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Original Article

A Pilot Study of Aerosolized Amiloride for the Treatment of Lung Disease in Cystic Fibrosis

List of authors.
  • Michael R. Knowles, M.D.,
  • Nina L. Church, M.S.,
  • William E. Waltner, M.D.,
  • James R. Yankaskas, M.D.,
  • Peter Gilligan, Ph.D.,
  • Malcolm King, Ph.D.,
  • Lloyd J. Edwards, M.S.,
  • Ronald W. Helms, Ph.D.,
  • and Richard C. Boucher, M.D.

Abstract

Excessive active absorption of sodium is a unique abnormality of the airway epithelium in patients with cystic fibrosis. This defect is associated with thickened mucus and poor clearance of airway secretions and may contribute to the pulmonary disease in these patients. To study whether the inhibition of excessive absorption of sodium might affect the course of lung disease in cystic fibrosis, we performed a double-blind, crossover trial comparing aerosolized amiloride (5 mmol per liter; 3.5 ml four times daily), a sodium-channel blocker, with vehicle alone.

Fourteen of the 18 adult patients initially enrolled in the study completed the one-year trial (25 weeks for each treatment). The mean (±SEM) loss of forced vital capacity (FVC) was reduced from 3.39±1.13 ml per day during treatment with vehicle alone to 1.44±0.67 ml per day during treatment with amiloride (P<0.04). A measured index of sputum viscosity and elasticity was abnormal during treatment with vehicle alone and improved during treatment with amiloride. Calculated indexes of mucociliary and cough clearance also improved during amiloride treatment. No systemic, respiratory, or subjective toxic effects of amiloride were noted.

We conclude from this preliminary study that aerosolized amiloride can be safely administered to adults with cystic fibrosis. The slowing of the loss of FVC and the improvement in sputum viscosity and elasticity suggest a beneficial clinical effect. Aerosolized amiloride deserves further evaluation in the treatment of lung disease in patients with cystic fibrosis. (N Engl J Med 1990; 322: 1189–94.)

Introduction

IN the airway epithelium of patients with cystic fibrosis, the combination of excessive absorption of sodium1 , 2 and defective regulation of the secretory chloride channel of the apical membrane3 4 5 6 probably leads to the dehydration of airway secretions, as reported in clinical studies.7 These ion-transport defects probably contribute to the abnormal rheologic features and poor clearance of airway secretions,8 obstruction of airflow, and chronic bacterial infection of the airways.9 The sodium-channel blocker amiloride inhibits the excessive absorption of sodium (and liquid) in vitro1 , 10 and in vivo11 when applied to the luminal surface of the airway epithelium of patients with cystic fibrosis. These findings suggested that the long-term inhalation of amiloride might improve the viscosity, elasticity, and clearance of secretions, protect the airways from intraluminal obstruction, and improve airflow.11 , 12

The present study was designed as a preliminary investigation of the safety and efficacy of long-term treatment with aerosolized amiloride for airway disease in cystic fibrosis. A double-blind, crossover design was employed, and each treatment period (25 weeks) was preceded by a course of parenteral antibiotics to standardize the recent use of antibiotics among the patients and enhance the delivery of the aerosol.

Methods

Study Subjects

Eighteen patients were recruited into the study. Guidelines for selection included the diagnosis of cystic fibrosis on the basis of clinical criteria and the results of sweat tests for chloride, partial pressure of arterial oxygen greater than 55 torr without chronic retention of carbon dioxide, normal renal function, and no long-term use of systemic steroids. Informed consent was obtained under the auspices of the Human Rights Committee of the University of North Carolina.

Study Design

A randomized, double-blind, crossover study was designed.* The nominal length of each treatment period was 25 weeks. Each period was preceded by 10 to 14 days of parenteral treatment with tobramycin and ceftazidime. Treatment with all respiratory medicines (oral and aerosolized antibiotics and bronchodilators) was withdrawn, and was withheld during the study period unless guidelines for reinstitution were met.

