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At least 973 records · Page 54Linked to original sources
PubMed2001

Isolation of a 2:1 hydrochlorothiazide-formaldehyde adduct impurity in hydrochlorothiazide drug substance by preparative chromatography and characterization by electrospray ionization LC-MS.

Hydrochlorothiazide drug substance (19 lots) from five different manufacturers and four different countries of origin (USA, Italy, Hungary, and Croatia) were analyzed for the presence of impurities using a gradient elution chromatographic system, with acetonitrile-water as the mobile phase. Two known impurities of hydrochlorothiazide, 4-amino-6-chloro-1,3-benzenedisulfonamide and chlorothiazide, were separated, as well as a late-eluting, unknown, recurring impurity. The unknown impurity was isolated by preparative liquid chromatography followed by preparative thin-layer chromatography. It was characterized by electrospray ionization LC-MS as a 2:1 hydrochlorothiazide-formaldehyde adduct of the parent drug substance. The adduct is believed to form through the double condensation reaction of hydrochlorothiazide with excess formaldehyde during the parent compound's synthesis. The concentration of this impurity ranged from 0.02 to 1.1% (area%), and was above the 0.1% USP Other Impurities threshold in 16 of the 19 lots examined.

Antihypertensive Agents↗
PubMed1997

Analysis of ion transport perturbations caused by hu MDR 1 protein overexpression.

In previous work [Luz et al. (1994) Biochemistry 33, 7239-7249; Roepe et al. (1994) Biochemistry 33, 11008-11015] we measured changes in Cl- and HCO3--dependent pHi regulation for LR73 Chinese hamster ovary fibroblasts overexpressing mu MDR 1 protein. However, only one clonal cell line overexpressing the protein but not previously exposed to chemotherapeutic drug (i.e., a "true" transfectant) was examined, since very few MDR cell lines of this nature have been constructed. Recently [Hoffman et al. (1996) J. Gen. Physiol. 108, 295-313] we derived a series of true LR73/hu MDR 1 transfectants that are valuable for defining the MDR phenotype mediated by MDR protein alone, without the additional complexities introduced by exposing cells to chemotherapeutic drugs. Several independently derived clones from these and additional transfection experiments exhibit expression of MDR protein that is higher than that found in other true transfectants, and that is similar to the highest level of overexpression yet recorded for drug selected MDR cells. We examined altered Cl--dependent pHi regulation for these clones using improved single-cell photometry (SCP) techniques. Short-term isotonic Cl- substitution experiments performed in the presence of CO2/HCO3- reveal that mild overexpression of hu MDR 1 protein alters anion exchange (Cl-/HCO3- exchange or AE) for LR73 cells, as expected on the basis of previous work [Luz et al. (1994) Biochemistry 33, 7239-7249]. Interestingly, we now find that several independently selected high-level MDR 1 overexpressing clones acidify quite extensively upon isotonic exchange of Cl- and then rapidly alkalinize upon restoring normal [Cl-]. These data suggest that MDR protein may effectively compete against AE. The MDR protein effect is not dependent on HCO3-/CO2 or K+, is partially inhibited by verapamil, is completely inhibited by substituting K+ or N-methylglucamine (NMG+) for Na+ in the SCP perfusate but is not affected by 100 microM levels of amiloride, bumetanide, chlorothiazide, or stilbene. ATP depletion inhibits the MDR 1 effect. We are unable to restore normal AE activity for the MDR clones via manipulation of Cl- or HCO3- gradients. We thus suggest that MDR protein overexpression provides a novel Na+- and Cl--dependent pathway for transmembrane H+ transport. From analysis of ion dependency and inhibitor sensitivities, we conclude the transport is not via altered regulation of any known K+/H+, Na+/H+, or Cl-/HCO3- antiporters, Na+:K+:2Cl-, Na+:K+:2HCO3-, K+:HCO3-, or Na+:HCO3- co-transporters, or any combination of these. Thus, it appears to represent a novel ATP and Na+-dependent Cl-/H+ antiport process that (1) may be directly mediated by the MDR protein, (2) may represent the modulation of one or more currently unidentified ion transport proteins by MDR protein, (3) may be due to some combination of direct ion transport and regulation of ion transport, or (4) may represent unusual passive H+ movement in response to a novel Cl--dependent electrical perturbation that occurs during our Cl- substitution protocol. The results have important implications for understanding drug resistance mediated by MDR 1 overexpression, as well as the physiologic function of endogenously expressed MDR protein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Link between drug absorption solubility and permeability measurements in Caco-2 cells.

