Hepatotoxicity of DR-3438, tienilic acid, indacrinone and furosemide studied in vitro

A new diuretic antihypertensive, DR-3438, and marketed diuretic drugs were evaluated for their toxicity in vitro. Hepatocytes were isolated from male rats by the collagenase perfusion method and incubated in Dulbecco's modified Eagle medium containing various doses of DR-3438, tienilic acid, indacrinone or furosemide. Tienilic acid decreased cell viability and glutathione content in hepatocytes and increased lipid peroxidation in the cells. Indacrinone also decreased cell viability, but neither cell viability nor glutathione content was affected by furosemide or DR-3438.     

Effect of tienilic acid and amiloride in healthy volunteers and in hypertensives with normal renal function

1 A double-blind comparison of the effect of tienilic acid (250 mg) and amiloride (5 mg) on renal function in healthy volunteers and of tienilic acid plus amiloride compared to hydrochlorothiazide (50 mg) plus amiloride in patients with mild to moderate essential hypertension for safety and hypotensive efficacy was made.

2 Renal plasma flow ([I¹²⁵] iodohippurate clearance) and glomerular filtration rate ([I¹³¹] iothalamate clearance and 24 h creatinine clearance) were not affected by tienilic acid or amiloride alone or in combination despite a rise in plasma urea and plasma creatinine (within the normal range) in healthy volunteers.

3 In hypertensive patients tienilic acid and tienilic acid plus amiloride treatments caused a rise in plasma urea and plasma creatinine similar to hydrochlorothiazide and hydrochlorothiazide plus amiloride but no significant change in creatinine clearance occurred with any of the treatments.

4 Tienilic acid and hydrochlorothiazide caused hypokalaemia in the patients which was normalized by addition of amiloride. Fewer subjects became hypokalaemic when amiloride was added to tienilic acid than when tienilic acid was given alone.

5 The antihypertensive effect of tienilic acid and tienilic acid plus amiloride was similar to hydrochlorothiazide and hydrochlorothiazide plus amiloride in patients with hypertension. No effect on blood pressure was observed in the healthy volunteers.

6 Plasma uric acid was significantly reduced by tienilic acid alone and in combination in patients and subjects whereas a significant elevation occurred with hydrochlorothiazide.

7 Side effects were increased when amiloride was added to either tienilic acid or hydrochlorothiazide, but side effects were less common after treatment with tienilic acid than following hydrochlorothiazide.

8 The combination of tienilic acid plus amiloride significantly reduces blood pressure and appears to be well tolerated with no adverse effects on renal function or plasma potassium in patients with mild to moderate hypertension and normal renal function. Addition of amiloride may be useful if hypokalaemia occurs following tienilic acid therapy in such patients.

     

Multicentre controlled trial of tienilic acid in hyperuricaemic, hypertensive subjects, with intensive monitoring of liver function.

1 Tienilic acid, a diuretic with potent uricosuric properties, has been compared with conventional diuretic therapy, mainly thiazide, in a parallel group (random allocation) multicentre study in hyperuricaemic hypertensives (n = 96). 2 The study was designed to last 1 year but tienilic acid was withdrawn for suspected hepatotoxicity before the study was complete. Mean follow-up was 8.5 (range 1-12) months and the mean daily dose of tienilic acid was 278 (range 125-500 mg). 3 Blood pressure levels on tienilic acid and on conventional diuretics were similar. 4 Serum potassium and sodium levels were also similar in the two groups, but serum urea and creatinine rose somewhat more in the tienilic acid group. 5 Serum uric acid fell dramatically in the patients on tienilic acid from 0.56 to 0.32 mmol/l, but did not alter significantly in the control group. 6 There were no problems with renal failure or urate deposition probably because patients were instructed to drink plenty of fluid when tienilic acid was started, because initial dose was low and because all previous diuretics were stopped for 3 days before tienilic acid was started. 7 Mean liver function indices did not rise in either group. Mild elevation in liver enzymes occurred in one control patient and one patient on tienilic acid; the latter drug was stopped and the values returned to normal. 8 The general incidence of side-effects was low. 9 Our impression was that tienilic acid was a useful drug. Whether it could have been used safely with monitoring of liver function will not now be known.     

