Simultaneous determination of the binary mixture of nifedipine and mefruside using derivate spectroscopy, capillary gas-liquid chromatography and high performance liquid chromatography.

Accurate, precise first-derivative ultraviolet spectrophotometric, gas-liquid and high performance liquid chromatographic methods for the determination of nifedipine and mefruside in tablet dosage form were described. The first-derivative method depends on measurements of the derivative amplitudes by peak-to-base and zero-crossing techniques, at 390 and 282 nm, for the determination of nifedipine and mefruside, respectively. Calibration graphs were linear (r = 0.9999) ranging from 8-40 and 20-60 micrograms ml-1 for nifedipine and mefruside, respectively, in presence of one another. The gas-liquid chromatographic method (GLC) was based on using cross-linked methylsilicone gum capillary column with flame ionization detector for the determination of nifedipine and mefruside in the binary mixture. The high performance liquid chromatographic (HPLC) method was based on using a reverse-phase column with a mobile phase of methanol-water (55-45, pH = 4.5) with UV detection at 260 nm. The three methods showed good linearity, precision and reproducibility. The proposed methods were successfully applied to the determination of both drugs in pharmaceutical tablets.

Antihypertensive mechanism of diuretics based on pressure-natriuresis relationship.

We analyzed the hypotensive mechanisms of a thiazide-type diuretic, mefruside, on the basis of the pressure-natriuresis relationship. We performed a 5-week study in eight patients with essential hypertension who were given a high sodium diet (15 to 18 g NaCl per day) during the 1st and 5th weeks, a severely sodium-restricted diet (1 to 3 g/d) during the 2nd week, and a mildly sodium-restricted diet (5 to 7 g/d) during the 3rd and 4th weeks. Mefruside (25 mg/d) was administered during the 4th and 5th weeks. Urinary sodium excretion rate and mean arterial pressure were measured at the end of each week, and the pressure-natriuresis relationship was drawn by plotting urinary sodium excretion rate on the ordinate and mean arterial pressure on the abscissa before and after mefruside treatment. Before treatment, the pressure-natriuresis relationship was linear, and mean arterial pressure was changed as a consequence of sodium intake alteration (1st week, 117 +/- 9 mm Hg; 2nd week, 105 +/- 7; 3rd week, 109 +/- 9). After treatment, however, the change in mean arterial pressure was very small (4th week, 102 +/- 8 mm Hg; 5th week, 104 +/- 7). Mefruside steepened the slope of the relationship (20.8 +/- 10.5 versus 143 +/- 85 [mmol/d]/mm Hg, P <.005) without significantly shifting the x intercept (104 +/- 6 versus 101 +/- 9 mm Hg, P=NS) of the relationship. The increase in the slope was greater in patients whose slope had been depressed and blood pressure was sodium sensitive before mefruside treatment. The hypotensive effect of mefruside during a high sodium diet correlated positively with both the hypotensive effect of sodium restriction (r=.84, P <.01) and the increase in the slope by mefruside (r=.83, P <.02). Thus, mefruside lowers blood pressure especially in patients with high sodium sensitivity mainly by making blood pressure sodium insensitive through its diuretic action. Strict sodium restriction seems unnecessary when diuretics are administered for blood pressure control.

Nitrendipine and mefruside in elderly hypertensives: effects on blood pressure, cardiac output, cerebral blood flow and metabolic parameters.

In this multicentre, randomised, double-blind, cross-over study, we evaluated and compared the effects of nitrendipine (a calcium entry blocker of the dihydropyridine group) and mefruside (a diuretic) on BP, cardiac output, cerebral blood flow and metabolic parameters in 22 elderly hypertensives. Eight weeks of treatment with nitrendipine (27.3 mg daily) and mefruside (30.7 mg daily) significantly reduced BP values to almost the same extent. Heart rate, cardiac output (n = 14), cerebral blood flow (n = 20), renin activity and aldosterone remained unchanged during nitrendipine and mefruside treatment. Nitrendipine did not alter any metabolic parameter (electrolytes, lipid values and blood glucose); in patients treated with mefruside serum potassium fell by 0.4 mmol/l (P < 0.001). Minor adverse events were reported in both treatment groups, mostly due to vasodilation. We conclude that both drugs possess potent and comparable haemodynamic and anti-hypertensive properties. They reduce BP by reducing total peripheral vascular resistance with maintained autoregulation of cerebral blood flow. The metabolic disturbances induced by mefruside seem to be less pronounced than that observed with other thiazide diuretics.

