A Systematic Review and Meta-Analysis of Metolazone Compared to Chlorothiazide for Treatment of Acute Decompensated Heart Failure.

Treatment of volume overload in the setting of acute decompensated heart failure (ADHF) is typically achieved through the use of loop diuretics. While they are highly effective, some patients may develop loop diuretic resistance. One strategy to overcome this scenario includes sequential nephron blockade with a thiazide-type diuretic; however, it is unknown which thiazide-type diuretic used in this setting is most effective. A systematic review and meta-analysis were performed to compare the efficacy and safety of chlorothiazide with metolazone as add-on therapy in the setting of loop diuretic resistance for the treatment of ADHF. Literature searches were conducted through PubMed, Google Scholar, and Science Direct from inception through February 2020 using the following search terms alone or in combination: metolazone, chlorothiazide, acute decompensated heart failure, loop diuretic, and urine output. All English-language prospective and retrospective trials and abstracts comparing metolazone to chlorothiazide for the treatment of ADHF were evaluated. Studies were included if they analyzed urine output for at least 24 hours in patients with ADHF. Meta-analysis was conducted to evaluate pooled effect size by using a random-effect model. Primary outcomes included net and total urine output. Secondary outcomes included commonly reported safety outcomes. Four studies comparing the use of metolazone to chlorothiazide as an adjunct to loop diuretics to treat ADHF were included in the evaluation. Metolazone was as effective as chlorothiazide to augment loop diuretic therapy in ADHF in most studies with no pooled difference in net or total urine output. However, there were notable differences in baseline loop diuretic dosing, ejection fraction, renal function, race, and endpoint timing across studies. Adverse effects were commonly observed and included electrolyte abnormalities, change in renal function, and hypotension but were comparable between groups. Metolazone is as effective as chlorothiazide as add-on to loop diuretics in treating ADHF without an increase in safety concerns.

Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial.

OBJECTIVES: This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR). BACKGROUND: Combination diuretic regimens to overcome loop DR are commonly used but with limited evidence. METHODS: This study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss. RESULTS: The cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: -2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: -1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. -1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001). CONCLUSIONS: In this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253).

Effectiveness of blood pressure-lowering drug treatment by levels of absolute risk: post hoc analysis of the Australian National Blood Pressure Study.

OBJECTIVES: In many current guidelines, blood pressure (BP)-lowering drug treatment for primary prevention of cardiovascular disease (CVD) is based on absolute risk. However, in clinical practice, therapeutic decisions are often based on BP levels alone. We sought to investigate which approach was superior by conducting a post hoc analysis of the Australian National Blood Pressure (ANBP) cohort, a seminal study establishing the efficacy of BP lowering in 'mild hypertensive' persons. DESIGN: A post hoc subgroup analysis of the ANBP trial results by baseline absolute risk tertile. SETTING AND PARTICIPANTS: 3244 participants aged 35-69 years in a community-based randomised placebo controlled trial of blood pressure-lowering medication. INTERVENTIONS: Chlorothiazide500 mg versus placebo. PRIMARY OUTCOME MEASURES: All-cause mortality and non-fatal events (non-fatal CVD, congestive cardiac failure, renal failure, hypertensive retinopathy or encephalopathy). RESULTS: Treatment effects were assessed by HR, absolute risk reduction and number needed to treat. Participants had an average 5-year CVD risk in the intermediate range (10.5±6.5) with moderately elevated BP (mean 159/103 mmHg) and were middle aged (52±8 years). In a subgroup analysis, the relative effects (HR) and absolute effects (absolute risk reduction and number needed to treat) did not statistically differ across the three risk groups except for the absolute benefit in all-cause mortality (p for heterogeneity=0.04). With respect to absolute benefit, drug treatment significantly reduced the number of events in the high-risk group regarding any event with a number needed to treat of 18 (10 to 64), death from any cause with 45 (25 to 196) and major CVD events with 23 (12 to 193). CONCLUSION: Our analysis confirms that the benefit of treatment was substantial only in the high-risk tertile, reaffirming the rationale of treating elevated blood pressure in the setting of all risk factors rather than in isolation.