The objective of this investigation was to establish a relationship between drug permeability and solubility in vitro and the extent of drug absorption in humans. We selected drugs with varying permeabilities and solubilities with the aim of establishing a relationship between permeability and solubility measurements in vitro and the extent of absorption in vivo. Effective permeability coefficients of the model drugs (naproxen, phenytoin, propranolol, diltiazem, salicylic acid, ephedrine, cimetidine, chlorothiazide, and furosemide) at 37 degrees C and pH 7.2 were estimated using the Caco-2 cell line. Saturation solubilities of the model drugs were estimated at pH 7.2 and at 37 degrees C. Data obtained from the permeability and solubility experiments were employed in classifying the drugs into high and low permeability-solubility groups. The permeability coefficients ranged from 1x10(-7) to 4x10(-5) cm/s, and a good correlation was observed between the permeability coefficients in Caco-2 cells and percent absorbed in humans. Drugs in the high permeability, high solubility class are completely absorbed (90% or higher). The study results indicate that there is a strong link between permeability measured in Caco-2 cells, solubility, and fraction of drug absorbed in humans.

Absorption↗
PubMed1997

Estimation of the relative contribution of the transcellular and paracellular pathway to the transport of passively absorbed drugs in the Caco-2 cell culture model.

PURPOSE: The objective of this investigation was to determine, using the Caco-2 cell culture model, the extent to which the paracellular and transcellular routes contributed to the transport of passively absorbed drugs. An effort was also made to determine the controlling factors in this process. METHODS: We selected a heterologous series of drugs with varying physicochemical parameters for the investigation. Effective permeability coefficients of the model drugs (naproxen, phenytoin, salicylic acid, chlorothiazide, furosemide, propranolol, diltiazem, ephedrine, and cimetidine), at pH 7.2 and pH 5.4, were estimated using confluent monolayers of Caco-2 cells. The biophysical model approach, based on molecular size restricted diffusion within an electrostatic field of force, used by Adson et al. (1,2), was employed to estimate the permeability coefficients of the ionized and unionized forms of the drugs for the paracellular and transcellular route. RESULTS AND CONCLUSIONS: The permeability coefficients of the acidic drugs was greater at pH 5.4, whereas that of the basic drugs was greater at pH 7.2 and the transcellular pathway was the favored pathway for most drugs, probably due to its larger accessible surface area. The paracellular permeability of the drugs was size and charge dependent. The permeability of the drugs through the tight junctions decreased with increasing molecular size. Further, the pathway also appeared to be cation-selective, with the positively charged cations of weak bases permeating the aqueous pores of the paracellular pathway at a faster rate than the negatively charged anions of weak acids. Thus, the extent to which the paracellular and transcellular routes are utilized in drug transport is influenced by the fraction of ionized and unionized species (which in turn depends upon the pKa of the drug and the pH of the solution), the intrinsic partition coefficient of the drug, the size of the molecule and its charge.

Absorption↗
PubMed2003

A physiologic model for simulating gastrointestinal flow and drug absorption in rats.

PURPOSE: The development of a physiologically based absorption model for orally administered drugs in rats is described. METHODS: Unlike other models that use a multicompartmental approach, the GI tract is modeled as a continuous tube with spatially varying properties. The mass transport through the intestinal lumen is described via an intestinal transit function. The only substance-specific input parameters of the model are the intestinal permeability coefficient and the solubility in the intestinal fluid. With this physiologic and physicochemical information, the complete temporal and spatial absorption profile can be calculated. RESULTS: A first performance test using portal concentration data published in the literature yielded an excellent agreement between measured and simulated temporal absorption profiles in the portal vein. Furthermore, the dose dependence of a compound with solubility-limited fraction dose absorbed in rats (chlorothiazide) could be adequately described by the model. CONCLUSIONS: The continuous absorption model is well suited to simulate drug flow and absorption in the GI tract of rats.