[Therapy of mild to moderate hypertension. Efficacy and tolerance of Amlodipine in comparison with the combination nifedipine/mefruside]. / Therapie der leichten bis mittelschweren Hypertonie. Wirksamkeit und Verträglichkeit von Amlodipin im Vergleich zur Fixkombination Nifedipin/Mefrusid.

Earlier clinical trials demonstrated the anti-hypertensive effect of amlodipine, a new calcium channel blocker of the dihydropyridine type. In the present comparative study, we investigated the anti-hypertensive effect of amlodipine in comparison with a combination of nifedipine and mefruside. In both groups, the anti-hypertensive effect was comparable. Normalization of the supine diastolic blood pressure was observed in 72.3% of patients treated with amlodipine and in 66.6% of those patients in the combination group. Both drugs were generally well tolerated, with a somewhat higher incidence of side effects being observed in the combination group. The study shows that amlodipine monotherapy in mild-to-moderate hypertension is equally as effective as combination therapy with nifedipine/mefruside, with amlodipine being superior in terms of tolerability.

Marked hypokalemic rhabdomyolysis with myoglobinuria due to diuretic treatment.

A 74-year-old male was admitted to hospital with acute rhabdomyolysis and myoglobinuria due to hypokalemia. The hypokalemia resulted from diuretic treatment. He had no family history of myopathy, and no diarrhea and vomiting. The neurological examination revealed painful quadriplegia. The blood pressure was 160/74 mm Hg. Laboratory examination showed hypokalemic and hypochloremic metabolic alkalosis (serum K 1.5 mEq/l, serum Cl 89 mEq/l, base excess + 20.9, HCO3- 44.9 mmol/l, pH 7.563) and marked elevations of serum CPK, LDH, GOT, GPT and myoglobin. Endocrinological and renal functions were normal. Muscle biopsy revealed marked necrosis with remarkable phagocytosis and vacuolar degeneration. The cessation of diuretics and intravenous infusion of potassium chloride resulted in a marked improvement in clinical and laboratory findings. The diuretics-induced hypokalemic myopathy is rare in the literature.

Influence of co-dergocrine mesilate/nifedipine compared to mefruside/nifedipine on circadian blood pressure in patients with essential hypertension.

This randomised, parallel group study was designed to compare the efficacy of nifedipine (40 mg once daily) combined with either the dopamine agonist, co-dergocrine mesilate (4 mg once daily) or the diuretic mefruside (25 mg once daily) in 40 patients with essential arterial hypertension and a diastolic blood pressure greater than 105 mmHg. Circadian blood pressure and heart rate were measured over 24 h every 15 min from 6 a.m. to 6 p.m. and every 30 min from 6 p.m. to 6 a.m. with an automatic, portable instrument (ICR 5300, Squibb) before and after a three-week treatment period. At the end of the three-week treatment period the mean value of all 24 h blood pressure measurements reflected highly significant decreases (2P less than 0.001), from 148/92 +/- 16/12 before treatment to 131/83 +/- 12/12 mmHg after treatment in the co-dergocrine mesilate/nifedipine group and from 145/92 +/- 16/10 before treatment to 129/84 +/- 10/6 mmHg after treatment in the mefruside/nifedipine group. Blood pressure reduction was still significant in both groups during the early morning hours at the end of the dosage interval. The efficacies of nifedipine combined with co-dergocrine mesilate or mefruside were comparable but side-effects were rated as more severe in the mefruside group. Therefore, the combination co-dergocrine mesilate/nifedipine may be preferable to the combination mefruside/nifedipine.

Effect of nifedipine and mefruside on renal reserve in hypertensive patients.

Changes in glomerular filtration rate and effective renal plasma flow following a protein meal were measured in seven patients with essential hypertension on no treatment and after 6 weeks' treatment with nifedipine and mefruside. Glomerular filtration rate and effective renal plasma flow increased significantly following a protein meal in patients on no treatment (P less than 0.01 and P less than 0.05 respectively). The response to a protein meal was lost following antihypertensive treatment (P less than 0.5 and P less than 0.1 respectively). Although there was some increase in the fasting values of glomerular filtration rate and effective renal plasma flow this was less pronounced and more difficult to demonstrate when only fasting values were compared. We propose that the loss of response to a protein meal is due to recruitment of renal reserve function and that protein meal challenge is a sensitive test for detecting changes in renal function.

Effects of diltiazem alone and combined with mefruside on cardiovascular response at rest and during exercise, carbohydrate metabolism and serum lipoproteins in patients with systemic hypertension.

