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Beta-adrenoceptor blocking drugs (beta-blockers) are one of the most frequently used class of cardiovascular drugs that are mainly used in conventional dosage forms., which have their own limitations including hepatic first-pass metabolism, high incidence of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Essentially, attempts have been made to develop novel drug delivery systems for beta-blockers, including transdermal delivery systems, to circumvent the drawbacks of conventional drug delivery. However, so far none of the beta-blocker drugs have been marketed as transdermal delivery systems. Nevertheless, there have been noteworthy research endeavours worldwide at the laboratory level to investigate the skin permeation and to develop transdermal formulations of beta-blockers including: propranolol, metoprolol, atenolol, timolol, levobunolol, bupranolol, bopindolol, mepindolol, sotalol, labetolol, pindolol, acebutolol and oxprenolol. Innovative research exploiting penetration-enhancing strategies, such as iontophoresis, electroporation, microneedles and sonophoresis, holds promise for the successful use of these drugs as consumer-friendly transdermal dosage forms in clinical practice. This paper presents an overview of the transdermal research on this important class of drugs.

1. The effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the beta 1-adrenoceptor mediated responses of the rat left atria and the beta 2-adrenoceptor mediated responses of the rat portal vein to isoprenaline have been determined. 2. Racemic and (-)-metoprolol were selective beta 1-adrenoceptor antagonists. (+)-Metoprolol was devoid of beta-adrenoceptor antagonistic activity. 3. Racemic and (-)-pindolol were potent and (+)-pindolol was a modest beta-adrenoceptor antagonist. 4. (+/-)-Mepindolol and (+/-)-bopindolol were apparently competitive antagonists of the isoprenaline beta 1-adrenoceptor mediated responses of the rat left atria but non-competitive antagonists of the isoprenaline beta 2-adrenoceptor mediated responses of the rat portal vein. 5. It is suggested that (+/-)-mepindolol and (+/-)-bopindolol are slowly dissociating beta-adrenoceptor antagonists and the non-competitive antagonism can only be detected on tissues with modest receptor reserves for maximum responses to isoprenaline.

The acid-catalysed electrophilic tandem substitutions of pindolol, mepindolol, and carazolol and some related model compounds with triethyl ortho formate give rise to new derivatives from the trishetaryl methan series. In some cases also further functionalised heterocycles were isolated. The structural aspects of the new trishetarylmethanes were discussed as C3-symmetric molecular propellers, respectively. The importance of the described reaction as colour reaction was mentioned. Zur Reaktion von Pindolol, Mepindolol, Carazolol und verwandten Modellverbindungen mit Orthoameisensauretriethylester: Reaktionswege und Produkte einer neuen Farbreaktion Bei der saurekatalysierten electrophilen Tandem-Substitution von Pindolol, Mepindolol und Carazolol sowie bei einigen verwandten Modellverbindungen werden mit Orthoameisensauretriethylester neue Trishetarylmethane erhalten. In einigen Fallen entstehen auch weitere funktionalisierte Heterocyclen. Die strukturellen Aspekte der neuen Trishetarylmethane als C3-symmetrische molekulare Propeller werden diskutiert, auf die Bedeutung der vorgestellten Reaktionen als Farbreaktion wird hingewiesen.

Most of the beta-blocking drugs for treating diseases of the cardiovascular system are chiral aryloxy-propanolamine derivatives. Tipically, the S(-) enantiomers are more active than the R(+) enantiomers. Only some of them (for example timolol) are used as single enantiomers, the others are employed as racemates. For the determination of the enantiomeric purity of timolol European Pharmacopoeia prescribes an HPLC method using chiral stationary phase. However, the use of chiral capillary zone electrophoresis for the determination of the enantiomeric purity is of pharmaceutical interest. This study describes the application of various cyclodextrin derivatives, hydroxypropyl-beta-cyclodextrin, randomly methylated beta-cyclodextrin, sulphated beta-cyclodextrin and sulphated alpha-cyclodextrin for the stereoselective analyses of beta-blockers. Baseline separation was obtained for bopindolol, carvedilol, mepindolol, pindolol and alprenolol, while only partial separation was observed for sotalol, propranolol, oxprenolol, atenolol, bisoprolol, bupranolol, and metoprolol. The uneven molecular recognition of the enantiomers of the beta-blockers, especially of the optical isomers of labetalol and nadolol, showed the importance of the chemical nature of the separators and the analytes.

Studies on chiral resolution of beta-blocker and H 1 -antihistamine drugs by CZE using human serum transferrin are described. The drugs with different structures passed a pseudostationary protein zone in a coated capillary applying the partial filling method for the chiral separation. In this study we screened 15 compounds; most of them showed longer migration time, indicating an interaction with transferrin. Stereoselective interaction was observed only for five beta-blockers (celiprolol, talinolol, mepindolol, bopindolol, and oxprenolol) and for one H 1 -antihistamine (brompheniramine). The most important finding was that very small differences in the chemical structure of the drug resulted in significant changes in the stereoselective recognition. Resolution of mepindolol enantiomers was observed showing the essential role of one methyl group compared to pindolol, which is not resolved by transferrin. Bopindolol, also a derivative of pindolol having bigger difference in the structure, showed more experienced separation. The very slight difference between alprenolol and oxprenolol was also revealed with these methods, since only oxprenolol enantiomers, having an extra oxygen in the structure, are resolved. Determining the migration order of the eutomers and distomers (chlorpheniramine, brompheniramine) we can deduct conclusions about the role of serum proteins in the delivery of drugs within the body.

