Download Eur J Clin Pharmacol (1986) 31 [Suppl]: 9

European Journal of
Clinical Pharmacology
Eur J Clin Pharmacol (1986) 31 [Suppl]: 9-14
© Springer-Verlag 1986
Study of the Tolerance and Diuretic Properties of Torasemide
Following Oral or Intravenous Administration to Healthy Volunteers
R. Lambe, O. Kennedy, M. Kenny, and A. Darragh
Institute of Clinical Pharmacology, Dublin, Ireland
Summary. The tolerance and diuretic properties of
torasemide after oral or intravenous administration
to healthy volunteers were studied. Six groups, each
of 6 subjects, were given single rising oral doses ranging from 10 to 100 mg; 8 subjects received ascending
i.v. doses on alternate days, ranging from 2.5 to
80 mg. At the highest oral doses investigated (80 mg
and l00mg) a number of volunteers complained of
cramps in the knees, calves and feet. These symptoms were generally of short duration. Similar effects
were not encountered during the intravenous study.
There were no significant changes in ECG. Some significant drug-related changes were encountered in
the within-study biochemistry and haematology assessments. Torasemide proved to be a potent diuretic
following oral administration at all the doses investigated and following intravenous administration at
all doses except 2.5 mg. A linear relationship existed
between the urine output and the logarithm of the
dose, and both sodium and chloride excretion were
linearly correlated with urine volume. The rate of potassium excretion was markedly lower than that of
sodium and chloride and was linearly correlated
with the logarithm of the urine volume. Torasemide
was well tolerated from all perspectives studied. It
showed a potent diuretic property, and was equally
effective by the oral and intravenous routes.
The present study has examined the tolerance
and diuretic properties of torasemide in groups of
healthy volunteers, given single rising oral doses of
10 to 100 mg, and in a single group of volunteers given ascending intravenous doses of 2.5 to 80 mg.
Keywords: torasemide; tolerance, diuretic, urine volume, electrolytes, adverse effects, oral route, intravenous route, side-effects
Oral Study. This was an open study with placebo
control in 6 dose groups, each consisting of 6 subjects (several subjects participated in more than one
dose group). The drug was administered as a single
oral dose in ascending order: 10, 20, 40, 60, 80 and
l00mg.
Continuance of the study to a higher dose depended on tolerance of the previous dose. Each
phase of the study took place over a period of 3 days.
There was a pretreatment control day during which
Torasemide,
l-isopropyl-3(4-M-toluidino-3-pyridyl)-sulphonyl-urea, is a newly developed compound with diuretic properties [1]. It belongs to the
group of pyridylsulphonyl urea derivatives.
Materials and Methods
Subjects
Twenty six healthy male volunteers aged 18-28 years
were selected for the oral study, and 8 aged
18-27 years were selected for the intravenous study.
From each a medical history was taken and, prior to
the study, a complete physical examination, a
12-lead electrocardiogram, and laboratory tests of
haematopoietic, hepatic and renal function were performed. The study was subject to Ethics Committee
approval, and the subjects gave their written informed consent to participate in it. The volunteers
were not permitted to take any medication for two
weeks prior to the study and were requested to refrain from alcohol consumption during the 12 h preceding and throughout the study periods.
Study Protocols
R. Lambe et al.: Torasemide Tolerance and Efficacy
10
Tablet. Effects of oral torasernide. Within-study plasma biochemistry changes (only parameters showing significant changes are presented)
Dose
Parameter
Units
20 mg
Uric acid
Potassium
(mg/dl)
(mmol/1)
4.7 ±0.6
4.1 ±0.3
5.8 ±1.0
4.8 ±0.2
<0.01
<0.01
40 mg
Uric acid
Potassium
(mg/dl)
(mmol/1)
4.1 ±1.4
4.4 + 0.5
5.7 ±1.2 3.
