female mongrel dogs, either intact or thyro-parathy-roidectomized (T-PTX), under pentobarbital anesthesia, to examine the unusual hypocalciuric property of thiazide diuretics. The relationship between calcium clearance (C(Ca)) and sodium clearance (C(Na)) was determined in normal dogs, C(Ca) = 0.79 C(Na); constant infusion of chlorothiazide (CTZ) to provide drug concentrations in plasma of approximately 40 mug/ml modified this relationship; C(Ca) = 0.30 C(Na) (P < 0.001). The magnitude of the dissociating effect of CTZ on the urinary Ca/Na relationship was found to be most highly correlated with urinary drug concentration. Infusion of CTZ (1 mg/min) into one renal artery caused a unilateral decrease (25%) in C(Ca)/GFR while producing a unilateral increase (80%) in C(Na)/GFR. The same dose of CTZ in T-PTX dogs produced an increase in C(Na)/GFR without causing a change in C(Ca)/GFR. The defective response in T-PTX dogs could be ascribed to poor tubular secretion of the drug; when urinary drug concentrations were elevated in T-PTX dogs to the levels found in intact dogs (by infusing more drug), C(Ca)/GFR fell to an equivalent extent. T-PTX dogs showed substantially lower renal extraction of CTZ (42%) than intact dogs (57%); PTH administration to T-PTX dogs increased extraction toward normal (49%). The defective secretion of CTZ could not be attributed to either a decreased tubular maximum or a decreased renal blood flow.

Animals↗
PubMed1975

The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.

The acute effects of chlorothiazide (CTZ) on total (TSCA) and ionized (SCA-plus 2) serum calcium concentrations were studied in three groups of people: (a) eight subjects with normal parathyroid function; (b) six patients with hypoparathyroidism; and (c) two patients with hyperparathyroidism. Most subjects were studied on four occasions; at least 3 days intervened between studies on an individual subject. During each experiment the subject received an i.v. influsion of 5% dextrose in water at 1 ml/min from 8 a.m. to 4 p.m. Additions to the infusions were (a) none; (b) CTZ to deliver 3.33 mg/kg/h; (c) parathyroid extract to deliver 1 U/kg/h; or (d) both CTZ and parathyroid extract at the rates previously indicated. CTZ, when used, was added to the infusion at 10 a.m., parathyroid extract at 8 a.m. When CTZ was infused, the diuretic-induced losses of Na and water were replaced by i.v. infusion. In normal subjects 2 h after the start of CTZ infusion, there was a transient increase in SCA-plus 2 which coincided in time of day with a transient decrease in SCA-plus 2 in control experiments. At that time of day SCA-plus 2 was 4.18 plus or minus 0.12 mg/100 ml in control experiments and 4.56 plus or minus 0.08 in experiments with CTZ, P smaller than 0.025. The corresponding values for (TSCA) were 9.32 plus or minus 0.15 and 9.80 plus or minus 0.30, P smaller than 0.01. Such differences were not observed in the group with hypoparathyroidism. In the two patients with hyperparathyroidism, CTZ produced sustained increases in TSCA and SCA-plus 2. In normal subjects and those with hypoparathyroidism, CTZ plus parathyroid extract infusion resulted in sustained increases in both SCA-plus 2 and TSCA throughout the periods of observation when compared to experiments in which only parathyroid extract was infused, P smaller than 0.01 in all instances. The results suggest that the acute hypercalcemic action of CTZ requires the presence of circulating parathyroid hormone.

Adult↗
PubMed1992

Mechanism of calcium transport stimulated by chlorothiazide in mouse distal convoluted tubule cells.