Intravenous Chlorothiazide Versus Enteral Metolazone to Augment Loop Diuretic Therapy in the Intensive Care Unit.

BACKGROUND: In cases of loop diuretic resistance in the intensive care unit (ICU), recommendations for a specific second-line thiazide agent are lacking. OBJECTIVE: To compare the effects of intravenous chlorothiazide (CTZ) and enteral metolazone (MET) on urine output (UOP) when added to furosemide monotherapy therapy in critically ill adults. METHODS: This was a retrospective cohort study conducted in the medical, surgical, and cardiothoracic ICUs of a quaternary medical center. The primary outcome was change in UOP induced by the study interventions compared with furosemide alone. Secondary outcomes included onset of diuresis, eventual need for hemodialysis, and incidence of adverse events. RESULTS: A total of 122 patients (58 in CTZ, 64 in MET) were included. When added to furosemide monotherapy, CTZ induced a greater change in UOP at 24 hours compared with MET (2405 vs 1646 mL, respectively; P = 0.01). CTZ also caused a more rapid dieresis: 1463 mL total UOP in the first 6 hours compared with 796 mL in the MET group ( P < 0.01). There were no differences found regarding ICU length of stay, need for renal replacement therapy, or survival to discharge. The CTZ arm required more potassium supplementation to maintain normokalemia (median 100 vs 57 mEq in MET; P = 0.02) and carried a higher cost (mean $97 vs $8, P < 0.01). CONCLUSION: Both CTZ and MET induced significant increases in UOP. CTZ induced a greater and more rapid change and was associated with higher cost and greater need for potassium replacement. Randomized controlled trials are needed to establish whether a preferable thiazide diuretic exists in this setting.

Efficacy of sequential nephron blockade with intravenous chlorothiazide to promote diuresis in cardiac intensive care infants.

BACKGROUND: Sequential nephron blockade using intravenous chlorothiazide is often used to enhance urine output in patients with inadequate response to loop diuretics. A few data exist to support this practice in critically ill infants. METHODS: We included 100 consecutive patients <1 year of age who were administered intravenous chlorothiazide while receiving furosemide therapy in the cardiac ICU in our study. The primary end point was change in urine output 24 hours after chlorothiazide administration, and patients were considered to be responders if an increase in urine output of 0.5 ml/kg/hour was documented. Data on demographic, clinical, fluid intake/output, and furosemide and chlorothiazide dosing were collected. Multivariable regression analyses were performed to determine variables significant for increase in urine output after chlorothiazide administration. RESULTS: The study population was 48% male, with a mean weight of 4.9±1.8 kg, and 69% had undergone previous cardiovascular surgery. Intravenous chlorothiazide was initiated at 89 days (interquartile range 20-127 days) of life at a dose of 4.6±2.7 mg/kg/day (maximum 12 mg/kg/day). Baseline estimated creatinine clearance was 83±42 ml/minute/1.73 m2. Furosemide dose before chlorothiazide administration was 2.8±1.4 mg/kg/day and 3.3±1.5 mg/kg/day after administration. A total of 43% of patients were categorised as responders, and increase in furosemide dose was the only variable significant for increase in urine output on multivariable analysis (p<0.05). No graphical trends were noted for change in urine output and dose of chlorothiazide. CONCLUSIONS: Sequential nephron blockade with intravenous chlorothiazide was not consistently associated with improved urine output in critically ill infants.

Efficacy of Intravenous Chlorothiazide for Refractory Acute Decompensated Heart Failure Unresponsive to Adjunct Metolazone.