Induction of microsomal epoxide hydrolase by tienilic acid in the rat

The effects of tienilic acid [2,3-dichloro-4-(2-thienylcarbonyl)phenoxy acetic acid] on drug-metabolizing enzymes in the rat liver and kidneys were studied. Short-term treatment for 2 weeks (450 mg per kg per day) increased the activity of microsomal epoxide hydrolase at least two-fold in both rat liver and kidneys. The effect of tienilic acid on the activity of microsomal epoxide hydrolase in the rat liver correlated with the dose at levels of 20-450 mg per kg per day for 14 days (r = 0.92). Tienilic acid had only marginal effects on cytochrome-P-450-mediated mono-oxygenases. Tienilic acid caused an approximately two-fold increase in glucuronide conjugation of 4-methylumbelliferone in the liver. No increase in the activity of rat hepatic microsomal UDP-glucuronosyltransferase toward O-aminophenol was detected. According to these results, tienilic acid can be regarded as one of the most specific inducers of microsomal epoxide hydrolase.     

Effect of chronic diuretic treatment on the plasma renin-angiotensin-aldosterone system in essential hypertension.

1 Chronic treatment with a constant dose of hydrochlorothiazide or tienilic acid increases plasma renin activity (PRA) acutely to reach a maximum within the first week. 2 During chronic diuretic therapy from 1 month to 1 year, PRA remained elevated at a rather constant level, though this was somewhat lower than the maximum level reached after 1 week. 3 A significant (P less than 0.01) correlation (r = 0.74) between changes in plasma angiotensin II and renin activity provoked by chronic treatment for 3 months with hydrochlorothiazide and tienilic acid was found. 4 The increase in plasma aldosterone during chronic treatment with hydrochlorothiazide and tienilic acid (1000 mg) is related (r = 0.68; P less than 0.01) to the rise in plasma angiotensin II.     

Relative potency of spironolactone, triamterene and potassium chloride in thiazide-induced hypokalaemia.

1 The influence of spironolactone 50 mg and 100 mg daily, triamterene 100 mg and 200 mg daily, potassium chloride 32 mmol and 64 mmol daily and placebo on plasma potassium and other variables was examined in a random crossover study of nine hypertensive patients taking bendrofluazide 10 mg daily. 2 Spironolactone and triamterene had significant and parallel dose-response curves for plasma potassium, with a relative potency for triamterene:spironolactone of 0.25:1, significantly lower than the accepted 0.5:1 ratio. These drugs also lowered serum sodium, bicarbonate and body weight, and increased serum urea and creatinine. 3 Potassium chloride increased plasma potassium above placebo values, but the dose-response was not significant and was not parallel with those of the potassium-sparing drugs. Seven of nine patients remained hypokalaemic despite treatment with 64 mmol potassium chloride daily. 4 The relative expense, convenience and toxicity of the potassium-sparing drugs should be assessed at equivalent doses, namely spironolactone 50 mg:triamterene 200 mg:amiloride 20 mg. Potassium chloride does not correct moderate diuretic-induced hypokalaemia even at doses of 64 mmol daily.     

Antihypertensive property of a novel uricosuric diuretic,S-8666, in rats

The antihypertensive, diuretic, and toxicological effects of S-8666 were studied in rats. At doses of more than 60 mg/kg/day, p.o., S-8666 was antihypertensive in DOCA-salt hypertensive rats with a potency corresponding to 1/20 of that of trichlormethiazide. The antihypertensive effect was dose-dependent, and, at the higher doses, S-8666 had a more potent depressor effect than trichlormethiazide. The antihypertensive activity of S-8666 was shown predominantly by the S-(?)-enantiomer, with the R-(+)-enantiomer being only slightly active. A similar dose-dependent antihypertensive effect was shown by furosemide, tienilic acid, or indacrinone, but the therapeutic index (LD₅₀/minimum effective dose) of S-8666 was the highest among them. The acute diuretic and natriuretic effects of S-8666 after oral administration of 60–200 mg/kg to DOCA-salt hypertensive rats correlated well with its antihypertensive effect, although such diuretic and natriuretic effects in normotensive rats had no effect on blood pressure. S-8666, like trichlormethiazide, showed a prophylactic effect on the development of hypertension in DOCA-salt hypertensive rats, salt-loaded spontaneously hypertensive rats (SHR), and salt-loaded Dahl-S rats, though it was much less potent. Moreover, the combination of S-8666 with captopril in SHR enhanced the depressor effect of captopril like hydrochlorothiazide. These results indicate that S-8666 can be an effective nonthiazide diuretic for use as an antihypertensive agent.     