Animals↗
PubMed1983

Thiazide diuretic effect on medullary collecting duct function in the rat.

The distal convoluted tubule is thought to be the principal site of action of thiazide diuretics, but, to our knowledge, there are no studies of their possible effects on collecting duct transport. Microcatheterization of the inner medullary collecting duct (IMCD) was carried out in rats undergoing a modest diuresis, natriuresis, and chloriuresis from hydro-chlorothiazide (2 mg/kg/hr) and in normal controls. Delivery of fluid, sodium, and chloride to the beginning of the IMCD was increased, but not significantly, while the load remaining at the papillary tip (end) of the duct was increased markedly by hydrochlorothiazide. Chloride reabsorption in the IMCD was affected most markedly; the chloride reabsorption between the beginning and end of the duct, as a fraction of the delivered load, was reduced from 70.4 +/- 5.4% in controls to insignificant amounts with hydrochlorothiazide (8.2 +/- 11.5%, P less than 0.001). The fraction of delivered sodium reabsorbed along the collecting duct was decreased from 78.5 +/- 4.9% in controls to 37.2 +/- 12.4% (P less than 0.005) in thiazide-treated rats and fluid reabsorption was decreased from 59.4 +/- 4.0% in controls to 31.9 +/- 5.1% (P less than 0.005). Small but significant potassium secretion into the IMCD occurred with hydrochlorothiazide, probably secondary to the marked increase in potassium delivery to the duct. Increased potassium excretion could account for a maximum of 50% of chloriuresis with hydrochlorothiazide. The observation that thiazide diuretics decrease chloride, sodium, and fluid reabsorption in the medullary collecting duct, like the recently demonstrated inhibitory effect of furosemide on this nephron segment, has significant implications for the rationale for diuretic use.

Animals↗
PubMed1996

The electroneutral Na(+)-(K+)-Cl- cotransport family.

Recently the molecular identification of the major electroneutral sodium-potassium-chloride entry mechanisms present on apical membranes of distal nephron segments of the mammalian kidney, on basolateral membranes of many non-renal epithelial cells and on certain non-epithelial tissues has been achieved. These transporters represent a major pathway for cellular uptake of chloride critical for chloride absorptive and secretory processes and for cell volume regulation following cell shrinkage. In the mammalian kidney, these sodium-coupled chloride cotransporters represent the major target sites for clinically useful diuretics including the "loop" diuretics [furosemide (Lasix) and bumetanide (Bumex)] and thiazides (such as, chlorothiazide, hydrochlorothiazide and metolazone). Although these Na-(K)-Cl cotransporters exhibit functional and pharmacological differences, they clearly evolved from a common ancestral gene and thus form a new gene family. This information is already advancing our understanding of the evolution, structure and function of these transporters both in renal handling of sodium and in hypertension.

Animals↗
PubMed1997

Defective renal calcium reabsorption in genetic hypercalciuric rats.

Idiopathic hypercalciuria is a frequent cause of calcium (Ca) containing kidney stones. We have previously shown that there is increased intestinal Ca absorption in selectively inbred genetic hypercalciuric stone forming (GHS) rats; however, excess Ca excretion persists when the rats are fed a low Ca diet indicating a defect in renal Ca reabsorption and/or increased bone resorption. To determine if GHS rats have a defect in renal Ca reabsorption we performed 14C-inulin clearance studies on parathyroidectomized female GHS and control (Ctl) rats. After three baseline collections, chlorothiazide (CTZ) or furosemide (FUR) was infused and three more collections were obtained. Both GFR and filtered load of Ca did not differ among the groups; however, fractional and absolute excretion (UcaV) of Ca was three times higher in GHS rats. The increased Ca excretion was not diminished by a low Ca diet. Urine flow rate nearly tripled in all rats after either FUR or CTZ. After CTZ, UcaV was decreased to a greater extent in GHS compared to Ctl rats. After FUR, UcaV was increased to a greater extent in Ctl rats compared to GHS rats. These data indicate that GHS rats have a defect in renal Ca reabsorption, in addition to increased intestinal Ca absorption. The effect of CTZ was greater, and that of FUR was smaller, in GHS compared with Ctl rats, suggesting that the defect in renal Ca handling might be at the level of the thick ascending limb.

