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PubMed1975

[Dose-effect comparison of antihypertensive combinations with and without alpha-methyldopa].

In an open clinical trial, 30 compensated cardiac patients with essential hypertension were selected and randomly distributed. Treatment was given by means of two combinations of active agents, one containing 0.15 mg reserpine, 15 mg mefruside and 150 mg inositol nicotinate and the other 0.10 mg reserpine, 10 mg mefruside and 125 mg alpha-methyldopa. A randomized control group of 30 patients with essential hypertension received 0.15 mg reserpine, 15 mg mefruside and 150 mg isositol nicotinate exclusively over the same treatment period. By substituting only 125 mg alpha-methyldopa for 150 mg inositol nicotinate, the reserpine-mefruside portion can be reduced by one third while still obtaining the same antihypertensive effect.

Aged↗
PubMed1990

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.

Adult↗
PubMed1986

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.

Acetazolamide↗
PubMed1987

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.

Acebutolol↗
PubMed1977

Effect of saluretic therapy on muscle content of water and electrolytes in relation to hemodynamic variables.

Muscle content of water and electrolytes (needle biopsy), intraarterial BP and cardiac output (dye dilution technique) were measured in 12 patients with essential hypertension before and after 4 months of mefruside therapy (25 mg/day). Before therapy there were no significant differences in muscle tissue electrolyte and water content compared with normotensive subjects. No correlation was found between central hemodynamic variables and the electrolyte and water content of muscle tissue either before or after therapy. After 4 months of mefruside therapy, muscle tissue water showed a mean decrease which was not significant. Serum potassium and muscle potassium content decreased significantly but there was no significant change in intracellular potassium concentration. Intracellular sodium concentration increased significantly, while muscle sodium content showed a mean increase which was not statistically significant. The change in intracellular sodium concentration showed a significant negative correlation with the decrease in mean arterial BP. The change in total cellular water content showed a significant negative correlation to the changes in total peripheral vascular resistance. Saluretic therapy seems to induce counterregulatory mechanisms that interfere with the hypotensive effect.

Adult↗
PubMed1977

Carotid baroreceptor function in hypertensive patients.

Carotid baroreceptor function has been studied in twenty-five patients with essential hypertension and in ten normotensive control subjects of corresponding age. The carotid baroreceptors were stimulated by increasing the transmural pressure over the carotid arteries by the application of negative pressure in a box enclosing the neck. Stimulation elicited significant decreases in intra-arterial blood pressure, heart rate and cardiac index in both hypertensive and normotensive subjects. Both groups also showed a significant decrease in stroke index and a significant increase in total peripheral vascular resistance index. The response to carotid sinus stimulation did not differ significantly between the two groups. In fourteen of the hypertensive subjects, carotid baroreceptor function was studied after 4 months of saluretic therapy, mefruside, and in nine of these patients after additional treatment with a beta-receptor blocking drug, alprenolol, for another 4 months. Both mefruside and alprenolol induced a significant decrease in mean arterial blood pressure but the response to the carotid baroreceptor stimulation was not significantly altered. The findings indicate that the carotid baroreceptor is re-set to the actual blood pressure level, with little or no change in gain in hypertensive subjects both without and during hypotensive therapy.

Adult↗
PubMed1982

[The effect of beta-receptor antagonists and diuretics and their combination on blood pressure and pressure-rate product during ergometric work in hypertensive patients (author's transl)].

1. Hypertensive patients are particularly endangered by disproportionately high increases in blood pressure during daily physical and emotional activity. For this reason, antihypertensive drugs should also be able to influence there pressure changes. 2. Therefore the ability of the beta-receptor antagonist acebutolol (400 mg/die) and of the diuretic mefrusid (25 mg/die) to reduce exercise-induced increases in blood pressure and pressure-rate product during and after standardized ergometric work (50--100 watts) was compared in a within-patient study of 42 outpatients with arterial hypertension (stage 1 to 2, WHO) aged 18 to 50 years. 3. Both drugs resulted in a significant reduction of systolic (p less than 0.05-p less than 0.001) and diastolic (p less than 0.05-p less than 0.001) blood pressure at rest. However, systolic and diastolic blood pressure (p less than 0.001) and pressure-rate product (p less than 0.001) during exercise were only significantly reduced by acebutolol. 4. The strongest blood pressure lowering effect under all conditions could be proven for the free and fixed combination of acebutolol and mefrusid. 5. From these findings it is concluded: (1) beta-adreno-receptor blocking agents are the drugs of first choice in the baseline therapy of mild to moderate arterial hypertension, (2) diuretic drugs potentiate the antihypertensive effect of beta-blocking agents. 6. This therapeutic regimen is recommended especially for hypertensives with ischemic heart disease, because diuretics fail to reduce pressure-rate product as a measure of myocardial O2-consumption.