TIENILIC ACID IN THE TREATMENT OF MILD TO MODERATE HYPERTENSION

1. A double-blind crossover trial comparing the antihypertensive effect of tienilic acid and hydrochlorothiazide was conducted in thirty-eight patients with mild to moderate hypertension. 2. Tienilic acid was shown to be as effective as hydrochlorothiazide in controlling blood pressure. 3. Tienilic acid significantly lowered serum uric acid levels compared with both placebo and hydrochlorothiazide. 4. Tienilic acid was generally well tolerated but one patient developed acute renal failure due to acute allergic interstitial nephritis whilst taking the drug.     

Multicentre comparative trial of tienilic acid and hydrochlorothiazide in hypertensive patients

Summary To compare the clinical and metabolic effects of a new diuretic uricosuric agent, tienilic acid, with those of hydrochlorothiazide, a multicentre double-blind trial was performed in 56 hypertensive patients. Twenty — eight patients were randomly assigned to take tienilic acid and 28 to take hydrochlorothiazide. The diuretic and anti-hypertensive actions of the two compounds were similar. No significant differences were observed between tienilic acid and hydrochlorothiazide in their effects on urinary and serum electrolytes, hepatic and renal function tests, and fasting lipids. The patients who received tienilic acid showed a significant fall in serum uric acid, mediated by the uricosuric effect. The availability of an agent combining diuretic, anti-hypertensive and hypouricemic effects offers promise in the treatment of arterial hypertension.     

Indapamide and bendrofluazide: a comparison in the management of essential hypertension.

1 To compare the efficacy of indapamide with that of bendrofluazide a randomised trial was carried out in twenty patients with essential hypertension. 2 Indapamide (2.5 mg a day) and bendrofluazide (5 mg a day) produced a significant but equivalent fall in blood pressure. 3 Both drugs caused a reduction in body weight and serum potassium with a rise in plasma renin activity but there were no other major side effects. 4 In twelve patients treated with a combination of indapamide and bendrofluazide there was no additional fall in mean blood pressure or serum potassium compared to treatment with bendrofluazide or indapamide alone.     

Ketanserin in essential hypertension: use as monotherapy and in combination with a diuretic or beta-adrenoceptor antagonist.

1. The antihypertensive efficacy and tolerability of twice-daily treatment with the 5-hydroxytryptamine antagonist ketanserin were examined in a double-blind, placebo-controlled trial of 7 weeks duration in 56 hypertensive patients. Twenty were untreated, 20 were already taking bendrofluazide 5 mg daily, and 16 were already taking atenolol 100 mg daily. Randomisation was stratified to compare ketanserin with placebo as monotherapy (n = 20), when added to bendrofluazide (n = 20), and when added to atenolol (n = 16). 2. The antihypertensive effect of ketanserin in all patients completing the study (mean daily dose 71 mg) was 10/6 mm Hg supine (P less than 0.01/P less than 0.01) and 6/6 mm Hg standing (NS/P less than 0.01) when blood pressure was measured 2 h after the morning dose. Responses were similar in patients taking ketanserin as monotherapy, in addition to bendrofluazide, and in addition to atenolol, with reductions in mean arterial pressure of 4.6, 7.4 and 8.9 mm Hg respectively. 3. Ketanserin had no antihypertensive effect when measured 14 h after the last dose. The rise in blood pressure between 2 and 14 h after dosing was 11/4 mm Hg supine (P less than 0.01/NS) and 8/5 mm Hg standing (P less than 0.05/P less than 0.05). 4. The antihypertensive response to ketanserin was positively related to initial blood pressure and, independent of this, to age. It was not related to plasma concentrations of ketanserin or ketanserinol. 5. Five of 28 patients taking ketanserin discontinued treatment because of side-effects, compared with one of 28 patients taking placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of diuretic therapy on adrenaline-induced hypokalaemia and hypomagnesaemia