Absorption↗
PubMed1997

Phosphate depletion diminishes Mg2+ uptake in mouse distal convoluted tubule cells.

Hypophosphatemia caused by phosphate depletion is associated with renal magnesium wasting. The cellular mechanisms of phosphate depletion were investigated in an immortalized mouse distal convoluted tubule (MDCT) cell line. Intracellular free Mg2+ concentration. [Mg2+]i was determined by microfluorescence. Mg2+ transport was assessed as a function of change in [Mg2+]i with time following placement of Mg(2+)-depleted cells into a buffer containing 1.5 mM magnesium. The uptake rate of Mg2+ into Mg(2+)-depleted cells cultured in normal phosphate, 1.0 mM, was 175 +/- 21 nM/second. Depletion of phosphate in the culture media was associated with a significant decrease in Mg2+ uptake, which was dependent on the degree of phosphate depletion and on the time cultured in phosphate-deficient media. Cells cultured for 16 hours in 0.3 mM and 0 mM phosphate possessed Mg2+ uptake rates of 105 +/- 18 nM/second and 15 +/- 12 nM/second, respectively. Diminished Mg2+ uptake was rapidly induced following placement in low phosphate and was fully reversed following readdition of phosphate to the culture media. The effects of phosphate depletion on Mg2+ uptake was post-translational in nature as fully up-regulated MDCT cells with maximal Mg2+ uptake was associated with a rapid decrease (within 30 min) in Mg2+ transport when placed in phosphate-deficient media. Although Mg2+ uptake is altered by the transmembrane voltage, diminished Mg2+ uptake associated with phosphate depletion was not dependent on changes in membrane voltage. Further, it was not associated with a sustained increase in intracellular Ca2+ concentration. Chlorothiazide, probably through hyperpolarization of the plasma membrane, stimulates Mg2+ uptake in normal. 283 +/- 23 nM/second, and phosphate-depleted cells, 203 +/- 29 nM/second, but failed to entirely correct the defective transport. These studies demonstrate that magnesium wasting associated with hypophosphatemia and phosphate depletion is due, in part, to diminished Mg2+ transport in the distal convoluted tubule. The evidence is that the actions of phosphate deficiency are through alterations of Mg2+ transport across the luminal membrane of the distal convoluted tubule cell.

Animals↗
PubMed2000

Evaluation of the effects of fixed combinations of sustained-release verapamil/trandolapril versus captopril/hydrochlorothiazide on metabolic and electrolyte parameters in patients with essential hypertension.

The objective of this randomised open, active controlled, cross-over study was to evaluate the effect of a fixed combination of verapamil SR/trandolapril compared to captopril/hydrochlorothiazide on serum lipids, lipoproteins, and other metabolic and electrolyte parameters in patients with essential hypertension. Another objective was to assess the efficacy and safety of both combinations. One hundred hypertensives with systolic blood pressure 140-209 mm Hg and diastolic blood pressure 90-119 mm Hg were evaluated after 16 weeks receiving a fixed combination of verapamil SR 180 mg/ trandolapril 2 mg (VT) or captopril 50 mg/hydro- chlorothiazide 25 mg (CH) both given once daily. Lipids and lipoproteins were assessed in duplicate on 2 consecutive days. The study was completed by 80 patients. There was no statistically significant difference between the two combined regimens with respect to low-density lipoprotein (LDL)-cholesterol for the 'intention-to-treat' population measured at the end of each treatment period (3.44 +/- 0.87 mmol/L with VT, and 3.46 +/- 0.86 mmol/L with CH). No differences were found for other lipid parameters like total cholesterol, triglycerides, apolipoproteins A1 and B, Lp(a). High-density lipoprotein (HDL)-cholesterol was significantly higher with VT (1.39 +/- 0.01 vs 1.35 +/- 0.01, P < 0. 03). Serum potassium declined while uric acid and glucose increased on CH. In conclusion, no significant differences were found in LDL-cholesterol and in other lipid parameters with the exception of HDL-cholesterol which was significantly higher on VT. Serum potassium declined while uric acid and glucose increased on CH (all significantly). Both fixed combinations were well tolerated. The incidence of adverse events was higher on CH. Both fixed combinations significantly lowered BP. Journal of Human Hypertension (2000) 14, 347-354