STUDY OBJECTIVE: To assess the efficacy of intravenous chlorothiazide in patients with acute decompensated heart failure (ADHF) who were determined to be loop diuretic resistant and refractory to metolazone. DESIGN: Retrospective cohort study with patients serving as their own controls. SETTING: Large, academic, tertiary care hospital. PATIENTS: Forty-five patients with ADHF who had an inadequate response to high-dose loop diuretics and then received at least one dose of oral metolazone 5 mg or greater (metolazone index dose) followed by at least one dose of intravenous chlorothiazide 500 mg (chlorothiazide index dose) if the response to metolazone was considered inadequate, according to the institutional protocol, between February 4, 2013, and February 28, 2015, were included. If multiple doses of metolazone were administered, the last dose given before the chlorothiazide index dose was considered the index dose; the metolazone index dose had to have been administered more than 2 hours before the chlorothiazide index dose. MEASUREMENTS AND MAIN RESULTS: Data for a total of 90 diuretic doses (45 metolazone, 45 chlorothiazide) were included in the analysis. The median dose of loop diuretic in intravenous furosemide equivalents given over the 24-hour period before the metolazone index dose was 400 mg. The average length of stay was 34.7 days, and in-hospital mortality was 35.6% (16/45 patients). The primary end point of a net-negative urine output of 500 ml or greater during the 12 hours after the index dose occurred in 42.2% (19/45 patients) and 35.5% (16/45 patients) for the chlorothiazide and metolazone doses, respectively (p=0.581). The median 12-hour urine output following administration of metolazone was 810 ml (interquartile range [IQR] 866 ml) versus 1075 ml (IQR 940 ml) following administration of chlorothiazide (p=0.363). Compared with metolazone, the chlorothiazide doses did not result in an increase in urine output of at least 500 ml during the 12 hours following the dose relative to the 12 hours before the dose (31.1% vs 22.2%, p=0.754). No significant difference in achievement of net-negative urine output of 500 ml or greater during the 12 hours following the chlorothiazide or metolazone dose was noted (42.2% for chlorothiazide vs 35.5% for metolazone, p=0.581). CONCLUSION: The addition of intravenous chlorothiazide did not result in improved diuresis in patients with ADHF determined to be refractory to loop diuretics and adjunctive oral metolazone.

Stability of chlorothiazide sodium in polypropylene syringes.

PURPOSE: The stability of a solution of chlorothiazide injection diluted with sterile water and stored in polypropylene syringes under refrigerated conditions was investigated. METHODS: Chlorothiazide solutions were compounded by adding 20 mL of sterile water for injection to a 500-mg vial of chlorothiazide sodium for injection. Six batches of chlorothiazide solution (25 mg/mL) were compounded; 0.5-mL portions were transferred to 1-mL polypropylene syringes, which were sealed with a Luer tip cap and stored at refrigeration temperatures (2-8 °C) protected from light. Three batches were potency tested by stability-indicating high-performance liquid chromatography (HPLC) assay using a 0.5-mL sample from each batch at designated time points. Visual and pH testing were performed using the three remaining batches; the contents of two syringes per batch were combined and visually inspected for container integrity and solution color and clarity, with duplicate pH testing performed at each time point. RESULTS: HPLC analyses showed that the remaining percentage of the initial chlorothiazide content declined at an average daily rate of 1.4%, decreasing to 93% by day 6. All samples remained intact, clear, and colorless, with no visible particulate matter or precipitation observed throughout the study period. For all samples of chlorothiazide solution, pH values remained within the range of 9.2-10.0 throughout the 10-day study period. CONCLUSION: When packaged in 1-mL polypropylene syringes and stored protected from light at refrigerated conditions, a solution of chlorothiazide sodium injection in water was stable for six days.

Implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit to reduce medication expenditures.