Summary We have examined the interaction between the administration of bendrofluazide, frusemide, spironolactone, and placebo and increased plasma adrenaline concentrations in a double-blind, placebo-controlled, cross over study.We studied healthy subjects on the fourteenth day of each treatment period and after a two hour infusion of adrenaline (0.06 µg·kg^–1·min^–1 {0.33 nmol·kg^–1·min^–1}) we measured their heart rates, blood pressures, and plasma potassium and magnesium concentrations.There were no differences in heart rates or blood pressures for all four treatments. Baseline potassium concentrations were not significantly different compared to placebo, and plasma potassium fell during the period of the infusion on all study days. this fall was significantly greater on frusemide (0.5 mmol·l^–1) and bendrofluazide (0.4 mmol·l^–1) compared with both placebo and spironolactone.Baseline plasma magnesium concentration were not different and similar falls in plasma magnesium were seen on all four treatments during and after the adrenaline infusion.We conclude that chronic diuretic therapy with a thiazide diuretic or frusemide may increase the severity of hypokalaemia during short-term rises in plasma adrenaline. Pretreatment with spironolactone had no effect on adrenaline-induced hypokalaemia. None of the diuretics studied altered adrenaline-induced hypomagnesaemia.     

Contribution of atenolol, bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

Uricosuric and diuretic activities of DR-3438 in dogs and rabbits

The purpose of this study was to evaluate the uricosuric and diuretic properties of the new diuretic agent DR-3438. In the conventional clearance studies in urate-loaded dogs, intravenous injection of DR-3438 (3-30 mg/kg) resulted in dose-related increases in fractional excretion of urate (FEua), urine flow and sodium excretion. At doses causing similar natriuresis, tienilic acid (50 mg/kg, i.v.) markedly increased the FEua value, whereas indacrinone (1 mg/kg, i.v.) had no significant effect on it. Trichloromethiazide (1 mg/kg, i.v.) and furosemide (0.3 mg/kg, i.v.) tended to decrease the FEua. Thus, the uricosuric activity of DR-3438 (30 mg/kg) was 0.6-fold that of tienilic acid and 3.4-fold that of indacrinone. In contrast, in urate-loaded rabbits that exhibit net tubular secretion of urate, intravenous DR-3438 (30 mg/kg) produced a significant decrease in FEua. Stop-flow studies in dogs revealed that DR-3438 (30 mg/kg) blocks both urate reabsorption and p-aminohippurate secretion in the proximal segment of the nephron and strongly inhibits reabsorption of water, sodium and potassium in the distal segments. These results suggest that DR-3438 exerts uricosuric activity through blocking urate transport in the proximal tubules and diuretic and saluretic activities by inhibiting water and sodium reabsorption in the distal segment of the nephron.     

Adequacy of twice daily dosing with potassium chloride and spironolactone in thiazide treated hypertensive patients.

1. The effects of 4-6 weeks treatment with placebo, potassium chloride 32 mmol 12 hourly, and spironolactone 25 mg 12 hourly upon the plasma potassium concentration-time profile were examined in hypertensive patients taking bendrofluazide 5 mg daily. 2. When compared with placebo, potassium chloride increased peak plasma potassium concentration (P less than 0.05), 12 h AUC for plasma potassium (P less than 0.1), and 12 h urine potassium excretion (P = 0.002). Spironolactone increased peak plasma potassium concentration (P less than 0.05), and 12 h AUC for plasma potassium (P less than 0.05), compared with placebo values. 3. Potassium chloride and spironolactone did not differ significantly in any respect other than 12 h urine potassium excretion. The 12 h AUC for plasma potassium was 35% larger with spironolactone than potassium chloride (not significant). 4. With both active drugs peak plasma potassium was observed 2-3 h after dosing, and efficacy tended to wane towards 12 h. However, variability of plasma potassium within the dose interval was not increased markedly, and 12 hourly dosing is probably satisfactory for both potassium chloride and spironolactone at the doses studied.     

Effects of different antihypertensive drugs on plasma fibrinogen in hypertensive patients.