Adolescent↗
PubMed1978

beta-Adrenoreceptor-blocking agents and lipid metabolism.

1. Chlorothiazide twice a day plus atenolol, metoprolol, pindolol and propranolol in single daily doses administered to patients with essential hypertension achieved effective control of blood pressure. 2. Each beta-adrenoreceptor-blocking drug was associated with small, but significant, increases in plasma triglyceride concentrations and suppression of fasting immuno-reactive glucagon concentrations.

Adolescent↗
PubMed1998

Dietary salt regulates expression of Tamm-Horsfall glycoprotein in rats.

BACKGROUND: Tamm-Horsfall glycoprotein (THP) is a unique protein that is produced exclusively by cells of the thick ascending limb of Henle's loop (TALH). This study examined whether dietary salt altered renal THP production. METHODS: Male Sprague-Dawley rats were examined on days 1, 4, and 15 following placement in metabolic cages on diet that contained 0.3%, 1.0% or 8.0% NaCl. THP expression was quantified using Northern hybridization and Western blotting analysis. RESULTS: An increase in dietary salt produced sustained increases in relative steady-state mRNA and protein levels of THP in the kidney. Addition of furosemide, but not chlorothiazide, to animals on the 8.0% NaCl diet further augmented steady-state mRNA levels of THP. CONCLUSIONS: An increase in dietary salt and the loop diuretic, furosemide, increased expression of THP in the rat. The data support the involvement of this unique protein in the function of the TALH during changes in dietary salt. These findings also suggest that restriction of dietary salt may be beneficial in cast nephropathy in multiple myeloma and recurrent nephrolithiasis, two diseases in which THP can play an important pathogenetic role.

Animals↗
PubMed1977

Granulocyte adherence in the elderly.

Granulocyte adherence was measured in blood samples from 57 subjects more than 60 years old and 50 subjects 11 to 59 years old. In contrast to mean hemoglobin levels, leukocyte counts, and neutrophil counts, which were lower in the samples from the older group, granulocyte adherence was greater for the older subjects (mean = 78.4%) than for the younger subjects (mean = 65.7%). Ingested aspirin, chlorothiazides, methyldopa, digitalis, antihistamines, and barbiturates had no effect on granulocyte adherence. Alcohol ingestion within 24 hours was associated with reduced granulocyte adherence in the older group. Granulocyte adherence was slightly greater for aged black than for aged white subjects, but the difference was not statistically significant. Granulocytes of women showed greater adherence than those of men, and this difference persisted after menopause into the ninth decade of life.

Adolescent↗
PubMed1975

Treatment of intra-abdominal and abdominal wall desmoid tumors with drugs that affect the metabolism of cyclic 3',5'-adenosine monophosphate.

A female patient with Gardner's syndrome was treated with delta1-testololactone (200 mg daily) because of growth of a large desmoid tumor in the pelvis and lower abdomen and a tumor in a scar from a previous laparotomy. There was also pain and swelling of the left leg. An immediate effect of the drug therapy was complete relief of pain followed shortly thereafter by disappearance of the edema of the leg. After two months, the numerous sebaceous cysts were less prominent. The gross measurements of the diameter of the pelvic and lower abdominal tumor clearly demonstrated tumor shrinkage following therapy. Small polyps scattered over the rectal mucosa and numerous osteomata were not demonstrably affected. After one year of treatment with delta1-testololactone, a laparotomy for partial small bowel obstruction was necessary. Obstruction was caused by the involvement of small bowel mesentery and the bowel itself in a contracted residuum of dense fibrous tissue. Substitution of theophylline and chlorothiazide for the testololactone in Januray 1974 was followed by further diminution of the measurable abdominal and pelvic desmoids. All of these compounds synergize the action of 3',5'-adenosine monophosphate and at least the latter two may function by inhibiting the action of 3',5'-adenosine monophosphate diesterase.

