595
COMPARISON OF TIENILIC ACID WITH
CYCLOPENTHIAZIDE IN HYPERURICÆMIC HYPERTENSIVE PATIENTS P. BOLLI
HENDRIKA
F. O. SIMPSON WAAL-MANNING J.
Wellcome Medical Research Institute, University of Otago Medical School, Dunedin, New Zealand
Tienilic acid, a diuretic with uricosuric properties, was compared with cyclopenthiazide, in an open, random-order, within-patient crossover study (3 months on each drug) in 36 hyperuricæmic hypertensive patients. All were on an established dose of cyclopenthiazide; most were also on a betablocker which they continued to take in their usual dose.
Summary
dose of 210 mg of tienilic acid gave the same antihypertensive and diuretic effect as a mean dose of 0·41 mg of cyclopenthiazide. Serum uric acid was very much lower when patients were on tienilic acid (0·29 mmol/l) than on cyclopenthiazide (0·50 mmol/l). Apart from slightly higher serum-chloride and serum-urea during the period on tienilic acid, no major differences in serum-electrolytes, renal-function tests, glucose tolerance, and fasting lipids were observed. Audiometric tests showed that tienilic acid was not ototoxic. S.G.O.T. and S.G.P.T. rose to pathological values in 3 women when they were on tienilic acid and, to a lesser extent, in 2 men when they were on cyclopenthiazide. There is no definite evidence that the changes in the transaminases were related to tienilic acid. Some postural hypotension or slight fluid retention occurred during the initial, dosefinding period, and 3 patients had mild indigestion but no patient had to discontinue the trial because of sideeffects. A
mean
Introduction HYPERURICAEMIA may appear in patients on longwith thiazide-type diuretics. Tienilic
term treatment
acid
(chloro-2, 3-thienyl-2-ketophenoxyacetic acid; ’Selacryn’, Smith, Kline, and French; ticrynafen in the U.S.A.) is an ethacrynic acid derivative 1which combines diuretic and antihypertensive with uricosuric properties.34Its diuretic action takes place at the diluting segment of the distal tubule/ while inhibition of urate reabsorption occurs at the proximal and distal tubules.6-8 We have used tienilic acid in
in
an
open,
crossover
study
whose bloodpressure was well controlled on an established dose of cyclopenthiazide plus, in most cases, a beta-blocker.
hyperuricaemic, hypertensive patients
Patients and Methods 38
hypertensive patients whose blood-pressure was well con-
trolled, by cyclopenthiazide (’Navidrex-K’), with
or without a uric acid levels were 0-48 mmol/1 or more, were randomly allocated either to take tienilic acid (19 patients) or to continue on their established dose of cyclopenthiazide (19 patients) for 3 months, after which each patient took the other drug for the next 3 months. 2 patients, aged 58 and 60 respectively, had to withdraw from the trial-the first was a man with transient cerebral ischaemia who had further ischaEmic attacks while on cyclopenthiazide; the other was a patient who had urinary retention 2 weeks
beta-blocker,
and whose
serum
after returning to her established dose of cyclopenthiazide-K, having completed 3 months on tienilic acid. The remaining 36 patients, 23 men and 13 women, aged 46 to 68 years (mean 58), completed the trial. 17 patients (12 men, 5 women) took tienilic acid for the first trial period and 19 patients (11 men, 8 women) for the second period. The dose of cyclopenthiazide taken ranged from 0-25 to 1.0 mg daily (mean 0.41 mg) but was kept constant for each patient. Patients had been taking cyclopenthiazide for 1 month to 12 years (mean 4 years) before entering the trial. 30 patients were also taking a beta-blocker, the dose of which was maintained-metoprolol (mean daily dose 177 mg), 12 patients; pindolol (mean daily dose 16 mg), 10 patients; oxprenolol (mean daily dose 225 mg), 4 patients; propranolol {mean daily dose 137 mg), 3 patients; alprenolol (400 mg/day), 1 patient. Patients had been taking these beta-blocking drugs for 1 month to 6 years (mean 2-8years). 19 patients had W.H.O. stage I hypertension and 17 patients W.H.O. stage n. 4 patients had a renal abnormality-polycystic kidneys, single cyst with microhoematuria, a small renal infarct, and small kidneys of uncertain cause. 2 patients had impaired glucose tolerance, treated by diet only. A 60-year-old woman had Paget’s disease with high alkaline phosphatase and a 60-year-old man had a history of duodenal ulcer. 4 patients had a history of gout, 2 of whom were taking allopurinol and 1 probenecid. 1 patient had been taking allopurinol for hyperuricxmia without clinical gout. All stopped the allopurinol or probenecid 1-2 months before entering the trial. The purpose of the trial was explained to each patient. All gave their consent.