Two base-line measurements of pulmonary function were obtained on separate days after the completion of parenteral antibiotic treatment. Each patient also had a physical examination, blood-chemistry tests, chest radiography, quantitative microbiologic testing of sputum, complete blood count, urinalysis, and 24-hour measurement of urinary aldosterone excretion at the same time. Aerosol treatment was initiated after base-line measurements were obtained, and physical examinations, spirometry, quantitative microbiologic testing, measurements of serum electrolytes, and renal-function testing were also performed at three-to-six-week intervals from week 3 to week 25. At the end of each period (at about week 25), duplicate or single measurements were obtained as at base line, and aerosol treatment was then discontinued. Sputum was obtained from six patients for biorheologic studies of viscosity and elasticity at the end of each period.13 A two-to-four-week washout period and treatment with parenteral antibiotics preceded the second period of aerosol therapy.

According to specific criteria, unscheduled visits and interventions with oral antibiotics (except quinolones) and bronchodilators were allowed for the treatment of mild exacerbations of disease. The therapy was discontinued after two to four weeks, but patients could receive a second (or third) course of therapy. Criteria were also established for episodes of illness (usually major hemoptysis) that required "extraordinary intervention" with parenteral antibiotics. Safety was monitored by a blinded, nonparticipating observer who periodically reviewed coded clinical and laboratory data.

Aerosol Solution and Delivery of the Drug

Amiloride hydrochloride was dissolved in 0.3 percent saline (5 mmol per liter; pH 7.0). A nebulizer (DeVilbiss 646) and compressed-air generator (Pulmoaide, DeVilbiss) were used to nebulize and deliver 3.5 ml of drug or vehicle (0.3 percent saline) four times daily. With proper inhalational technique, this approach deposits an effective dose of amiloride (about 0.1 mmol per liter) on airway surfaces.14 , 15

Tests

Pulmonary-function tests (spirometric measurements before and after use of a bronchodilator and measurement of single-breath diffusing capacity [Gould 2400], measurement of arterial blood gases [Radiometer ABL 30], and plethysmographic measurement of lung volumes [Jaeger]) were performed according to American Thoracic Society standards16 at least three hours after the patient had arisen and three hours after the administration of the aerosol. Quantitative bacterial cultures of sputum were performed with a technique equivalent to quantitation using mucolytic agents.17 , 18 Sputum for biorheologic testing was obtained three hours after the administration of aerosol at the end of each study period in a manner designed to minimize salivary contamination.13 Rheologic studies used the technique of the magnetic oscillating sphere,19 and the percentage of solids was measured after microwave drying. Chest radiographs were graded according to a published scoring system.20 The urinary aldosterone level was measured by radioimmunoassay (Smith-Kline BioScience). Twelve pulmonary and systemic symptoms or measures (chest tightness; shortness of breath; wheezing; cough during the first two hours of the day, during the rest of the day, or during sleep; hemoptysis; color, consistency, and volume of sputum; appetite; and general well-being) were graded weekly by the patients, using an ordinal scale and a diary designed for the study.*

Statistical Analysis

In both treatment periods 3 of the 14 patients who completed the study had episodes of acute illness that qualified for extraordinary parenteral antibiotic therapy. After the intervention, the patients resumed aerosol therapy and completed the treatment period so that toxicity could be evaluated. In these three patients, only data collected before the extraordinary intervention were used in our analyses of efficacy.

The use of complete, balanced analysis-of-variance or multiple-analyses-of-variance methods was precluded because of the irregular timing of visits. Analyses were performed by two statistical methods selected before the study. In method 1, the mean change from base line (i.e., the difference between the mean base-line value and the mean of the values during treatment) with vehicle and amiloride was computed for each subject. In method 2, the slopes from unweighted simple linear regression (including base-line data) for each subject for each period and for each variable (forced vital capacity [FVC] and forced expiratory volume in one second [FEV1], for example) were analyzed. The difference between the slopes during treatment with vehicle and treatment with amiloride was computed for each subject. Comparisons of treatments as assessed by methods 1 and 2 were based on these differences in unweighted, two-tailed, paired t-tests and signed-rank tests, which yielded similar outcomes except as indicated. A separate analysis was performed for each response variable. To test for differences in rheologic features and bacterial counts in the sputum obtained near the end of each study period, paired t-tests were employed with log-transformed data. All hypotheses regarding efficacy and safety were specified before the analysis began. A Type I error rate of 0.05 was used to judge statistical significance. All but one investigator remained blinded to the assigned treatments during the analyses. Results are reported as means ±SEM unless otherwise indicated.