PURPOSE: The implementation of a diuretic stewardship program in a pediatric cardiovascular intensive care unit (ICU) is described. METHODS: This retrospective study compared the use of i.v. chlorothiazide and i.v. ethacrynic acid in pediatric cardiovascular surgery patients before and after implementation of a diuretic stewardship program. All pediatric patients admitted to the pediatric cardiovascular service were included. The cardiovascular surgery service was educated on formal indications for specific diuretic agents, and the diuretic stewardship program was implemented on January 1, 2013. Under the stewardship program, i.v. ethacrynic acid was indicated in patients with a sulfonamide allergy, and i.v. chlorothiazide was considered appropriate in patients receiving maximized i.v. loop diuretic doses. A detailed review of the pharmacy database and medical records was performed for each patient to determine i.v. chlorothiazide and i.v. ethacrynic acid use and expenditures, appropriateness of use, days using a ventilator, and cardiovascular ICU length of stay. RESULTS: After implementation of diuretic stewardship, the use of i.v. chlorothiazide decreased by 74% (531 fewer doses) while i.v. ethacrynic acid use decreased by 92% (47 fewer doses), resulting in a total reduction of $91,398 in expenditures on these diuretics over the six-month study period and an estimated annual saving of over $182,000. The median number of days using a ventilator and the length of ICU stay did not differ significantly during the study period. CONCLUSION: Implementation of a diuretic stewardship program reduced the use of i.v. chlorothiazide and i.v. ethacrynic acid without adversely affecting clinical outcomes such as ventilator days and length of stay in a pediatric cardiovascular ICU.

Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance.

AIMS: Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head studies are lacking and equipoise exists regarding the preferred thiazide-like diuretic in this setting. We thus compared the effectiveness of oral metolazone versus intravenous (IV) chlorothiazide as add-on therapy to loop diuretics in hospitalized patients with ADHF and renal dysfunction. METHODS: This retrospective cohort study evaluated the efficacy and safety of oral metolazone versus IV chlorothiazide as add-on therapy to loop diuretics in patients hospitalized with ADHF and renal dysfunction. The primary endpoint was net urine output (UOP) at 72 h after initiation of thiazide-like diuretics. Safety endpoints included worsening renal function, hypotension, and electrolyte abnormalities. RESULTS: Fifty-five patients were enrolled with 33 patients receiving metolazone and 22 patients receiving chlorothiazide. There was no difference in median net UOP at 72 h in those receiving metolazone (4828 mL, interquartile range [IQR] 2800-7209 mL) compared to chlorothiazide (3779 mL, IQR 1885-6535 mL) (P = 0.16). There was no difference in hypotension, worsening renal function, hyponatremia, or hypokalemia (P = NS for all comparisons). Hospital length of stay was shorter in the metolazone cohort (median 7 days) compared to chlorothiazide (median 15 days), suggesting the chlorothiazide cohort was likely sicker. CONCLUSION: Sequential nephron blockade with either metolazone or chlorothiazide appears to be efficacious and safe in ADHF, renal dysfunction, and diuretic resistance. Given the considerable cost difference favoring oral metolazone, larger randomized studies are warranted to confirm our findings and to exclude the possibility of confounding by indication.

Comparison of the effects of combination diuretic therapy with oral hydrochlorothiazide or intravenous chlorothiazide in patients receiving intravenous furosemide therapy for the treatment of heart failure.

STUDY OBJECTIVE: To compare the effects of combination diuretic therapy with oral hydrochlorothiazide or intravenous chlorothiazide added to background intravenous loop diuretic therapy among patients hospitalized with heart failure. DESIGN: Single-center, retrospective review. SETTING: Cardiovascular hospital within a university-affiliated teaching institution. PATIENTS: Eighty-two patients hospitalized for heart failure between September 1, 2009, and August 31, 2011, who were receiving background intravenous furosemide therapy (total daily dose ≥ 160 mg); of those patients, 28 patients also received oral hydrochlorothiazide (median dose 25 mg [interquartile range 25-50 mg]), and 54 patients also received intravenous chlorothiazide (median dose 500 mg [interquartile range 250-750 mg]). MEASUREMENTS AND MAIN RESULTS: The primary outcome was change in 24-hour urine output. Urine output was recorded from the 24 hours before and after the first administration of either oral hydrochlorothiazide or intravenous chlorothiazide. Baseline characteristics, with the exception of female sex (p=0.01) and home loop diuretic dose (p=0.03), were similar between groups. Twenty-four-hour urine output before administration of the thiazide diuretic was not significantly different between groups. After treatment, 24-hour urine output increased in both groups; however, urine output increased to a lesser extent with oral hydrochlorothiazide (from mean ± SD 2104 ± 830 ml to 3038 ± 917 ml) than with intravenous chlorothiazide (from 2342 ± 978 ml to 4128 ± 1755 ml) (p=0.005). Hypokalemia occurred frequently in both groups: 71.4% and 83.3% in the oral hydrochlorothiazide and intravenous chlorothiazide groups, respectively (p=0.21). CONCLUSION: Among hospitalized patients with heart failure receiving intravenous loop diuretics, the addition of either oral hydrochlorothiazide or intravenous chlorothiazide augmented diuresis. Urine output increased to a greater extent with intravenous chlorothiazide compared with oral hydrochlorothiazide. However, given the positive response observed, ease of administration, and lower drug cost, oral hydrochlorothiazide should still be considered as an option for combination diuretic therapy in this patient population.