Thiazide diuretics inhibit Na+ and stimulate Ca2+ absorption in renal distal convoluted tubules. Experiments were performed on immortalized mouse distal convoluted tubule (MDCT) cells to determine the mechanism underlying the dissociation of sodium from calcium transport and the stimulation of calcium absorption induced by thiazide diuretics. Control rates of 22Na+ uptake averaged 272 +/- 35 nmol min-1 mg protein-1 and were inhibited 40% by chlorothiazide (CTZ, 10(-4) M). Control rates of 36Cl- uptake averaged 340 +/- 50 nmol min-1 mg protein-1 and were inhibited 50% by CTZ. CTZ stimulated 45Ca2+ uptake by 45% from resting levels of 2.86 +/- 0.26 nmol min-1 mg protein-1. Bumetanide (10(-4) M) had no effect on 22Na+, 36Cl-, or 45Ca2+ uptake. Control levels of intracellular calcium activity ([Ca2+]i) averaged 91 +/- 12 nM. CTZ elicited concentration-dependent increases of [Ca2+]i to a maximum of 654 +/- 31 nM at 10(-4) M. CTZ reduced intracellular chloride activity ([Cl-]i), as determined with the chloride-sensitive fluorescent dye 6-methoxy-N-(3-sulfopropyl)quinolinium. The chloride channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 10(-5) M) abolished the effect of CTZ on [Cl-]i. NPPB also blocked CTZ-induced increases of 45Ca2+. Resting membrane voltage, measured in cells loaded with the potential-sensitive dye 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)], averaged -72 +/- 2 mV. CTZ hyperpolarized cells in a concentration-dependent and reversible manner. At 10(-4) M, CTZ hyperpolarized MDCT cells by 20.4 +/- 7.2 mV. Reduction of extracellular Cl- or addition of NPPB abolished CTZ-induced hyperpolarization. Direct membrane hyperpolarization increased 45Ca2+ uptake whereas depolarization inhibited 45Ca2+ uptake. CTZ-stimulated 45Ca2+ uptake was inhibited by the Ca2+ channel blocker nifedipine (10(-5) M). We conclude that thiazide diuretics block cellular chloride entry mediated by apical membrane NaCl cotransport. Intracellular chloride, which under control conditions is above its equilibrium value, exits the cell through NPPB-sensitive chloride channels. This decrease of intracellular chloride hyperpolarizes MDCT cells and stimulates Ca2+ entry by apical membrane, dihydropyridine-sensitive Ca2+ channels.

Animals↗
PubMed1989

Single-dose and steady-state pharmacokinetics of doxazosin given in combination with chlorothiazide to hypertensive subjects.

The pharmacokinetics of doxazosin were determined in hypertensive subjects after a single dose of 1 mg, and at steady-state while receiving doses of 1, 2, 4 and 8 mg of the drug daily. Chlorothiazide 500 mg once daily was administered as additional therapy throughout the study. After a single dose doxazosin was rapidly absorbed, with peak plasma drug concentrations (Cmax) occurring after 2.1 +/- 0.4 hours. The elimination half-life in plasma was 10.7 +/- 1.2 hours. These parameters remained essentially unchanged during maintenance administration of doxazosin at each of the dose levels. Calculations of Cmax and area under the concentration-time curve (AUC0----infinity) indicated that the pharmacokinetic disposition of the drug remained linear over the dose range 1 to 8 mg.

Adult↗
PubMed2001

Physicochemical properties of liposomes incorporating hydrochlorothiazide and chlorothiazide.

In an attempt to study the effect of hydrophobic drugs on liposome properties, multilamellar liposomes (MLV) consisting of phosphatidylcholine (PC) and incorporating chlorothiazide (CT) or hydrochlorothiazide (HCT), were prepared and characterized. Liposome size, surface charge, stability (in buffer, plasma and sodium cholate) and calcium-induced aggregation were studied for drug-incorporating liposomes and empty liposomes for comparison. Results show that drug incorporation affects liposome size, z-potential and stability in presence of buffer and plasma proteins. Indeed, drug-incorporating liposomes are slightly larger and have a negative surface charge, which increases with the amount of drug incorporated in the lipid membrane. The membrane integrity of drug incorporating liposomes (in absence and presence of plasma proteins) is significantly higher when compared with that of empty liposomes (for both drugs studied). On the contrary, vesicle membrane integrity in presence of sodium cholate and calcium induced vesicle aggregation, are not affected by drug incorporation. Leakage of thiazides from liposomes was demonstrated to be induced by dilution. Low amounts of thiazides (around 10-15%) are released when lipid concentration is over 0.1 mM, while further dilution increased drug leakage exponentially. Concluding, results demonstrate that the presence of HCT or CT in liposome membranes has a significant effect on main vesicle properties, which are known to influence vesicle targeting ability. Thereby, it is very interesting to continue studies in this respect, especially with more lipophilic drugs.

Antihypertensive Agents↗
PubMedDate not supplied

Encapsulation of chlorothiazide in whey proteins: effects of wall-to-core ratio and cross-linking conditions on microcapsule properties and drug release.