Results

Table 1. Table 1. Clinical Characteristics of the 14 Patients Who Completed the Study.*

Of the 18 patients who were recruited, 3 withdrew from the study (after 3, 10, and 18 weeks) because they were unable to follow the protocol. One other patient withdrew (after 13 weeks) after hemolytic anemia associated with Epstein–Barrvirus seroconversion developed; a subsequent trial of aerosolized amiloride in the patient produced no adverse effect. Table 1 outlines the clinical features of the 14 patients who completed the study.

Seven of the 14 patients were randomly assigned to vehicle and 7 to amiloride for the first period. The mean duration of treatment with vehicle and amiloride was well matched (24.7 weeks in each period), and there was no seasonal bias in either treatment period. There was an equal degree of compliance during treatment with vehicle (79.0±6.0 percent of scheduled doses) and amiloride (80.3±4.7 percent).

Efficacy

Table 2. Table 2. Changes in Mean Forced Vital Capacity (FVC) during the Study Periods.

Before treatment with vehicle and treatment with amiloride, the base-line FVC (3.66±0.28 and 3.60± 0.29 liters, respectively) and FEV1 (2.25±0.24 and 2.22±0.25 liters, respectively) were nearly identical. The mean decrease in FVC from base line (analyzed according to method 1) during treatment with vehicle (296±79 ml) was approximately twice as large as that during treatment with amiloride (160±53 ml; P<0.04). The data on FVC are shown in Table 2. The mean decrease in FEV1 during treatment with vehicle (291±95 ml) was not significantly different from that during treatment with aerosolized amiloride (202±51 ml; P ≈ 0.20). After treatment with an inhaled bronchodilator, a similar pattern was observed for FVC and FEV1. There was a larger loss of FVC during treatment with vehicle (222±50 ml) than during treatment with amiloride (117±57 ml; P = 0.03 by signed-rank test and 0.11 by t-test), but the decrease in FEV1 during treatment with vehicle (225±50 ml) was not significantly different from the decrease during treatment with amiloride (170±54 ml; P = 0.32 by signed-rank test and 0.23 by t-test). No carry-over effects between the two periods were detected. The mean duration of expiration for FVC was the same during the two periods (10.0±0.7 seconds).

Figure 1. Figure 1. Changes in Mean Forced Vital Capacity (FVC) and Forced Expiratory Volume (FEV1) during the Study Periods.

Panel A shows the mean (±SEM) base-line FVC and the mean slope of FVC as a function of time during treatment with vehicle (□) and amiloride (■). The slopes reflect 7.3 and 7.1 measurements per patient (n = 14), including base-line values, for vehicle and amiloride, respectively (P<0.04 for the differences in slopes). FVC decreased by 3.39±1.13 ml per day during treatment with vehicle, and by 1.44±0.67 ml per day during treatment with amiloride.

Panel B shows the mean (±SEM) base-line FEV1 and the mean slope of FEV1 as a function of time during treatment with vehicle (□) and amiloride (■). The slopes reflect 7.3 and 7.1 measurements per patient (n = 14), including base-line values, for vehicle and amiloride, respectively (P = 0.09 for the differences in slopes). FEV1 decreased by 3.21±1.11 ml per day during treatment with vehicle, and by 2.09±0.86 ml per day during treatment with amiloride.

The analysis of slopes (method 2) is illustrated in Figure 1. The mean rate of decrease in FVC during treatment with vehicle (3.39±1.13 ml per day) was reduced by more than half during treatment with amiloride (1.44±0.67 ml per day; P<0.04). The difference in the rate of decrease in FEV1 between the two periods was not statistically significant (vehicle, 3.21 ±1.11 ml per day; amiloride, 2.09±0.86 ml per day; P ≈ 0.09).