Variability in duration of outpatient diuretic therapy in bronchopulmonary dysplasia: a clinical experience.

We describe usual duration of outpatient diuretic therapy and duration of tapering of outpatient diuretics in infants with established bronchopulmonary dysplasia (BPD), and we identify factors associated with duration of diuretic taper. Infants with BPD discharged from the neonatal intensive care unit on diuretic therapy were identified and data were abstracted from clinical databases and medical records. BPD was defined as oxygen dependence at 28 days of life. Infants with chromosomal abnormalities or congenital heart disease and those requiring tracheostomy placement were excluded. Descriptive, univariate, and multivariate analyses were performed. Of 59 patients discharged on diuretic therapy, 10 were also discharged on oxygen. Median (25th, 75th percentiles) duration of outpatient diuretic therapy was 94 (69, 115) days and 30 (14, 84) days for duration of diuretic taper. Duration of therapy and duration of taper were significantly longer in infants discharged on oxygen. In Cox proportional hazards modeling, longer diuretic taper was associated with a higher dose of chlorothiazide at discharge, shorter interval to first outpatient visit, need for rehospitalization, and African-American race. Birth weight, gestational age, and various discharge therapies were not significantly associated with duration of taper after adjusting for these factors. In 58% of all patients, diuretics were tapered or discontinued at the first outpatient visit. This study demonstrated great variability in the duration of diuretic therapy and diuretic taper. Discharge on oxygen was associated with longer duration of diuretic therapy and taper. Active taper is successful in the majority of patients and should be considered in patients with stable BPD.

Relative bioavailability of chlorothiazide from mucoadhesive compacts in pigs.

The relative bioavailability of chlorothiazide from mucoadhesive polymeric compacts is compared to commercial oral suspension in pigs. A single-dose randomized study was conducted in 12 healthy pigs that are 9-10 weeks old. After overnight fasting, pigs were divided into two groups of six animals. To the first group, a reference product containing 50 mg of chlorothiazide suspension, and in the second group, test product (mucoadhesive compacts) chlorothiazide (50 mg) was administered with 75 mL of water via gastric tubes. Blood samples were collected between 0 to 24 h using catheters inserted into the jugular vein. Plasma was separated by protein precipitation, and chlorothiazide concentrations were determined using a high-performance liquid chromatography method. The mean Tmax and the Cmax of chlorothiazide following the administration of oral suspension and mucoadhesive compacts were 0.58+/-0.20 h and 682.97+/-415.69 ng/mL and 2.17+/-0.98 h and 99.42+/-124.08 ng/mL, respectively. The Kel and T1/2 of chlorothiazide were found to be 1.06+/-0.28 h(-1) and 0.70+/-0.21 h from suspension and 0.95+/-1.11 h(-1) and 2.05+/-1.90 h from the compacts, respectively. The Tmax of mucoadhesive compacts were significantly longer (p<0.05; 2.17 h) than the reference products (0.58 h), whereas the Cmax of compacts were significantly lower (99 ng/mL) than the reference product (683 ng/mL; p<0.05). The area under the curve (AUC) of compacts accounts only 50.15% (404.32+/-449.93 ng h/mL) of the reference product's AUC (806.27+/-395.97 ng h/mL). The relative bioavailability of the compacts was lower than that of the suspension, and this may be due to the narrow window of absorption for chlorothiazide.