9 ±0.4
<0.05
<0.05
60 mg
Uric acid
Potassium
Total protein
4.4 ±0.9
4.8 + 0.3
7.0 + 0.5
5.9 ±0.8
4.1 ±0.3
7.5 + 0.5
<0.01
<0.01
<0.05
80 mg
Uric acid
(mg/dl)
(mmol/1)
(g/dl)
(mg/dl)
4.3 ±0.6
6.4 ±0.8
<0.01
Uric acid Total
protein
Sodium
Chloride
(mg/dl)
(g/dl)
(mmol/1)
(mmol/1)
4.5 + 0.7 6.8
+ 0.4 149.8
±2.9 107.8
+ 1.5
5.7 ±1.2 7.7
±0.3 145.7
±1.6 104.5
±1.6
<0.05
<0.01
<0.01
<0.01
100 mg
Pre-torasemide
24 hours-post
torasemide
Significance level
Table 2. Effects of i.v. torasemide. Within-study plasma biochemistry changes (only parameters showing significant changes are presented)
Dose
Parameter
Units
Pre-torasemide
24 hours-post
torasemide
Significance level
20 mg
Total protein
(g/dl)
6.9 ±0.7
7.6 ±0.4
<0.05
40 mg
Total protein
Uric acid
(g/df)
(mg/dl)
7.3 + 0.4
5.8 ±0.9
7.8 ±0.4
6.5 ±0.8
<0.01
<0.05
80 mg
Total protein
Uric acid
(g/dl)
(mg/dl)
7.1+0.6
5.4 ±0.8
7.8 + 0.7
6.3 ±1.1
< 0.025
<0.05
placebo only was administered, a "study day" in
which active drug was administered and a follow-up
day without treatment. The volunteers were admitted
to the Institute at 19.00 h on the day preceding Day 1
of the study period and remained under observation
until 48 h after the administration of torasemide. Following a light breakfast at 06.00 h, the appropriate
number of drug or placebo tablets was administered
at 08.00 h with 250 ml water.
Clinical Assessment. Adverse effects were assessed by
questioning the volunteers during the study. A
12-lead ECG was performed 3 h post placebo
(Day 1) and 3 h post-drug (Day 2). The ECG was repeated at the corresponding time on Day 3.
Blood Sampling. Blood for biochemistry and haematology investigation was collected at the following
times; before administration of placebo and drug on
Days 1 and 2, respectively, and just before 08.00 h on
Day 3 of the study, when no treatment was administered.
This was an open study with a pre-treatment control
day.
Eight healthy male volunteers were given ascending, intravenous doses of torasemide on alternate
days, so that there was a wash-out period of 48 h between successive doses. The doses administered
were: 2.5, 5.0,10, 20,40 and 80 mg.
The subjects were admitted to the Institute at
19.00 h on the evening preceding Day 1 (control day)
of the study and remained under observation until
48 h after the last dose of torasemide. The drug was
administered 2 h after a light breakfast.
Urine Collection. Urine was collected over the following time intervals on each of the 3 days of the
study: pre-treatment control and 0-2, 2-4, 4-8, 8-12
and 12-24 h. The urine volumes were recorded and
an aliquot taken for the analysis of sodium, potassium and chloride. At the end of each collection period each subject was given a further 250 ml water to
drink. A careful record of each subject's fluid intake
was kept for each of the 3 days of the study period.
Intravenous Study
Blood Sampling. Blood samples for routine biochemistry and haematology investigation were taken just
before breakfast each morning of the study.
R. Lambe et al.: Torasemide Tolerance and Efficacy
11
Table 3. Effects of oral torasemide. Significant within-study haematological changes
Dose
Parameter
Units
10 mg
20 mg
40 mg
60 mg
80 mg
100 mg
Pre-torasemide
24 hours-post
torasemide
Significance level
No significant changes observed
RBC
Hb
PCV
RBC
Hb
PCV
RBC
Hb
PCV
RBC
Hb
PCV
(x10 9 /l)
(g/dl)
(1/1)
( x 109/l)
(g/dl)
(1/1)
( x 109/1)
(g/dl)
(1/1)
( x 109/I)
(g/dl)
(1/1)
No significant changes observed
5.00 + 0.26
5.34 ±0.24
14.4 ±0.5
15.8 ±0.9
0.43+0.3
0.46 + 0.2
5.04 + 0.32
5.56 ±0.32
14.3 ±0.9
15.8 +0.9
0.43 ±0.02
0.46 + 0.02
5.30 ±0.43
5.74 ±0.44
15.1 ±0.8
16.6 ±0.8
0.45 ±0.01
0.48 + 0.01
5.18 ±0.41
5.64 + 0.31
15.0 ±1.2
16.6 ±1.1
0.45 ±0.03
0.48 + 0.03
<0.05
<0.02
<0.01
<0.02
<0.02
<0.02
<0.05
<0.01
<0.01
<0.05
<0.02
<0.02
RBC = Red blood cells; Hb = Haemoglobin; PCV = Packed cell volume
Table 4. Effects of i. v. torasemide. Significant within-study haematological changes
Dose
Parameter
Units
Pre-torasemide
24 hours-post
torasemide
Significance level
40 mg
RBC
Hb
PCV
5.22 + 0.20
14.9 ±0.6
0.43+0.02
5.50 ±0.33
15.7 +0.6
0.46 ±0.02
<0.05
<0.01
<0.05
80 mg
RBC
Hb
PCV
(xl0 9/l)
(g/dl)
(1/1)
(xl0 9/l)
(g/dl)
(1/1)
5.13+0.32
14.5 +0.6
0.43 ±0.02
5.62 + 0.34
16.0 ±0.7
0.46 + 0.01
<0.01
< 0.001
<0.01
RBC = Red blood cells; Hb = Haemoglobin; PCV = Packed cell volume
Urine Collection. All urine excreted over the following time intervals on each day of the study was collected: pre-treatment control, 0-2, 2-4, 4-8, 8-12
and 12-24 h. The urine volumes were accurately recorded and an aliquot was transferred to the laboratory for analysis of sodium, chloride and potassium.
