Efficacy of furosemide for sodium excretion (efficacy index 1) was defined by dividing urinary sodium excretion by the urinary excretion of furosemide. Diuretic index 1 for sodium was calculated for the for the total 0 to 4 hour urine collection.

All patients who received at least one dose of study drug and had evaluable pharmacodynamic (PD) data with no major protocol deviation in at least one period were included in the PD analysis set.

Efficacy of furosemide for sodium excretion (efficacy index 1) was defined by dividing urinary sodium excretion by the urinary excretion of furosemide. Diuretic index 1 for sodium was calculated for the for the total 0 to 24 hour urine collection.

All patients who received at least one dose of study drug and had evaluable pharmacodynamic (PD) data with no major protocol deviation in at least one period were included in the PD analysis set.

Pharmacokinetic (PK) parameters were determined from the plasma concentration time profile of furosemide using a non-compartmental method:

AUCtau: Area under the plasma concentration-time curve from time zero to the end of the dosing interval

AUC (0-24): Area under the plasma concentration-time curve from time zero to 24 hours

AUClast: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated as the sum of linear trapezoids using non-compartmental analysis.

AUCinf: Area under the plasma concentration-time curve from time zero to infinity. AUCinf was calculated by adding AUClast and the value obtained from dividing the last measurable plasma concentration by λz, where λz was determined from automated linear regression of the last three time points with non-zero concentrations in the terminal phase of the log-transformed concentration-time profile

All patients who received at least one dose of study drug and had evaluable Pharmacokinetic (PK) data with no major protocol deviation in at least one period were included in the PK analysis set.

Cmax,ss was directly determined from the raw plasma concentration-time data.

All patients who received at least one dose of study drug and had evaluable pharmacokinetic (PK) data with no major protocol deviation in at least one period were included in the PK analysis set

Tmax was directly determined from the raw plasma concentration-time data.

All patients who received at least one dose of study drug and had evaluable PK data with no major protocol deviation in at least one period were included in the PK analysis set

The average steady-state drug concentration in the plasma, blood, serum, or other body fluids during multiple dosing [amount x volume-1]. This was estimated as AUCτ/τ

All subjects with evaluable pharmacokinetic parameter data with no exclusion flags and no major protocol deviations.

The minimum observed steady-state drug concentration in the plasma, blood, serum, or other body fluids at the end of the dosing interval during multiple dosing [amount x volume-1]

All patients who received at least one dose of study drug and had evaluable PK data with no major protocol deviation in at least one period were included in the PK analysis set

The area under the plasma (or serum or blood) concentration-time curve from time zero to 24 h [mass × time × volume-1]

All patients who received at least one dose of study drug and had evaluable PK data with no major protocol deviation in at least one period were included in the PK analysis set

The renal clearance of drug [volume x time-1]

All patients who received at least one dose of study drug and had evaluable pharmacodynamic (PD) data with no major protocol deviation in at least one period were included in the PD analysis set.

Creatinine clearance= (Urine creatinine/Serum creatinine) x (Urine volume/(24*60)).

All patients who received at least one dose of study drug and had evaluable PD data with no major protocol deviation in at least one period were included in the PD analysis set.

Urine was collected 4 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 4 hours.

All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.

Urine was collected 8 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 8 hours.

All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.

Urine was collected 12 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 12 hours.

All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.

Urine was collected 24 hours postdose in all treatment groups for sodium and potassium analysis. Each patient was required to void their bladder before drug administration and at the end 24 hours.

All patients who received at least one dose of study drug and had evaluable pharmacodynamics (PD)data with no major protocol deviation in at least one period were included in the PD analysis set.

Sitting blood pressure was measured three times at 1 to 2-minute intervals. The mean of the three sitting blood pressure measurements was used as the average of the sitting office blood pressure. The msSBP and msDBP data were analyzed using a mixed effect model with fixed effects from treatment and treatment*time; random effect from patients and predose as covariate.

Safety analysis set include subjects that received study drug.

Efficacy of furosemide for water excretion (efficacy index 2) was defined by dividing urine volume by the urinary excretion of furosemide.Diuretic index 2 for water was calculated for the 0 to 4 hour fraction urine collection.

All patients who received at least one dose of study drug and had evaluable PD data with no major protocol deviation in at least one period were included in the PD analysis set.

Efficacy of furosemide for water excretion (efficacy index 2) was defined by dividing urine volume by the urinary excretion of furosemide.Diuretic index 2 for water was calculated for the 0 to 4 hour fraction and for the total 0 to 24 hour urine collection.

All patients who received at least one dose of study drug and had evaluable PD data with no major protocol deviation in at least one period were included in the PD analysis set.