A model drug with limited water-solubility, chlorothiazide, was successfully encapsulated in whey protein-based wall systems cross-linked by glutaraldehyde-saturated toluene via an organic phase. The effects of drug content of the core-in-wall suspension and of cross-linking conditions on core retention and on microcapsule size, structure and core release properties were investigated. Spherical, surface cracks-free microcapsules ranging in diameter from approximately 200-1300 microm were obtained. Particle size distribution of microcapsules was affected by core content and cross-linking conditions. Core retention in microcapsules prepared at different cross-linking conditions and different wall-to-core ratios ranged from 48.9-81%, from 42.2-76.1% and from 37.3-67.2% in large (L), medium-size (M) and small (S) microcapsules, respectively. In all cases, drug crystals were physically entrapped and embedded throughout the cross-linked protein matrix. Core release from the microcapsules into enzyme-free simulated gastric fluid was governed by a diffusion-controlled mechanism and did not involve erosion or softening of the wall matrix. Rate of core release was significantly affected by a combined influence of core content, microcapsule size and cross-linking density. Complete core release from L, M and S microcapsule prepared at different wall-to-core ratios and cross-linking conditions ranged from 28.6-81.2 h, from 16.8-28.6 h and from 7.2-15.9 h, respectively. Results suggested that whey protein-based wall matrix cross-linked by GAST may provide significant opportunities in modulating the release of an encapsulated core with a limited water solubility.

Antihypertensive Agents↗
PubMed1976

Effect of chlorothiazide and furosemide diuresis on in vivo growth of Staphylococcus aureus in kidneys of mice.

In mice subcutaneous administration of the diuretics chlorothiazide or furosemide resulted in a prompt diuresis characterized by production of dilute urine within 30 min and lasting for 6 hr. In vivo proliferation or clearance of Staphylococcus aureus from the kidneys was only temporarily impaired during the time of maximum diuresis. When treatment was delayed until after phagocytosis was initiated, there was no effect on clearance. Clinically it would appear that bacterial proliferations in the renal parenchyma would not be promoted as a consequence of diuretic treatment.

Animals↗
PubMed1992

Effects of chlorothiazide on urinary excretion of calcium in clinically normal dogs.

Administration of thiazide diuretics has been recommended to prevent calcium oxalate urolith development in dogs. To evaluate the effects of thiazide diuretics in dogs, 24-hour urine excretion of calcium was measured in 6 clinically normal Beagles after administration of chlorothiazide (CTZ) for 2 weeks, administration of CTZ for 10 weeks, and administration of calcium carbonate and CTZ for 2 weeks. Compared with baseline values, 24-hour urine calcium excretion did not decrease after CTZ administration. When CTZ was given at a high dosage (130 mg/kg of body weight), urinary calcium excretion was significantly (P < 0.04) higher than baseline values. Based on these observations, we do not recommend CTZ for treatment or prevention of canine calcium oxalate urolithiasis.

Administration, Oral↗
PubMedDate not supplied

[Effect of sustained release alprenolol in hypertension uncontrolled by chlorothiazide and dihydralazine. Study in double blind (author's transl)].

In 20 hypertensive patients with functioning renal graft, sustained release alprenolol or placebo was given orally for 2 months, in combination with chlorothiazide and dihydralazine, after previous failure of these 2 last drugs. Blood pressure was normalized with alprenolol during the length of the study, but is was not with placebo. Mean plasma renine level decreased of 45 p. cent.

Administration, Oral↗
PubMedDate not supplied

Effect of nafenopin (SU-13437) on liver function. Influence on the hepatic transport of phenolphthalein glucuronide and chlorothiazide.

In rats treated with the hypolipidemic drug, nafenopin (NP), for 2 days the biliary excretion of phenolphthalein glucuronide (PPG) was markedly decreased, while in contrast that of chlorothiazide (CTZ) was enhanced. This suggests the existence of independent hepatic transport mechanisms for these two anions. For both PPG and CTZ blood disappearance curves showed an initial, rapid phase followed by a second, slow phase. The rapid phase for both compounds is affected only slightly by pretreatment with NP. Therefore, it is inferred that suppression of biliary excretion was attributable mainly to impairment of the liver-to-bile transport process. The increased bile flow induced by NP treatment was previously shown to be related to the biliary excretion of NP and its metabolites. Inhibition of NP choleresis by PPG may involve competition for biliary transport of these compounds. The marked hepatomegaly and choleresis seen after NP pretreatment was more evident in male rats than in females.

Animals↗
PubMed1983

Lack of hyperglycemic effect of chlorothiazide in normal rats fed diets with different carbohydrate content.

The effect of chlorothiazide (CT) on blood glucose and liver glycogen was investigated in rats fed either a standard, a carbohydrate-rich, or a carbohydrate-poor diet. CT did not alter blood glucose concentration or liver glycogen content in rats fed the carbohydrate-rich diet. After 5 days on the carbohydrate-poor diet, an oral glucose load produced significantly smaller rate constant for glucose disappearance from blood and significantly greater area below the glucose concentration--time curve than after a standard diet, but CT did not further alter these parameters. Nor did oral CT for 19 days alter glucose tolerance. In conclusion, CT in single dose or short term studies does not seem to alter glucose metabolism in the normal male rat.

Animals↗