Clinical Science (1979)5’1,3679-369s
An evaluation of tienilic acid, a new diuretic uricosuric
agent, in the therapy of arterial hypertension
A. L E C H I , G . C O V I , G . D A N T I , A. D A L L A R I V A , E. P E D R O L L I A N D
S . POMARI
CIinica Medica 111, Universitci di Verona, Verona. Italy
Summary
1. Tienilic acid and hydrochlorothiazide were
evaluated in a double-blind trial in order to
investigate their antihypertensive and metabolic
effects.
2. After 5 weeks, the decreases in blood pressure and the changes in plasma or serum electrolytes, urea, creatinine, glucose, cholesterol and
triglycerides, and in creatinine clearance, did not
differ in the two groups of patients.
3. In patients taking tienilic acid a significant
decrease in serum uric acid and an increase in urate
clearance was observed, whereas in patients receiving hydrochlorothiazide a slight increase in serum
uric acid, with no modification of urate clearance,
occurred.
4. The diuretic and antihypertensive actions of
tienilic acid and hydrochlorothiazide are very
similar. The uricosuric/hypouricaemic effect of
tienilic acid could assume clinical relevance in longterm therapy of hypertensive patients.
contrast to the thiazides, tienilic acid possesses the
unique property of having a potent uricosuric effect
in animals and in man (Reese & Steele, 1976); the
increased urate excretion is due to inhibition of
reabsorption of both filtered and secreted urate
(Lau, Stote, Goldberg & Agus, 1977; Lemieux,
Gougoux, Vinary, Kiss & Baverel, 1978).
In view of the potential renal and vascular
damage caused by urate accumulation, the
availability of a natriuretic uricosuric agent might
be useful in the long-term therapy of hypertensive
patients. In order to investigate the metabolic and
antihypertensive effects of tienilic acid, compared
with those of a currently used diuretic agent, we
have carried out a double-blind trial in 28 hypertensive patients, who were randomly allocated to take
tienilic acid or hydrochlorothiazide.
Patients and methods
Twenty-eight patients (1 5 males and 13 females,
aged 18-66 years) with essential hypertension,
WHO stage 0-1, were admitted to the study. Eleven
Key words: diuretics, hydrochlorothiazide, tienilic
patients had never been treated before; in the
acid, uric acid.
remaining 17 patients all antihypertensive drug
therapy was discontinued at least 1 week before
admission.
Introduction
Fourteen patients (seven males and seven
Tienilic
acid
[2,3-dichloro-4-(2-thienyl-car- females) received tienilic acid, 250 mg/day in a
bony1)phenoxyacetic acid] is a new diuretic with a
single oral dose, and 14 patients (eight males and
chemical structure similar to that of ethacrynic acid
six females) received hydrochlorothiazide, 50
and a diuretic potency comparable with that of
mg/day in a single oral dose. After 2 weeks of
thiazide agents (Masbenard, Guidicelli &
treatment, if the diastolic blood pressure had not
Kamaludin, 1976). Its natriuretic activity occurs in
decreased by at least 10 mmHg, the dose was
the distal nephron at the cortical diluting site. In
doubled for a further 3 weeks. Final doses were 57
f 5 mg/day for hydrochlorothiazide and 303 k 28
Correspondence: Dr A. Lechi, Cliica Medica 111,
Policlinico Borgo Roma,37100 Verona, Italy.
mg/day for tienilic acid.
367s
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A . Lechi et al.
Blood pressure, determined by sphygmomanometer, and pulse rate were measured supine
and standing before admission and then every week
in all patients. Laboratory analyses, namely
urinalysis, plasma and urinary electrolytes, serum
and urinary urea, creatinine and uric acid, plasma
glucose, cholesterol and triglycerides, were carried
out in all patients before and after 5 weeks of
therapy (Autoanalyzer, Technicon). All the
patients were informed of the investigational nature
of the trial and gave their informed consent.
Student's paired t-test was used to test
significance.
was found, and in the group of patients who
received tienilic acid a significant decrease was
observed. Uric acid clearance was not modified by
hydrochlorothiazide, but doubled during therapy
with tienilic acid.
The overall incidence of side-effects of the two
drugs was similar: four patients (two on tienilic
acid and two on hydrochlorothiazide) experienced
tiredness and four patients (two on tienilic acid and
two on hydrochlorothiazide) experienced tachycardia; one patient on tienilic acid complained of
postural dizziness. None of these patients was
withdrawn from the trial because of side-effects.