Preparation and characterization of novel semi-interpenetrating polymer network hydrogel microspheres of chitosan and hydroxypropyl cellulose for controlled release of chlorothiazide.

Novel semi-interpenetrating polymer network (IPN) hydrogel microspheres of chitosan (CS) and hydroxypropyl cellulose (HPC) were prepared by emulsion-cross-linking method using glutaraldehyde (GA) as a cross-linker. Chlorothiazide (CT), a diuretic and anti-hypertensive drug with limited water solubility, was successfully encapsulated into IPN microspheres. Various formulations were prepared by varying the ratio of CS and HPC, percentage drug loading and amount of GA. Microspheres were characterized by Fourier transform infrared (FTIR) spectroscopy to investigate the formation of IPN structure and to confirm the absence of chemical interactions between drug, polymer and cross-linking agent. Scanning electron microscopy (SEM) was performed to study the surface morphology of the microspheres. SEM showed that microspheres have smooth surfaces. Particle size, as measured by laser light scattering technique, gave an average size ranging from 199-359 mum. Differential scanning calorimetry (DSC) was performed to know the formation of IPN structure. X-ray diffraction (X-RD) studies were performed to understand the crystalline nature of the drug after encapsulation into IPN microspheres. Encapsulation of drug up to 76% was achieved as measured by UV spectroscopy. Both equilibrium and dynamic swelling experiments were performed in 0.1 N HCl. Diffusion coefficients (D) for water transport through the microspheres were estimated using an empirical equation. In vitro release studies indicated the dependence of release rate on the extent of cross-linking, drug loading and the amount of HPC used to produce the microspheres; slow release was extended up to 12 h. The release data were also fitted to an empirical equation to compute the diffusional exponent (n), which indicated that the release followed the non-Fickian trend.

Effect of thiazide on renal gene expression of apical calcium channels and calbindins.

Thiazide diuretics are specific inhibitors of the Na-Cl cotransporter in the distal convoluted tubule (DCT). In addition to producing diuresis and natriuresis, they have a hypocalciuric effect. Recently, two apical calcium channels have been identified, transient receptor potential vanilloid 5 (TRPV5) and TRPV6; both are expressed in the DCT. We studied the effects of thiazides on mouse renal calcium handling and renal gene expression of TRPV5 and TRPV6, as well as calbindin-D(28k) and calbindin-D(9k), both of which are calcium transport facilitators located in the DCT. Upregulation of renal TRPV5 was found 4 h after intraperitoneal injection of chlorothiazide (CTZ) at both 25 and 50 mg/kg, but not at 100 mg/kg. Chronic treatment with CTZ at 25 mg/kg twice daily for 3 days, with or without salt supplementation of 0.8% NaCl and 0.1% KCl in the drinking water, caused hypocalciuria, but the gene expression patterns were different. Without salt supplementation, mice developed volume contraction and there were no changes in gene expression. When volume contraction was prevented by salt supplementation, there was a significant increase in gene expression of TRPV5, calbindin-D(28k), and calbindin-D(9k). Salt supplementation alone also induced significant upregulation of TRPV5, TRPV6, and both calbindins. The upregulation of TRPV5 by CTZ and salt supplementation and salt alone was further confirmed with immunofluorescent staining studies. Our studies suggest that thiazides induce hypocalciuria through different mechanisms depending on volume status. With volume contraction, increased calcium reabsorption in the proximal tubule plays the major role. Without volume contraction, hypocalciuria is probably achieved through increased calcium reabsorption in the DCT by the activation of a transcellular calcium transport system and upregulation of apical calcium channel TRPV5, calbindin-D(28k), and calbindin-D(9k).

Preparation of albumin microspheres by an improved process.

Albumin is widely used to prepare microspheres and microcapsules. In this study microspheres were prepared by the suspension crosslinking method for the first time in the absence of any surface active agent, using paraffin oil as the dispersion medium and formaldehyde as the crosslinking agent. The microspheres thus obtained were characterized using a Scanning Electron Microscope and found to be spherical and having a particle size distribution in the range 50-400 microns. A preliminary drug release study of chlorothiazide in-vitro indicated a diffusion controlled release of the drug. This method, being simple and cost effective, could be a promising technique for the large scale manufacture of microspheres.