Acebutolol↗
PubMed2002

Transport of anionic drugs across the basolateral membrane of proximal S2 segments of the rabbit kidney. Inverse relationship between the affinity to the p-aminohippurate transport system and the transport rate.

The renal p-aminohippurate (PAH) transport system, which resides in the S2 segments of proximal tubules, is a main tubular secretory system for drugs. Previous studies have shown that the hydrophobicity of drugs is positively correlated with their affinity for the basolateral PAH transporter. Affinity was deduced from inhibition of tubular 3H-PAH uptake. However, up to now, no studies are available which tested the relationship between hydrophobicity and transport rate of drugs. Therefore, in the present study, the basolateral transport rates of several drugs (probenecid, CAS 57-66-9, furosemide, CAS 54-31-9, bumetanide, CAS 28395-03-1, mefruside, CAS 7195-27-9) which are substrates of the PAH transporter and which differ markedly regarding their hydrophobic properties (log P values ranging from 1-3) were determined on non-perfused proximal S2 segments microdissected from rabbit kidneys without the use of enzymatic solutions. To measure the transport rate advantage of the finding was taken that the PAH transporter in the basolateral membrane of proximal S2 segments acts as a countertransporter which exchanges PAH with dicarboxylates (glutarate or alpha-keto-glutarate). Hence, the stimulatory effect of a drug on the 14C-glutarate efflux rate of 14C-glutarate preloaded S2 segments is a measure of its translocation across the basolateral cell membrane. The results revealed that with increasing hydrophobicity (mefruside < furosemide < bumetanide < probenecid) the stimulating effect of the drugs on 14C-glutarate efflux decreased indicating that the compounds are more slowly translocated although their potency to inhibit 3H-PAH uptake increased. Thus, an inverse relationship between hydrophobicity and hence affinity of the drugs for the PAH transporter and transport rate could be established.

Algorithms↗
PubMed1977

Sex hormone binding globulin binding capacity, testosterone, 5alpha-dihydrotestosterone, oestradiol and prolactin in plasma of patients with prostatic carcinoma under various types of hormonal treatment.

Sex hormone binding globulin (SHBG) binding capacity, the concentrations of testosterone (T), of 5alpha-dihydrotestosterone (DHT), of oestradiol-17beta (Oe2), of oestrone (Oe1), of prolactin (hPr) and the percentual specific binding of T to SHBG (%TB) were measured in plasma of patients suffering from prostatic carcinoma and of a control group of similar age. No significant differences in any of the investigated parameters were found between the control group and the carcinoma patients before treatment although 15% of the latter showed distinctly elevated hPr values. Treatment of carcinoma patients with 1) Antiandrogen (cyproterone acetate, Androcur) resulted in a significant decrease of T, Oe2 and SHBG. The DHT/T-ratio increased. n=5. 2) Orchidectomy caused an even more pronounced fall in T, DHT, Oe1 and Oe2 blood levels. SHBG was not altered. DHT/T-ratio increased. n=32. 3) Cyproterone acetate after orchidectomy led to elevated hPr values. n=5. 4) Oestrogen (diethylstiboestrol-diphosphate, Honvan) after orchidectomy increased SHBG and hPr. n=6. 5) Corticosteroid (Prednisone, Decortin) after orchidectomy decreased T and SHBG below the levels found after orchidectomy alone. n=5. 6) Diureticum (Mefruside, Baycaron) (n=5) or 7) a placebo (n=7) did not alter any of the parameters measured. 8) Treatment with HCG (Primogonyl) of patients suffering from oligozoospermia resulted in a significant increase of T, DHT and Oe2. SHBG was not altered. DHT/T-ratio decreased. n=7.

Chorionic Gonadotropin↗
PubMed1991

[Therapy of mild to moderate hypertension. Efficacy and tolerance of Amlodipine in comparison with the combination nifedipine/mefruside].

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.

Adult↗
PubMed1975

Comparison of the local effects of amiloride hydrochloride on the isotonic fluid absorption in the distal and proximal convoluted tubule.