Results
Discussion
Supine and standing systolic and diastolic blood
pressures decreased similarly after 5 weeks in the
two groups of patients (Table 1). Pulse rate was not
significantly altered. The average initial dose ratio
tienilic acid/hydrochlorothiazide was 5 :1 and the
average final dose ratio was 5 . 3 : l . A significant
decrease in plasma chloride and slight but insignificant decreases in plasma sodium and potassium
were observed with both drugs; no changes in
serum urea, serum creatinine or creatinine
clearance were observed. No differences were
found between the two agents in influencing any of
these variables. In patients receiving hydrochlorothiazide a significant increase in serum uric acid
This study demonstrates that tienilic acid and
hydrochlorothiazide have similar diuretic and
antihypertensive activities, and our results are
consistent with previous reports (Nemati, Kyle &
Fries, 1977; Bolli, Simpson & Waal-Manning,
1978). The ultimate falls in blood pressure achieved
by tienilic acid and hydrochlorothiazide were
comparable. Tienilic acid and hydrochlorothiazide
produced slight and very similar decreases in
plasma potassium, whereas serum urea and creatinine clearance remained unchanged with both
drugs. In this respect, tienilic acid would appear to
have no advantage. Bolli et al. (1978) observed a
slight, but insignificant decrease in plasma trigly-
TABLE1. Comparison of the effects of hydrochlorothiazide and tienilic acid on blood pressure, pulse rate and on
laboratory tests
Mean results f SEM are shown.Significance: P < 0.05; ** P
H ydrochlorothiazide
Before treatment
Blood pressure (mmHg)
supine systolic
diastolic
standing systolic
diastolic
Pulse rate (beatshin)
Plasma sodium (mmol/l)
Plasma potassium (mmolh)
Plasma chloride (mmol/l)
Serum urea (mmolh)
Serum creatinine @mol/l)
Serum uric acid @mol/l)
Plasma glucose (mmol/l)
Plasma cholesterol (mmolh)
Plasma triglycerides (mmol/l)
Creatinine clearance (ml/min)
Uric acid clearance (ml/min)
186 f 4
114f 2
170 ?- 4
114f2
70 f 4
141.3 f 2.5
4.2 f 0.3
106.0 f 2.9
2 . 9 f 0.8
82.2 f 2.7
262 f 85
5.3 f 0.6
5.33 f 0.59
1.75 f 0.99
93 f 19
6.3 f 4.4
< 0.01; *** P < 0@01.
Tienilic acid
After treatment
Before treatment
162 f 5***
107 f 2**
151 f 4..
108 f 3
69 f 4
139.9 i 2.5
3.9 f 0.5
100.8 f 2.3..
2.8 f 0 . 7
84.0 f 3.5
324 f 91.
5 . 5 f 0.7
5.64 f 0.67
1.35 f 0.57
102 f 33
7 . 0 f 3.4
188 f 6
113 f 3
175 f 6
114 f 3
72 f 3
140.8 f 2.1 I
4 . 2 f 0.5
103.6 f 2.8
3.1 f 0 . 7
85.7 f 2.7
329 f 94
5.5 f 0.5
5.48 f 0.82
1.45 f 0.49
97 f 28
5.0 f 2.8
After treatment
165 4***
105 f 4'
157 f 5*
111 f 4
74 f 4
140.4 f 3.3
4.0 f0.3
100.6 f 4.3.
3.0 f 0 . 6
83.1 f 3.5
231 f 66..
5.5 f 0 . 7
5.74 f 0.85
1.53 f 0.79
97 f 24
10.3 f 3.9***
A n evaluation of tienilic acid
cerides during tienilic acid therapy. In our patients
we did not observe any significant variation:
however, it is impossible to evaluate these data
since no particular diet was assigned to our patients
during therapy.
Hyperuricaemia, probably related to renal urate
retention, is often associated with arterial hypertension (Cannon, Statson, De Martini, Summers &
Laragh, 1966). Prolonged thiazide therapy may
also cause hyperuricaemia in about 60% of patients
by decreasing urate clearance (Hull, Suki, Rector
& Seldin, 1967). Diuretic drugs and uric acid might
compete for active tubular secretion; moreover,
hyperuricaemia might be due partly to extracelMar fluid volume contraction caused by diuretics.
The accumulation of uric acid may lead to gouty
arthritis and deposition of urate in the renal parenchyma (‘gouty kidney’). Hyperuricaemia may also
be a relatively common contributing factor in the
pathogenesis of interstitial nephritis (Murray &
Goldberg, 1976). These lesions may perpetuate a
vicious circle:
-.
parenchymal
hypertension + urate deposition
and/or vascular renal disease + hypertension
Tienilic acid is a moderately potent diuretic and
antihypertensive agent. Because of its strong
369s
uricosuric and hypouricaemic effect, it appears
particularly promising in the long-term therapy for
hypertensive patients.
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