The antihypertensive effects of the calcium antagonist diltiazem, both alone and combined with the diuretic mefruside, were assessed over 14 months in 36 patients with essential hypertension. Patients received 180 or 270 mg/day; those with inadequate response were given 270 mg/day plus mefruside, 20 mg/day. Both monotherapy and combination therapy significantly reduced blood pressure (BP) at rest and during exercise. However, adding mefruside did not significantly decrease BP below that achieved with diltiazem alone. After 14 months of therapy, the percentage of responders (patients with at least 10% reduction in diastolic BP at rest) was 64% for all patients, 100% (by definition) for those receiving diltiazem alone and 47% for those receiving the combination. Diltiazem decreased heart rate by 6% (4 beats/min at rest) (p less than 0.05). Combined therapy with mefruside did not further reduce heart rate. There were few adverse effects and no undesirable metabolic effects with either monotherapy or combined therapy. Plasma renin activity, aldosterone levels, carbohydrate metabolism, serum lipoprotein levels and routine laboratory test results were unchanged in both groups at the end of the study. Thus, diltiazem is an effective antihypertensive agent and apparently the combination of diltiazem and mefruside does not potentiate the antihypertensive effect of diltiazem alone during long-term therapy.

Calcium entry blockade or beta-blockade in long-term management of hypertension in blacks.

The long-term efficacy of nitrendipine and acebutolol was assessed during a 40-week double-blind randomized trial in 60 hypertensive blacks. Nitrendipine (mean dose 32 mg/day) and acebutolol (414 mg/day) were administered in monotherapy in increasing dosage and mefruside was added in patients not controlled by monotherapy. The recumbent and standing blood pressures were reduced (P less than 0.01 or less) during monotherapy with nitrendipine and acebutolol, but the magnitude of blood pressure reduction was greater (P less than 0.05 or less) during nitrendipine dosing. Pulse rate decreased (P less than 0.01) during acebutolol whereas nitrendipine induced a nonsignificant increase. Both treatments induced no changes in serum electrolytes, creatinine, urea, uric acid, lipids, plasma renin activity, and plasma and urinary aldosterone. The overall incidence of side effects was similar with both treatments but four patients discontinued nitrendipine because of headache. The addition of mefruside to nitrendipine or acebutolol produced a further fall of blood pressure in patients not controlled with monotherapy. Monotherapy with nitrendipine or acebutolol offers an effective, safe first-line antihypertensive treatment in blacks entered in this study; with the described dosages and therapeutic schedule, nitrendipine was somewhat more effective than acebutolol.

Effect of nifedipine and mefruside on renal function and platelet function in hypertensive patients.

A study was carried out in 16 patients with moderately severe hypertension to investigate the effects of nifedipine, given alone or combined with a diuretic, on blood pressure and on renal and platelet function. After 4 weeks on placebo, patients were randomized to receive treatment for 6 weeks with either 20 mg, nifedipine twice daily or 25 mg mefruside once daily on a double-blind, double-dummy basis. All patients then received treatment for a further 6 weeks with a combination of the two drugs in the same dosage as before. The results of blood pressure measurements and laboratory investigations during the three phases of the study showed that significantly better blood pressure control was achieved with nifedipine alone than with mefruside alone. Mefruside had an additional hypotensive effect when added to nifedipine. There was no significant change in the renal blood flow or glomerular filtration rate, with a satisfactory control of blood pressure. There was also no detectable change in platelet aggregation with increasing concentrations of ADP and ristocetin. An adaptive mechanism could be responsible for the apparent lack of change compared with single dose studies.

A double-blind, placebo-controlled, crossover trial to investigate the additive hypotensive effect of a diuretic (mefruside) to that produced by nifedipine.

Several reports suggest that when diuretics are added to nifedipine (N), they do not exert any additional hypotensive effect to that produced by N alone. We present the first double-blind, crossover trial to investigate this interaction. Twenty-four black patients with moderate to severe essential hypertension entered the trial. After an initial "open" 4 weeks of therapy with N slow release (SR) 20 mg. b.i.d., those 17 patients whose blood pressures (BP) were not controlled (greater than 160 mm Hg systolic and/or greater than 90 mm Hg diastolic) were randomly allocated (double-blind) to 4 weeks treatment with N SR 20 mg. b.i.d., plus either mefruside 1 q.d. (a thiazide-like diuretic) or matching placebo. Patients then crossed over for a second 4 week treatment period. Blood pressures were measured at 2 weekly intervals under the same conditions using Hawksley random zero sphgymomanometers by one of two standardized observers after patients had been lying for 5 min and standing for 2 min. Analysis (taking account of period effect) of the mean results for the 16 patients completing the trial confirms that, contrary to what previous uncontrolled data suggest, lying and standing systolic and diastolic BPs are significantly lower (8.5/4.5 mm Hg: 2p less than 0.01 and 7.9/5.0 mm Hg: 2p less than 0.05, respectively) with nifedipine plus diuretic than with nifedipine plus placebo.