The isotonic fluid absorption (Jv) was measured under standard conditions in the proximal and distal convolution of the rat kidney. The peritubular blood capillaries were perfused simultaneously. Amiloride was applied either intraluminally or peritubularly. When applied intraluminally, amiloride strongly inhibited Jv in the distal tubule at concentrations up to 10(-6) M. In the proximal tubule similar effects were obtained only after intraluminal application of one thousand-fold greater concentrations of amiloride. In contrast to amphibian epithelia, amiloride also inhibits Jv in the distal tubule when applied peritubularly, but at higher concentrations and less completely than after intraluminal application. Amiloride was found to be generally more effective in the distal tubule than furosemide and mefruside, although in the proximal tubule it was less effective than these diuretics. That amiloride is most effective after intraluminal application in the distal tubule would suggest a dominant action at the luminal membrane of the distal tubule cell, while not excluding a concomitant effect at the peritubular membrane.

Absorption↗
PubMed1979

Extramicrosomal drug metabolism.

Drug metabolizing enzymes which are not located in the microsomes such as oxidoreductases are reviewed. It has been reported that a cytoplasmic NAD+-dependent dehydrogenase could be involved in the dehydrogenation of secondary or primary alcohols, and that peroxidases, located in all extranuclear cell-fractions, are able to oxidize certain drugs. Among the conjugating enzymes, mainly the glucuronidases and 0-Methyltransferases have been reported to be localised in the microsomes. Sulfatation, mercapturic acid formation and acetylation seem to occur in the supernatant of animal liver cells. Binding to glycine has been found in the mitochondria. Examples of combined action of microsomes and other cell fractions are presented. Esterases are found in the microsomes and cytoplasmic fraction of animal cells and also in the extracellular fluid (blood-plasma). They are more stable than monooxygenases whose activity depends on the intact microsomal structure and are therefore readily accessible in human biological material. Metabolic problems involving human esterases can often easily be solved by in vitro experiments. Results concerning the biochemical degradation of propanidid, mefrusid, acetyl salicylic acid and an acetyl salicylic acid ester are reported.

Animals↗
PubMed1987

The role of antihypertensive pharmacologic treatment in countering adverse pathophysiological profiles: influence on small arteries.

Usually, when antihypertensive therapy is considered in the hypertensive patient, structural cardiovascular changes are already well established and the structure of the cardiovascular system is redesigned to maintain higher than normal pressure. Left ventricular hypertrophy has been shown to be an independent risk factor for all manifestations of coronary heart disease. In hypertension, the increased pressure load over a long period of time induces degenerative changes in, for example, cerebral, renal, and coronary vessels, with well-known clinical consequences. Independent of the primary cause of hypertension, full reversal to normotension will probably occur only when the structurally reset cardiovascular system has been returned to normal dimensions by regression of structural vascular changes. In animal models several forms of antihypertensive treatment have prevented the development of or induced regression of left ventricular hypertrophy as well as medial hypertrophy of the vessels. These effects have been related both to the extent of blood pressure reduction and to the degree of inhibition of neurohormonal trophic influences. In humans the results have been somewhat contradictory. Plethysmography has demonstrated a reduction of resistance at maximal dilatation with either combination therapy or pindolol but not with mefruside or atenolol. There may be several explanations for the difficulties in showing regression of structural vascular changes in humans: (1) inadequate treatment of high blood pressure, (2) reflexogenic activation of neurohormonal trophic factors, (3) investigation of an unsuitable vascular bed, or (4) treatment started too late. The ultimate goal in the treatment of hypertension is, of course, reduction of cardiovascular morbidity and mortality, but normalization of structural cardiovascular changes is clearly the second most important therapeutic goal.

Adaptation, Biological↗
PubMed1987

Liquid chromatographic screening of diuretics in urine.

We describe a liquid chromatographic screening procedure for the detection, in urine, of twelve of the fifteen potassium-depleting diuretics available in Australia. A 2-ml urine sample was acidified with NaH2PO4 (pH 4.1) and extracted with 4 ml ethyl acetate. The sample was cleaned up further by washing with 5 ml Na2HPO4 (pH 7.5). The ethyl acetate was then evaporated to dryness, the residue reconstituted in 100 microliters mobile phase and 5 microliter were injected onto a Merck LiChrosorb RP-18 (5 microns) column. The ultraviolet absorbance of the eluent was monitored at 271 nm for 10 min. The screen was evaluated by giving each of thirty volunteers the lowest recommended dose of one of the diuretics in the study and obtaining urine samples 4, 8 and 24 h after having taken the dose. Twelve diuretics, chlorothiazide, hydrochlorothiazide, quinethazone, chlorthalidone, methyclothiazide, clopamide, frusemide, metolazone, mefruside, bendrofluazide, cyclopenthiazide and bumetanide, were all detectable up to 24 h after a dose. We therefore conclude that the screen would be reliable for the detection of these diuretics in urine.