Table 3. Table 3. Biorheologic Features of Airway Secretions after Long-Term Treatment with Vehicle and Amiloride.*

Matched pairs of sputum samples obtained from six patients who completed both periods without a need for parenteral antibiotics were analyzed for biorheologic features21 and the results compared with normal values (Table 3). Log G*1 and log G*100, indexes of the mechanical impedance of mucus, were different for amiloride and vehicle. The loss tangents (tan δ 1 and tan δ 100), indexes of the ratio of viscous to elastic strain, were not different. Calculated indexes of mucociliary clearance21 and cough clearance22 differed significantly between vehicle and amiloride (Table 3). The rheologic values of sputum obtained during long-term treatment with aerosolized amiloride approximated normal values. The solid content of the sputum obtained during treatment with vehicle (7.5±3.2 percent) did not differ from that of the sputum obtained during treatment with amiloride (8.3±4.1 percent).

Several monitored indexes were not altered by amiloride treatment. Measures of nonspirometric lung function at the beginning and end of each treatment period were available only for the patients who completed both periods without parenteral antibiotics (n = 11). There was no difference between the vehicle and amiloride periods with respect to changes in arterial blood gases (alveolar—arterial gradient, 0.3±1.7 and 1.1 ±1.9 torr, respectively) or diffusing capacity (−0.9±0.5 and +0.3±0.8 ml per mm Hg per minute). Bacterial densities — the number of organisms (log10) per milliliter of sputum —were similar in the sputum from patients without antibiotic intervention and in the sputum from all patients. Total bacterial densities were 8.16±0.18 and 8.13±0.20, and densities of Pseudomonas aeruginosa were 7.96±0.21 and 7.79±0.35 during 12 to 25 weeks of treatment with vehicle and amiloride, respectively. No differences were noted in bacterial densities or the incidence of positive cultures for Staphylococcus aureus between the vehicle and amiloride periods.

Interventions

Table 4. Table 4. Summary of Drug Interventions in Each Study Period.*

The therapeutic interventions are summarized in Table 4. The use of oral antibiotics, bronchodilators, and prednisone did not differ between the vehicle and amiloride periods when it was analyzed on the basis of individual or grouped data.

Safety

Table 5. Table 5. Indexes of Systemic Salt and Water Metabolism during the Study Periods.*

No evidence of pulmonary or systemic toxicity emerged from analyses of pulmonary function, symptoms, physical examinations, or laboratory tests (Table 5). No difference in the incidence of aspergillus or candida species in sputum cultures was observed during treatment with amiloride, nor was any new microbial or multidrug-resistant organism identified.

Discussion

Several features appeared to be critical in the design of this study of long-term inhalation of amiloride in the treatment of lung disease in patients with cystic fibrosis. First, effective delivery of the drug to the airway surfaces was required. The concentration of amiloride in airway-surface liquid needed to produce effective blockade (more than 90 percent inhibition) of the absorption of sodium in patients with cystic fibrosis is about 0.01 mmol per liter (the median effective dose is 0.001 mmol per liter).1 , 10 , 11 Because amiloride is rapidly cleared from human airways (half time, about 40 minutes),14 , 15 a peak concentration of about 0.5 mmol per liter on airway surfaces four times daily is required to maintain an effective concentration. Optimizing the system of nebulizing the liquid, we achieved a peak concentration of about 0.08 mmol per liter of amiloride in the bronchi of patients with cystic fibrosis.15 We accepted this dose because respirable amiloride was available only in this formulation and we expected compliance to be poor if dosage frequency exceeded four times daily. Second, because no information is available regarding outcome variables pertinent to aerosolized diuretic agents, we selected measures of outcome on the basis of the hypothesis that amiloride would inhibit the excessive absorption of sodium and would hydrate secretions and improve their biorheologic properties and clearance from the airways. The results of a spirometric test were selected as the chief criteria of efficacy because the test measures both the retention of airway secretions23 and the functional benefit to the patient.9 Measurements that assess the rheologic features of sputum more directly were undertaken to explore the feasibility of performing them in a therapeutic study. Third, the outcome of this initial study of the long-term use of an aerosolized diuretic agent in humans involved questions of drug safety. We monitored our patients for any adverse effect of amiloride as a potassium-sparing diuretic agent and for deleterious effects on pulmonary function. Finally, because amiloride is not approved for use in children, we selected a cohort of adults.