Clinical Assessment. Adverse effects were assessed by
questioning the volunteers during the study. A
12-lead ECG was performed on each subject on the
first day and 3 h following drug administration on
drug administration days.
Statistical Analysis. Statistical analysis of the data for
both studies was performed using the paired t-test.
Results
Tolerance
Torasemide was well tolerated at all doses investigated after oral and intravenous administration. Sideeffects reported were mild. At the highest oral doses
(80 mg and 100 mg) cramps in the knees, calves and
feet were reported by a number of volunteers. The
symptoms were generally of short duration and were
relieved by massage or by walking. Adverse effects of
this nature were not reported after any of the intravenous doses. Following the 40 mg oral dose, several
subjects complained of suprapubic discomfort and
urgency, which was relieved by micturition. These
symptoms were not regarded as clinically significant
and were presumably related to the onset of diuretic
action. Headache was reported by 3 subjects at intermittent periods during the intravenous study.
Significant drug related changes were encountered in some of the within study biochemistry and
haematology assessments for both of the studies. The
biochemistry parameters in which drug-related
changes occurred in the oral study included uric
acid, protein, potassium, sodium and chloride.
Changes were observed only in uric acid and protein
during the intravenous study. The mean values before dosing and 24 h post-torasemide, for those parameters in which significant post-drug changes were
12
R.Lambe et al.: Torasemide Tolerance and Efficacy
Fig. 1. Torasemide oral study. Urine volumes (log
dose/response correlation)
TORASEMIDE DOSE (mg)
Fig.2. Torasemide i.v. study. Urine volumes (log dose/response correlation)
R. Lambe et al.: Torasemide Tolerance and Efficacy
13
Fig. 4. Torasemide i.v. study. Urine and electrolyte excretion for 4h following each dose
observed, are presented in Tables 1 and 2. Drug related changes in haematology were encountered in the
packed cell volume, red blood cell and haemoglobin
during both the oral and intravenous studies. The
mean values pre and 24 h after the dose of torasemide are outlined in Tables 3 and 4.
Diuretic Properties
Torasemide proved to be a potent diuretic following
oral administration at all the doses investigated, and
after intravenous administration at all doses from 5
to 80mg. The diuresis following 2.5mg i.v. was not
significant. At the 10 mg oral dose there was a highly
significant (p < 0.001) increase in urine excretion,
from a mean of 350 ml following placebo to a mean
of 1,160ml following torasemide for the 0 to 4-h period. When urine volumes were plotted against the
logarithm of the dose, both for orally and intravenously administered torasemide, a linear relationship was observed for the 0-4 h and 0-8 h cumulative volumes, as illustrated in Figs.l and 2. Torase-
R.Lambe et al.:Torasemide Tolerance and Efficacy
14
mide had a rapid onset of action, as indicated by the
greatly increased urine volume over the control during the 0 to 2-h collection interval. The diuretic effect
continued during the 2 to 4-h collection interval and
extended to the 4 to 8-h collection interval with the
higher doses. With any active dose, the diuresis was
as large after oral as after intravenous administration
(Figs.l and 2).