Prolonged therapy by the combination of furosemide and thiazides in refractory heart failure and other fluid retaining conditions.

The efficacy and side effects of the combination therapy of thiazide and furosemide administered to patients with refractory heart failure, for a prolonged period of time, were assessed. Thirty-two patients were hospitalized during the years 1985-1991. Left heart failure (left ventricular ejection fraction (LVEF = 22.4% +/- 6.6%) was present in 26 patients, right heart failure in 3 patients, chronic renal failure, cirrhosis and bilateral pleural effusion were present each in one patient. Chlorothiazide 0.5 g daily was added to conventional therapy. Patients were monitored closely during hospitalization and later as outpatients. During hospitalization, addition of chlorothiazide caused a reduction of 4.8 +/- 4.0 kg in patients' weight, serum potassium decreased from 4.4 +/- 0.6 to 4.0 +/- 0.5 mmol/l (P < 0.005) and serum sodium from 139.0 +/- 4.7 to 136.8 +/- 5.5 mmol/l (P < 0.05). The duration of the combined therapy was 17.2 +/- 19.1 months. Thirteen patients had short treatment (1.6 +/- 0.8 months) and 19 patients had prolonged treatment (26.5 +/- 19.0 months). No specific characteristics distinguished patients in both groups. Thiazides were discontinued in 19 patients, 10 of which had side effects. In only 5 of the 19 patients treated for the prolonged period had thiazides to be discontinued because of side effects. Addition of thiazides to furosemide is efficacious in severe heart failure. The combination should be started during hospitalization. Many patients can be maintained on this combination for a prolonged period of time on an ambulatory basis.

The effect of chlorothiazide on bone-related biochemical variables in normal post-menopausal women.

OBJECTIVE: To evaluate the effects of short-term administration of chlorothiazide on fasting urinary hydroxyproline, an index of bone resorption, and other bone-related biochemical parameters in normal post-menopausal women. DESIGN: Subjects served as their own control before and after chlorothiazide treatment. SETTING: Subjects were recruited by advertisement. PARTICIPANTS: Thirteen healthy post-menopausal women with a mean age of 65 years. INTERVENTION: Each subject was given chlorothiazide 500 mg bd po for 7 days. Fasting blood and urine samples were obtained immediately before the commencement of chlorothiazide (day 1) and 2 and 7 days after starting chlorothiazide. RESULTS: Chlorothiazide decreased the urinary calcium/creatinine (mean value day 1, 0.267; day 2, 0.143; day 7, 0.135; P < 0.001) and hydroxyproline/creatinine (day 1, 0.0192; day 2, 0.0145; day 7, 0.0139; P < 0.02) molar ratios. CONCLUSION: Chlorothiazide decreases fasting urinary hydroxyproline, a marker of bone resorption in post-menopausal women. This observation supports a potential role for thiazide diuretics in the prevention of osteoporosis. The observed fall in urinary hydroxyproline is of the same order as that seen after treatment with estrogen or calcium supplements.

The effect of diuretics on components of the urinary kallikrein-kininogen-kinin system in man.

The effects of acute infusions of diuretics on components of the human urinary kallikrein-kininogen-kinin system were determined. Normal human subjects were given infusions of chlorothiazide and furosemide in doses calculated to produce a comparable natriuresis and diuresis. Alterations in urine electrolyte excretion, kinins, total and intact kininogen, and total active kallikrein were determined before and after the diuretic administration. Chlorothiazide caused a significant increase in total, but not active, kallikrein and had no effect on kinins and total or intact kininogen. Furosemide did not alter total or active kallikrein, or intact kininogen, but did decrease kinin and total kininogen excretion significantly. These differences in effects were not related to urinary sodium excretion or urinary flow because both diuretics produced comparable effects on these parameters. We conclude that acute infusions of diuretics do not activate the kallikrein-kininogen-kinin system and that some of the previously described effects of diuretics on this system may be related to their site of action.