The long-term inhalation of amiloride produced no pulmonary or systemic toxicity. No patient had either drug-related bronchoconstrictive symptoms or reductions in gas exchange or diffusing capacity that might indicate alveolar toxicity. No adverse effects of amiloride were seen on hematologic or liver-function tests or measurements of vascular volume, renal function, or serum electrolytes. These findings are consistent with those from animal studies24 , 25 (and Boucher RC, et al.: unpublished data).

Amiloride aerosol appears to slow the decline in pulmonary function associated with cystic fibrosis. The rate of loss of FVC was reduced by approximately 50 percent during the amiloride period as compared with the vehicle period. However, a significant difference in FEV1 was not observed. This relatively smaller change in FEV1 parallels the pattern of spirometric changes reported in studies exploring the efficacy of antibiotics in patients with cystic fibrosis.26 Because the effects of vehicle and amiloride were compared after parenteral antibiotic therapy, the decline in FVC during vehicle may have been more rapid than usual.

We analyzed drug interventions to determine whether the effects of amiloride on spirometric features could be attributed to differences in medical therapy. It is clear that these effects were not due to excessive intervention with bronchodilators and oral antibiotics during treatment with amiloride.

The mechanism of amiloride's beneficial effect is uncertain. The effect does not appear to reflect a direct bronchodilating activity of amiloride, because differences in FVC between the study periods persisted after the administration of beta-agonist bronchodilators, and no acute bronchodilating effect of amiloride has been observed in patients with cystic fibrosis.14 , 27 The effect also does not appear to reflect a direct antimicrobial action of amiloride,28 29 30 because bacterial densities did not differ between study periods. Therefore, it is more likely that amiloride exerts a beneficial effect at least in part by increasing the clearance of secretions, as has been reported in short-term studies.27

We hypothesized that amiloride might increase the clearance of airway secretions by improving their biorheologic properties. There are few available data that directly measure the rheologic features of sputum as an index of therapeutic efficacy.31 To test the feasibility of performing such measurements, we collected sputum specimens at the end of each period and studied them in a blinded fashion, using techniques developed by Puchelle et al.13 Indexes of sputum rheologic features were better after long-term treatment with amiloride than after treatment with vehicle, and they were similar to values reported for healthy subjects.21 The biorheologic changes predict increases in the rates of mucociliary transport and cough clearance that are consistent with those reported in short-term studies of aerosolized amiloride.27

We did not detect the change in the percentage of solids in dried sputum that would be expected if amiloride improved the rheologic features of mucus by increasing its water content. This finding may reflect the insensitivity of the techniques employed to detect small but functionally important changes in the water content of sputum. Further studies are required to establish the mechanism of amiloride's effects on the viscosity, elasticity, and clearance of mucus.

In conclusion, this study of a small number of patients provides preliminary evidence that amiloride may be moderately effective in the treatment of adults with cystic fibrosis and established lung disease.

Funding and Disclosures

Supported by grants from the Cystic Fibrosis Foundation (RRDP, RO15, and A014), the National Institutes of Health (HL34322 and MOI RR00046), the Canadian Cystic Fibrosis Foundation, and the Mr. and Mrs. James Snyder Fund.

In accordance with the Journal's policy, the authors have stated that Drs. Knowles and Boucher have an interest in the patent for the use of aerosolized amiloride in the treatment of lung disease in cystic fibrosis.