Liver carbonic anhydrase and urea synthesis. The effect of diuretics.

In isolated perfused rat liver, urea synthesis is rapid and reversibly inhibited not only by the well-known carbonic anhydrase inhibitors acetazolamide, methazolamide and ethoxzolamide, but also by diuretics, like xipamide, mefruside, chlortalidone, and chlorothiazide. Furosemide was without effect. Similar to findings with isolated perfused rat liver, acetazolamide inhibits urea synthesis from ammonium ions in normal and cirrhotic human liver slices. Inhibition of urea synthesis by xipamide and acetazolamide is accompanied by a 70% decrease of the cellular citrulline content and the tissue levels of 2-oxoglutarate and citrate, suggesting a block of urea synthesis at a step prior to citrulline formation. At a constant extracellular pH (7.4), inhibition of urea synthesis by xipamide, mefruside and acetazolamide was overcome by increasing the extracellular concentrations of HCO3- and CO2 to above twice the normal values. This shows that inhibition of urea synthesis by these diuretics is not due to an unspecific inhibition of one of the urea cycle enzymes but is due to an inhibition of mitochondrial carbonic anhydrase and therefore due to an impaired HCO3- provision for mitochondrial carbamoylphosphate synthesis. It is concluded that the activity of mitochondrial carbonic anhydrase is required for urea synthesis also in human liver and that several diuretics impair urea synthesis by inhibition of mitochondrial carbonic anhydrase. The pathophysiological significance of these data is discussed with respect to the development of diuretics-induced hyperammonemia and alkalosis in liver disease.

Comparison of nifedipine (retard formulation) and mefruside in the treatment of mild to moderate hypertension--a prospective randomized double-blind crossover study in general practice.

Twenty-two patients under general practice care, suffering mild to moderate hypertension and receiving no active treatment had three baseline blood pressure measurements taken during a single blind 4-week placebo run-in period. One patient was secondarily excluded at this stage because of a placebo response and one patient dropped out for personal reasons. The remaining 20 patients were randomized to receive either nifedipine 20 mg twice a day or mefruside 25 mg once a day in a classical two-period crossover design with 8-week treatment periods separated by a 4-week single-blind placebo washout. During 8 weeks nifedipine therapy the mean supine blood pressure was reduced from 173 (s.d. = 15.4)/107(s.d. = 6.4) mmHg to 150(s.d. = 16.7)/93(s.d. = 10.8) mmHg whereas the corresponding reduction for mefruside was from 174(s.d. = 15.9)/107(s.d. = 9.4) mmHg to 153(s.d. = 19.1)/94(s.d. = 9.7) mmHg. Neither drug affected postural changes in blood pressure. Standing blood pressure measurements under 8 weeks nifedipine therapy fell from 172(s.d. = 12.3)/103(s.d. = 5.6) mmHg to 150(s.d. = 17.9)/94(s.d. = 10.0) mmHg with corresponding changes for mefruside being 174(s.d. = 14.7)/106(s.d. = 9.0) mmHg to 150(s.d. = 20.2)/95(s.d. = 9.4) mmHg. Since blood pressures returned to within 4% of baseline values by the end of the placebo washout period it can be inferred that each therapy was a significant (P less than 0.05 for all blood pressure variables) antihypertensive treatment in its own right.

Effects of acebutolol combined with mefruside on total-body and serum potassium in essential hypertensive patients.

Fifteen essentially hypertensive patients were treated with a fixed combination of the beta-adrenoceptor antagonist acebutolol and the diuretic substance mefruside for 6 weeks. The systolic and diastolic blood pressure as well as the heart rate were significantly reduced. Before and after the treatment period, total-body and serum potassium were examined. Both parameters were not significantly changed. Diuretic therapy causes hypokalemia by increased potassium excretion in the distal tubulus, whereas beta-adrenoceptor antagonists could compensate this effect by a mechanism which is not yet clarified.