Chromatography, High Pressure Liquid↗
PubMed1976

Within-patient comparisons between different anti-hypertensive drugs.

1. By substituting one anti-hypertensive drug for the other in a panel of hypertensive patients equipotent doses have been determined. 2. Thus 40 mg of propranolol is equivalent to 4-5 mg of pindolol, 98 mg of practolol, 128 mg of alprenolol, 49 mg of metoprolol, 42 mg of tolamolol and 4-4 mg of timolol. 3. Bendorfluazide (10 mg) is eqivalent to 1-6 mg of bumetanide, 20 mg of chlorthalidone, 35 mg of mefruside and 3-5 mg of amiloride together with 35 mg of hydrochlorthiazide. 4. Methyldopa (250 mg) is equivalent to 6-0 mg of debrisoquine and 0-5 mg of St 600 (Boehringer), which is a clonidine-like substituted imidazoline.

Adrenergic beta-Antagonists↗
PubMed1978

Increased ratio between serum beta- and alpha-lipoproteins during diuretic therapy: an adverse effect?

1. The effect of diuretic therapy on serum lipids and lipoprotein fractions was evaluated in 16 normal or labile hypertensive subjects who received in cross-over fashion chlorthalidone, frusemide or mefruside, each for 4 weeks (group A); and in 13 patients with essential hypertension treated with chlorthalidone for 6 weeks (group B). 2. All three diuretics significantly increased the ratio between serum beta- and alpha-lipoprotein fractions. This was due to an increase of the serum beta-lipoprotein fraction while the alpha-lipoprotein fraction was not changed significantly (group A) or decreased (group B). Serum cholesterol or triglycerides tended to be increased, but mean changes were often not significant. 3. The observed alterations in serum lipoproteins are consistent with the possibility of an increased risk for coronary heart disease which could offset partly the beneficial effects of a lowered blood pressure in diuretic-treated patients with hypertension.

Blood Volume↗
PubMed2005

Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation.

A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the detection of diuretics, uricosurics, and/or their metabolites in human urine after extractive methylation. Phase-transfer catalyst remaining in the organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated by GC and identified by MS in the full-scan mode. The possible presence of the following drugs and/or their metabolites could be indicated using mass chromatography with the given ions: m/z 267, 352, 353, 355, 386, and 392 for thiazide diuretics bemetizide, bendroflumethiazide, butizide, chlorothiazide, cyclopenthiazide, cyclothiazide, hydrochlorothiazide, metolazone, polythiazide, and for canrenoic acid and spironolactone; m/z 77, 81, 181, 261, 270, 295, 406, and 438 for loop diuretics bumetanide, ethacrynic acid, furosemide, piretanide, torasemide, as well as the uricosurics benzbromarone, probenecid, and sulfinpyrazone; m/z 84, 85, 111, 112, 135, 161, 249, 253, 289, and 363 for the other diuretics acetazolamide, carzenide, chlorthalidone, clopamide, diclofenamide, etozoline, indapamide, mefruside, tienilic acid, and xipamide. The identity of positive signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass spectra with reference spectra. This method allowed the detection of the abovementioned drugs and/or their metabolites in human urine samples, except torasemide. The limits of detection ranged from 0.001 to 5 mg/L in the full-scan mode. Recoveries of selected diuretics and uricosurics, representing the different chemical classes, ranged from 46% to 99% with coefficients of variation of less than 21%. After ingestion of the lowest therapeutic doses, furosemide was detectable in urine samples for 67 hours, hydrochlorothiazide for 48 hours, and spironolactone for 52 hours (via its target analyte canrenone). The procedure described here is part of a systematic toxicological analysis procedure for acidic drugs and poisons.

Diuretics↗
PubMed1996

Inhibition of thiazide photohemolysis in vitro by antioxidants and a nitrogen atmosphere.

The diuretics acetazolamide, bemetizide, bendroflumethiazide, benzthiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlorazanile, chlorothiazide, chlortalidone, clopamide, cyclopenthiazide, cyclothiazide, diazoxide, etozoline, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, mefruside, metolazone, piretanide, polythiazide, trichlormethiazide, and xipamide were screened in vitro for phototoxic effects by means of a photohemolysis test. In all, 19 out of the 25 test substances revealed phototoxic hemolytic properties after irradiation with either solar stimulating irradiation, UVA and/or visible light. Addition of the antioxidants ascorbic acid, alpha-tocopherole or superoxide dismutase significantly inhibited the phototoxic hemolysis, as well as did investigations carried out in a nitrogen rich atmosphere, findings which indicate the involvement of reactive oxygen species in the phototoxic process.

Antioxidants↗