We are indebted to Al Spock, M.D., and Al Driver, M.D., for patient referrals; Brian Boehlecke, M.D., Floyd Denny, M.D., and Arnold Smith, M.D., for discussions of study design; Kathleen McCarroll, Ph.D., for assistance in planning data collection and storage; Nancy Anderson for assistance in design of the computer data base; Beth Funk, M.D., David Henke, M.D., Richard Mann, M.D., Raphael Perez, M.D., and Lorraine Trow, M.D., for patient management; Betty Hornaday for special assistance with pulmonary-function testing; Richard Kowalski, Ph.D., for assistance in lung scans; David Delany, M.D., and Al Parker, M.D., for reviewing and scoring chest radiographs and lung scans; Mary George, Ph.D., and Ric Hodinka, Ph.D., for performing quantitative bacterial sputum cultures; Oscar Ramirez, M.D., and J. Gustavo Zayas, M.D., for sputum rheologic analysis; Cynthia Taylor and Teresa Mace for assistance in specimen and data collection; Martha Clarke, R.N., and personnel of the clinical research unit for special assistance in patient management; Gerald Fernald, M.D., for monitoring of toxicity as a blinded nonparticipant; Gerald Strope, M.D., Eastern Virginia Medical School, for serving as an external reviewer of study design, data collection, and primary data; Thomas Boat, M.D., Robert Wood, M.D., and Philip Bromberg, M.D., for useful discussions and critical review of the manuscript; Lisa Brown and Rachel Knowles for assistance in preparation of the manuscript; Biomedical Home Care for generous support and the management of parenteral antibiotic therapy; DeVilbiss Healthcare for the donation of nebulizers and Pulmoaide compressed-air generators; Glaxo for the donation of Fortaz (ceftazidime); SensorMedics for the donation of pulmonary-function equipment; Merck, Sharp & Dohme for the donation of amiloride hydrochloride; and, finally, the patients and their families for their diligence and sense of humor throughout the study.

Author Affiliations

From the University of North Carolina, Chapel Hill (M.R.K., N.L.C., W.E.W., J.R.Y., P.G., L.J.E., R.W.H., R.C.B.), and the University of Alberta, Edmonton (M.K.). Address reprint requests to Dr. Knowles at the Division of Pulmonary Diseases, 724 Burnett-Womack Bldg., CB# 7020, University of North Carolina, Chapel Hill, NC 27599–7020.

References (33)

  1. *See NAPS document no. 04768 for 16 pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada add postage of $4.50 ($1.50 for microfiche postage).

  2. *See NAPS document no. 04768 for 16 pages of supplementary material. Order from NAPS c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163–3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada add postage of $4.50 ($1.50 for microfiche postage).

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  8. 6. Li M, McCann JD, Liedtke CM, Nairn achéal, Greengard P, Welsh MJ. . Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium . Nature 1988; 331:358–60.

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Citing Articles (255)

    Letters

    Figures/Media

    1. Table 1. Clinical Characteristics of the 14 Patients Who Completed the Study.*
      Table 1. Clinical Characteristics of the 14 Patients Who Completed the Study.*
    2. Table 2. Changes in Mean Forced Vital Capacity (FVC) during the Study Periods.
      Table 2. Changes in Mean Forced Vital Capacity (FVC) during the Study Periods.
    3. Figure 1. Changes in Mean Forced Vital Capacity (FVC) and Forced Expiratory Volume (FEV1) during the Study Periods.
      Figure 1. Changes in Mean Forced Vital Capacity (FVC) and Forced Expiratory Volume (FEV1) during the Study Periods.

      Panel A shows the mean (±SEM) base-line FVC and the mean slope of FVC as a function of time during treatment with vehicle (□) and amiloride (■). The slopes reflect 7.3 and 7.1 measurements per patient (n = 14), including base-line values, for vehicle and amiloride, respectively (P<0.04 for the differences in slopes). FVC decreased by 3.39±1.13 ml per day during treatment with vehicle, and by 1.44±0.67 ml per day during treatment with amiloride.

      Panel B shows the mean (±SEM) base-line FEV1 and the mean slope of FEV1 as a function of time during treatment with vehicle (□) and amiloride (■). The slopes reflect 7.3 and 7.1 measurements per patient (n = 14), including base-line values, for vehicle and amiloride, respectively (P = 0.09 for the differences in slopes). FEV1 decreased by 3.21±1.11 ml per day during treatment with vehicle, and by 2.09±0.86 ml per day during treatment with amiloride.

    4. Table 3. Biorheologic Features of Airway Secretions after Long-Term Treatment with Vehicle and Amiloride.*
      Table 3. Biorheologic Features of Airway Secretions after Long-Term Treatment with Vehicle and Amiloride.*
    5. Table 4. Summary of Drug Interventions in Each Study Period.*
      Table 4. Summary of Drug Interventions in Each Study Period.*
    6. Table 5. Indexes of Systemic Salt and Water Metabolism during the Study Periods.*
      Table 5. Indexes of Systemic Salt and Water Metabolism during the Study Periods.*

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