Analysis of the urinary electrolyte data demonstrated a highly significant (p< 0.001) increase in sodium and chloride excretion, from mean values of
42.9 and 38.2 mmol (following placebo) to 118.0 and
128.2mmol, respectively, following oral administration of 10 mg torasemide in the 0 to 4-h period. The
change in sodium/chloride excretion was dose-related over the complete dose range investigated in the
oral study, and over the range 5-80 mg for the intravenous study. Analysis of the 0 to 4-h cumulative
output data indicated that the excretion of both electrolytes was linearly correlated with urine volume
(Figs. 3 and 4). The incremental increases in potassium excretion with increasing doses of torasemide
were significantly less marked, and for this ion the
urinary output did not parallel the urine volume
(Figs. 3 and 4).
Discussion
Torasemide was well tolerated from all the perspectives investigated following oral administration of 10
to 100 mg, and after intravenous injection of 2.5 to
80 mg. The main adverse effects encountered were
cramps in the knees, calves and feet, which were reported at the highest oral doses (80 mg and 100 mg),
but not during the intravenous study. Muscle cramps
have previously been reported in association with
frusemide and bumetanide therapy [2, 3].
Drug related changes in the haematology parameters, packed cell volume, red blood cell count and
haemoglobin following both oral and intravenous
administration of torasemide were also encountered
in a multiple oral dose study [Lambe et al. 1984, personal communication], and are consistent with diminished extracellular fluid volume due to the diuresis. Hyperuricaemia is a common side-effect of
diuretics [4, 5], and a significant increase in serum
uric acid was noted in the present studies and during
multiple dosing with torasemide [6]. In addition,
changes were observed in plasma sodium, chloride,
potassium and protein, of which only changes in
plasma protein were encountered during the intravenous study. Changes in plasma protein were not observed during the multiple dose study [Lambe et al.
1984, personal communication]. Significant changes
in plasma protein, uric acid, chloride, potassium,
urea, creatinine, inorganic phosphorus and packed
cell volume have been observed in volunteers given a
single oral dose of 80 mg frusemide [7].
Torasemide was a potent diuretic following all
the oral doses investigated and all the intravenous
doses over the range 5 to 80 mg. There was a rapid
onset of action, similar to that reported for frusemide
and bumetanide [5, 8, 9]. The diuresis after both the
oral and intravenous studies was similar. The urine
output was dose-related and was linearly correlated
with the logarithm of the dose for both the 0 to 4-h
and 0 to 8-h cumulative volumes. Sodium and chloride excretion were linearly correlated with urine
volume. The rate of potassium excretion was lower
than that of sodium and chloride, and for this ion the
urinary output was linearly correlated with the logarithm of the urine volume.
Torasemide was generally well tolerated. A few
transient side-effects were encountered following the
higher oral doses. It proved to be a potent diuretic
with a rapid onset of action, which lasted for at least 4
h after drug administration.
References
1. Lesne M, Clerckx-Braun F, Duhoux P, van Ypersele de StrihouxCh (1982) Pharmacokinetic study of torasemide in humans
: An overview of its diuretic effect. Int J Clin Pharmacol Ther
Toxicol 20 [8]: 382-397
2. Hutcheon DE, Genevieve L (1967) Diuretic and antihypertensive actions of furosemide. J Clin Pharmacol 7: 26-33
3.Olesen JH, Sigurd B, Steiness E, Leth A (1973) Bumetanide, a
new potent diuretic. Acta Med Scand 193:119-131
4. SteeleTH, Oppenheimer S (1969) Factors affecting urate excre
tion following diuretic administration in man. Am J Med 47:
564-574
5. Roberts CJC, Homeida M, Roberts F (1978) Effects of piretanide, bumetanide and frusemide on electrolyte and urate excre
tion in normal subjects. Br J Clin Pharmacol 6:129-133
6. Ambroes Y, Ronflette I, Dodion L (1984) Diuretic activity, safety and pharmacokinetics of chronic treatment with torasemide
in normal subjects. Eur J Clin Pharmacol 31 [Suppl]: 1-7 7.
0'HaugT (1976) Time course of changes in concentration of
some plasma components after frusemide. Br Med J9: 622
8. Murdoch WR, Auld WHR (1975) Bumetanide - acute and long
term studies of a new high potency diuretic. Postgrad Med J 51:
10-14
9. Davies DL, Lant AF, Millard NR, Smith AJ, Ward JW, Wil
son GM (1974) Renal action, therapeutic use, and pharmaco
kinetics of the diuretic bumetanide. Clin Pharmacol Ther 15 [2]:
141-155
Received: August 15, 1985
accepted: July 21,1986
Dr. L. Dodion Medical
Department
A.Christiaens S. A. Rue
de I'Etuve 60 B-1000
Brussels Belgium