The Public
patients attended the hypertension clinic at Dunedin Hospital, at 3, 6, 9, and 12 weeks (more often if necessary) during the 3 months on tienilic acid and at 6, 9, and 12 weeks during 3 months on cyclopenthiazide. Before patients were started on tienilic acid, their dose of cyclopenthiazide was halved for 3 days and stopped completely for 4 days. The initial dose of tienilic acid was 125 mg daily; this was gradually increased until the blood-pressure was approximately the same as that which had been maintained by cyclopenthiazide. When they were on tienilic acid patients should have taken the same amount of potassium (in the form of ’Slow-K’) as had been contained in their established dose of navidrex-K; 5 patients misunderstood this instruction and took less, and this mistake is reflected in the mean dose of potassium chloride taken (table I). Blood-pressure and pulse-rates were measured with the patient lying and after 2 min standing, with an electronic version of the London School of Hygiene and Tropical Medicine "blind" manometer. Phase iv oi the Korotkoff sounds was taken as the diastolic pressure. The mean values of 4 recordings of blood-pressure and pulse-rate over 3-4 h were used for the analysis. Laboratory tests were carried out at the end of each 3 months; some were done also at 3 and 6 weeks on patients on tienilic acid or more often if necessary. Glomerular filtration rate (5’Cr-E.D.T.A. clearance)9 and renal blood-flow (125-iodohippurate clearance) 10 were measured at the end of each of the two drug periods in 14 patients. Audiometry" was carried out before the trial (i.e., when patients were on cyclopenthiazide), after 6 and 12 weeks of tienilic acid, and after 12 weeks of cyclopenthiazide. One patient’s audiometry results had to be discarded since his ears were syringed during the trial; there was no evidence that tienilic acid had affected his hearing in any way. The significance of the results was assessed by means of Student’st test for paired values.
Results
Effect on Blood-pressure, Pulse-rate, and Body-weight (Table I) Tienilic acid, mean dose 210 mg (62.5 to 500 mg) per day, produced an antihypertensive effect similar to that
596 TABLE I-MEAN
BLOOD-PRESSURE, PULSE-RATE, BODY-WEIGHT,
AND DAILY DOSE OF DRUGS
(36 PATIENTS)
a normal lipoprotein electrophoretic patwhile 1 had a type ua, 3 a type nb, and 8 a type tern, IV pattern; after 3 months on cyclopenthiazide only 14 patients had a normal pattern, while 3 had a type ita, 3 a type lib and 13 a type iv pattern. These differences did not reach statistical significance (-x2 and Fisher’s
patients had
exact
test).
Mean glucose and insulin values during a glucosetolerance test were very similar on the two treatments (table IV) even in the two diabetic patients.
Effect on Hcematological Tests Haemoglobin levels were significantly (P
COMPARISON OF TIENILIC ACID WITH
CYCLOPENTHIAZIDE IN HYPERURICÆMIC HYPERTENSIVE PATIENTS P. BOLLI
HENDRIKA
F. O. SIMPSON WAAL-MANNING J.
Wellcome Medical Research Institute, University of Otago Medical School, Dunedin, New Zealand
Tienilic acid, a diuretic with uricosuric properties, was compared with cyclopenthiazide, in an open, random-order, within-patient crossover study (3 months on each drug) in 36 hyperuricæmic hypertensive patients. All were on an established dose of cyclopenthiazide; most were also on a betablocker which they continued to take in their usual dose.
Summary
dose of 210 mg of tienilic acid gave the same antihypertensive and diuretic effect as a mean dose of 0·41 mg of cyclopenthiazide. Serum uric acid was very much lower when patients were on tienilic acid (0·29 mmol/l) than on cyclopenthiazide (0·50 mmol/l). Apart from slightly higher serum-chloride and serum-urea during the period on tienilic acid, no major differences in serum-electrolytes, renal-function tests, glucose tolerance, and fasting lipids were observed. Audiometric tests showed that tienilic acid was not ototoxic. S.G.O.T. and S.G.P.T. rose to pathological values in 3 women when they were on tienilic acid and, to a lesser extent, in 2 men when they were on cyclopenthiazide. There is no definite evidence that the changes in the transaminases were related to tienilic acid. Some postural hypotension or slight fluid retention occurred during the initial, dosefinding period, and 3 patients had mild indigestion but no patient had to discontinue the trial because of sideeffects. A
mean
Introduction HYPERURICAEMIA may appear in patients on longwith thiazide-type diuretics. Tienilic
term treatment
acid
(chloro-2, 3-thienyl-2-ketophenoxyacetic acid; ’Selacryn’, Smith, Kline, and French; ticrynafen in the U.S.A.) is an ethacrynic acid derivative 1which combines diuretic and antihypertensive with uricosuric properties.34Its diuretic action takes place at the diluting segment of the distal tubule/ while inhibition of urate reabsorption occurs at the proximal and distal tubules.6-8 We have used tienilic acid in
in
an
open,
crossover
study
whose bloodpressure was well controlled on an established dose of cyclopenthiazide plus, in most cases, a beta-blocker.