1. In order to evaluate whether treatment with different antihypertensive drugs would affect plasma fibrinogen levels, 118 mild to moderate essential hypertensive subjects, all males, aged 18 to 65 years, were randomly treated with amlodipine 10 mg, atenolol 100 mg, hydrochlorothiazide 25 mg or lisinopril 20 mg, all given once daily for 8 weeks. 2. Before and after 8 weeks' treatment, blood pressure (BP), heart rate (HR), fibrinogen, total cholesterol (TC), HDL-C, LDL-C, triglycerides (TG), plasma glucose, plasma uric acid, serum creatinine and serum potassium were evaluated. 3. All four medications significantly reduced BP values, although the BP lowering effect of lisinopril, amlodipine and atenolol was significantly greater compared with that of hydrochlorothiazide. 4. Plasma fibrinogen levels were unaffected by atenolol, hydrochlorothiazide and amlodipine, whereas they were significantly decreased by lisinopril (-11.2%, P = 0.002). This fibrinogen lowering effect was more evident in smokers (-17.7%) than in non smokers (-7.4%). 5. Atenolol and amlodipine did not significantly affect plasma lipids, hydrochlorothiazide increased TC, LDL-C and TG and reduced HDL-C; lisinopril increased HDL-C and decreased TC and LDL-C. 6. Hydrochlorothiazide increased plasma glucose and uric acid concentrations, which were unaffected by the other drugs. The diuretic also reduced serum potassium. 7. The results of this study indicate that lisinopril reduces levels of plasma fibrinogen and confirm that different antihypertensive drugs may elicit different metabolic effects, which may variously influence the overall risk profile of the hypertensive patients.     

A new uricosuric diuretic, S-8666, in rats and chimpanzees

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyli c acid (S-8666) was studied as a possible new uricosuric diuretic agent using rats and chimpanzees. Various new compounds belonging to the 5-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acids were clearly diuretic with uricosuric activity in intraperitoneally oxonate-treated rats. S-8666 was chosen as a favorable candidate because its uricosuric activity due to the effects of tubular transport of uric acid were apparently more marked than those of known uricosuric agents such as probenecid, benzbromarone, tienilic acid and indacrinone in oxonate-treated rats. S-8666 was also uricosuric in rats not given urate oxidase inhibitor. The diuretic effect of S-8666 in oxonate-treated rats was as high-ceilinged as that of furosemide, while those of tienilic acid, indacrinone and a known compound of a 5-carbonyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid were rather low-ceilinged. These uricosuric and diuretic activities of S-8666 were manifested by two enantiomers, of which the (+)-enantiomer displayed predominantly uricosuric activity and the (-)-enantiomer, diuretic activity like furosemide. The new compound was also uricosuric and diuretic in chimpanzees, although the potency of the uricosuric activity was similar to that of probenecid and less than that of indacrinone. Thus, it seems that S-8666 is a different type of uricosuric diuretic from known agents which have already been tried in humans.     

Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study

AIMS: Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio. METHODS: We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed-up for a period of up to 3 years. RESULTS: We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BP相似文献   

Spironolactone in thiazide-induced hypokalaemia: variable response between patients.

1 The influence of spironolactone 25, 50, 100 and 200 mg daily, and placebo, on plasma potassium and other variables was examined in a random crossover study of 15 hypertensive patients taking bendrofluazide 10 mg daily. 2 Spironolactone produced significant dose-related increases in plasma potassium and aldosterone, and reductions in plasma sodium and bicarbonate. 3 In 14 compliant patients plasma concentrations of the major metabolite canrenone were related linearly to the dose of spironolactone, and there was less than twofold variation between patients. The plasma canrenone concentration correlated negatively with body weight (r = -0.77, P less than 0.001). 4 The plasma potassium response to spironolactone varied sevenfold between compliant patients. The response correlated negatively with placebo plasma potassium (r = -0.62, P less than 0.02), positively with plasma canrenone (r = +0.55, P less than 0.05), but was unrelated to plasma aldosterone (r = -0.22). In one patient relative resistance to spironolactone was attributed to exaggerated secondary hyperaldosteronism induced by the drug. 5 The variability in response to spironolactone between patients is such that fixed dose thiazide-spironolactone combination tablets are unlikely to prevent hypokalaemia reliably.     

Toxicological studies on tienilic acid in rats

The subacute oral toxicity of tienilic acid in male and female Sprague-Dawley rats has been studied. Animals were given tienilic acid 0, 30, 120 and 480 mg/kg body weight as a 3% gum arabic suspension for 28 days. At 30 mg tienilic acid blood pressure and serum uric acid decreased. At the two higher dose-levels a slight decrease in hemoglobin and an increase in S-GPT was noticed and there was a significant increase in the liver weight and serum magnesium concentration of male rats, while the liver weight of female rats increased only slightly. On microscopic examination, unicellular necrosis of small groups of liver cells was noted, together with focal round-cell infiltration and some stasis of the two higher dose-levels in some animals. Tienilic acid had no noticeable effects on other organs or parameters.