Abdominal Muscles↗
PubMed1983

Thiazide-induced hyponatremia.

A 54-year-old woman had seizures and a focal neurologic deficit associated with hyponatremia induced by a thiazide diuretic. Prompt correction of hyponatremia by administration of hypertonic saline solution was followed by resolution of all neurologic defects. Metabolic balance studies and rechallenge with hydrochlorothiazide were undertaken to investigate the mechanism of the thiazide-induced hyponatremia. Abnormal vasopressin secretion was shown by a plasma vasopressin concentration of 0.5 microU/ml with a plasma osmolality of 268 mOsm/kg water after administration of a fluid challenge consisting of 45 ml/kg body weight. Rechallenge with chlorothiazide while on a sodium- and potassium-controlled balanced diet resulted in a decrease in serum sodium concentration (136 to 124 mEq/L) and plasma osmolality (283 to 261 mOsm/kg) within 18 hours. During this period, urine losses of monovalent cation were only 55 mEq and body weight was constant at 48.2 kg. A second challenge while the patient received all fluids and electrolytes intravenously again resulted in decreased serum sodium concentration (134 to 126 mEq/L) after urinary loss of only 69 mEq of cation. Thus this patient's hyponatremia cannot be accounted for solely by changes in external water and electrolyte balance; the rapidity with which changes were produced suggests that osmolar inactivation, probably intracellularly, may contribute to the severe hypotonicity seen in some patients.

Drug Combinations↗
PubMed1988

Desmoid tumors: experience with new modes of therapy.

The oncology group at Tulane has been instrumental in the development of isolated regional perfusion techniques for treatment of melanomas. The perfusion is usually accompanied by wide excision. Our success encouraged similar attempts with persistent, widely invasive desmoid tumors. We used regional chemotherapy in conjunction with wide excision in four cases. Neither the technique nor combination chemotherapy has been used previously against desmoid tumors. Tumor response occurred with nitrogen mustard and with combinations of actinomycin D, thiotepa, and methotrexate. Additionally, one apparent response followed testolactone and chlorothiazide therapy.

Adolescent↗
PubMed2005

Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation.

A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of diuretics, uricosurics, and/or their metabolites in human urine after extractive methylation. Phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by GC and identified by MS in the full-scan mode. The possible presence of the following drugs and/or their metabolites could be indicated using mass chromatography with the given ions: m/z 267, 352, 353, 355, 386, and 392 for thiazide diuretics bemetizide, bendroflumethiazide, butizide, chlorothiazide, cyclopenthiazide, cyclothiazide, hydrochlorothiazide, metolazone, polythiazide, and for canrenoic acid and spironolactone; m/z 77, 81, 181, 261, 270, 295, 406, and 438 for loop diuretics bumetanide, ethacrynic acid, furosemide, piretanide, torasemide, as well as the uricosurics benzbromarone, probenecid, and sulfinpyrazone; m/z 84, 85, 111, 112, 135, 161, 249, 253, 289, and 363 for the other diuretics acetazolamide, carzenide, chlorthalidone, clopamide, diclofenamide, etozoline, indapamide, mefruside, tienilic acid, and xipamide. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with reference spectra. This method allowed the detection of the abovementioned drugs and/or their metabolites in human urine samples, except torasemide. The limits of detection ranged from 0.001 to 5 mg/L in the full-scan mode. Recoveries of selected diuretics and uricosurics, representing the different chemical classes, ranged from 46% to 99% with coefficients of variation of less than 21%. After ingestion of the lowest therapeutic doses, furosemide was detectable in urine samples for 67 hours, hydrochlorothiazide for 48 hours, and spironolactone for 52 hours (via its target analyte canrenone). The procedure described here is part of a systematic toxicological analysis procedure for acidic drugs and poisons.

Diuretics↗