hyperuricaemic, hypertensive patients
Patients and Methods 38
hypertensive patients whose blood-pressure was well con-
trolled, by cyclopenthiazide (’Navidrex-K’), with
or without a uric acid levels were 0-48 mmol/1 or more, were randomly allocated either to take tienilic acid (19 patients) or to continue on their established dose of cyclopenthiazide (19 patients) for 3 months, after which each patient took the other drug for the next 3 months. 2 patients, aged 58 and 60 respectively, had to withdraw from the trial-the first was a man with transient cerebral ischaemia who had further ischaEmic attacks while on cyclopenthiazide; the other was a patient who had urinary retention 2 weeks
beta-blocker,
and whose
serum
after returning to her established dose of cyclopenthiazide-K, having completed 3 months on tienilic acid. The remaining 36 patients, 23 men and 13 women, aged 46 to 68 years (mean 58), completed the trial. 17 patients (12 men, 5 women) took tienilic acid for the first trial period and 19 patients (11 men, 8 women) for the second period. The dose of cyclopenthiazide taken ranged from 0-25 to 1.0 mg daily (mean 0.41 mg) but was kept constant for each patient. Patients had been taking cyclopenthiazide for 1 month to 12 years (mean 4 years) before entering the trial. 30 patients were also taking a beta-blocker, the dose of which was maintained-metoprolol (mean daily dose 177 mg), 12 patients; pindolol (mean daily dose 16 mg), 10 patients; oxprenolol (mean daily dose 225 mg), 4 patients; propranolol {mean daily dose 137 mg), 3 patients; alprenolol (400 mg/day), 1 patient. Patients had been taking these beta-blocking drugs for 1 month to 6 years (mean 2-8years). 19 patients had W.H.O. stage I hypertension and 17 patients W.H.O. stage n. 4 patients had a renal abnormality-polycystic kidneys, single cyst with microhoematuria, a small renal infarct, and small kidneys of uncertain cause. 2 patients had impaired glucose tolerance, treated by diet only. A 60-year-old woman had Paget’s disease with high alkaline phosphatase and a 60-year-old man had a history of duodenal ulcer. 4 patients had a history of gout, 2 of whom were taking allopurinol and 1 probenecid. 1 patient had been taking allopurinol for hyperuricxmia without clinical gout. All stopped the allopurinol or probenecid 1-2 months before entering the trial. The purpose of the trial was explained to each patient. All gave their consent.
The Public
patients attended the hypertension clinic at Dunedin Hospital, at 3, 6, 9, and 12 weeks (more often if necessary) during the 3 months on tienilic acid and at 6, 9, and 12 weeks during 3 months on cyclopenthiazide. Before patients were started on tienilic acid, their dose of cyclopenthiazide was halved for 3 days and stopped completely for 4 days. The initial dose of tienilic acid was 125 mg daily; this was gradually increased until the blood-pressure was approximately the same as that which had been maintained by cyclopenthiazide. When they were on tienilic acid patients should have taken the same amount of potassium (in the form of ’Slow-K’) as had been contained in their established dose of navidrex-K; 5 patients misunderstood this instruction and took less, and this mistake is reflected in the mean dose of potassium chloride taken (table I). Blood-pressure and pulse-rates were measured with the patient lying and after 2 min standing, with an electronic version of the London School of Hygiene and Tropical Medicine "blind" manometer. Phase iv oi the Korotkoff sounds was taken as the diastolic pressure. The mean values of 4 recordings of blood-pressure and pulse-rate over 3-4 h were used for the analysis. Laboratory tests were carried out at the end of each 3 months; some were done also at 3 and 6 weeks on patients on tienilic acid or more often if necessary. Glomerular filtration rate (5’Cr-E.D.T.A. clearance)9 and renal blood-flow (125-iodohippurate clearance) 10 were measured at the end of each of the two drug periods in 14 patients. Audiometry" was carried out before the trial (i.e., when patients were on cyclopenthiazide), after 6 and 12 weeks of tienilic acid, and after 12 weeks of cyclopenthiazide. One patient’s audiometry results had to be discarded since his ears were syringed during the trial; there was no evidence that tienilic acid had affected his hearing in any way. The significance of the results was assessed by means of Student’st test for paired values.
Results
Effect on Blood-pressure, Pulse-rate, and Body-weight (Table I) Tienilic acid, mean dose 210 mg (62.5 to 500 mg) per day, produced an antihypertensive effect similar to that
596 TABLE I-MEAN
BLOOD-PRESSURE, PULSE-RATE, BODY-WEIGHT,
AND DAILY DOSE OF DRUGS
(36 PATIENTS)
a normal lipoprotein electrophoretic patwhile 1 had a type ua, 3 a type nb, and 8 a type tern, IV pattern; after 3 months on cyclopenthiazide only 14 patients had a normal pattern, while 3 had a type ita, 3 a type lib and 13 a type iv pattern. These differences did not reach statistical significance (-x2 and Fisher’s
patients had
exact
test).
Mean glucose and insulin values during a glucosetolerance test were very similar on the two treatments (table IV) even in the two diabetic patients.
Effect on Hcematological Tests Haemoglobin levels were significantly (P