The acid-catalysed electrophilic tandem substitutions of pindolol, mepindolol, and carazolol and some related model compounds with triethyl ortho formate give rise to new derivatives from the trishetaryl methan series. In some cases also further functionalised heterocycles were isolated. The structural aspects of the new trishetarylmethanes were discussed as C3-symmetric molecular propellers, respectively. The importance of the described reaction as colour reaction was mentioned. Zur Reaktion von Pindolol, Mepindolol, Carazolol und verwandten Modellverbindungen mit Orthoameisensauretriethylester: Reaktionswege und Produkte einer neuen Farbreaktion Bei der saurekatalysierten electrophilen Tandem-Substitution von Pindolol, Mepindolol und Carazolol sowie bei einigen verwandten Modellverbindungen werden mit Orthoameisensauretriethylester neue Trishetarylmethane erhalten. In einigen Fallen entstehen auch weitere funktionalisierte Heterocyclen. Die strukturellen Aspekte der neuen Trishetarylmethane als C3-symmetrische molekulare Propeller werden diskutiert, auf die Bedeutung der vorgestellten Reaktionen als Farbreaktion wird hingewiesen.

In a randomized 6-month study of 201 patients, the antihypertensive efficiency of the calcium antagonist nitrendipine, the beta 1-selective blocker metoprolol, mepindolol, the beta blocker with intrinsic activity and the angiotensin-converting enzyme inhibitor enalapril were compared as monitored by 24-hour ambulatory blood pressure (BP) measurements. The study was designed so that a comparable decrease in casual BP values was obtained with all 4 drugs. If normotension was not achieved with monotherapy, a diuretic also was administered. Pretreatment casual BP and mean 24-hour ambulatory BP values did not differ between the 4 groups. Normotension as assessed by casual BP measurements was observed in all 4 groups after 6 months of therapy, there being no significant differences between the groups. However, significantly more diuretics were required in the mepindolol (n = 14) and in the enalapril (n = 20) groups compared to the nitrendipine (n = 5) and metoprolol (n = 7) groups. Despite comparable casual BP control, the 4 groups differed significantly in their mean 24-hour measurements. The greatest systolic and diastolic BP decreases were seen in the metoprolol group. Metoprolol was also the most effective drug in decreasing the frequency of systolic pressure peaks greater than 180 mm Hg. Both beta blockers and enalapril significantly decreased the morning BP increase compared to the values before treatment, while nitrendipine did not. These data show that casual BP measurement is not a good predictor of 24-hour BP in patients taking hypertensive therapy. Despite an equal degree of "office" BP control, different antihypertensive regimens do not confer the same degree of "nonoffice" BP control.

The bioavailability and pharmacokinetics of 10 mg of mepindolol sulphate and of 25 mg of hydrochlorothiazide were compared in a cross-over design in five healthy volunteers after the administration of either the single drugs (Corindolan® and Esidrix®) or in combination (Tenesor®). Maximum concentrations of mepindolol in the plasma of 25 ng ml−1 were achieved 1·6 h after both treatments and the half-life of disposition was calculated to be 4·5 h, being somewhat longer after the combination tablet. The amount of hydrochlorothiazide renally eliminated up to 48 h after drug intake was about 60 per cent of the dose. The half-life of renal excretion was 3 h. The two formulations of mepindolol sulphate and hydrochlorothiazide proved to be bioequivalent with a tendency to better mepindolol bioavailability in the combination form.

1. The force of the electrically driven rat right ventricle strip is increased by isoprenaline but not by procaterol, a beta 2-adrenoceptor agonist. The effects of some beta-adrenoreceptor antagonists on the responses of the strip to isoprenaline have been determined. 2. Metoprolol (a beta 1-adrenoreceptor-selective antagonist) at 3 x 10(-8)-3 x 10(-7) moll-1 and ICI 118,551 (a potent beta 2-adrenoreceptor-selective antagonist) at 10(-7)-10(-6) moll-1 had no effect on maximum responses to isoprenaline and caused parallel rightward shifts of the isoprenaline response curves. The pA2 values for metoprolol and ICI 118,551 were 7.86 and 7.40, respectively. Thus the isoprenaline responses of the rat right ventricle strip are due to stimulation of beta 1-adrenoreceptors. 3. Metoprolol at 10(-6) moll-1 acted as a dual antagonist of the responses of the ventricle strip to isoprenaline causing parallel rightward shifts of the concentration-response curves which was due to beta 1-adrenoreceptor antagonism and a depression of the maximum response to isoprenaline which was probably due to membrane stabilizing activity. 4. Low concentrations of (+/-)-pindolol (10(-8) moll-1), (+)-pindolol (10(-7) moll-1), (-)-pindolol (10(-8) moll-1) and mepindolol (10(-10) moll-1) had no effect on isoprenaline maximum responses and caused parallel rightward shifts of isoprenaline response curves. Both (+/-)- and (-)-pindolol at 10(-7) moll-1, mepindolol at 10(-9)-10(-7) moll-1 and bopindolol at 10(-9)-10(-7) moll-1 reduced the isoprenaline maximum responses and caused non-parallel rightward shifts of the isoprenaline response curves. 5. BAAM (an irreversible beta-adrenoreceptor antagonist) treatment (3 x 10(-6) moll-1) for 30 min followed by 60 min washout reduced the isoprenaline maximum responses and caused a non-parallel rightward shift of the isoprenaline response curve. The kA (dissociation constant) for isoprenaline was 1.10 x 10(-6) moll-1. Calculation of receptor occupancy demonstrated that in order to produce a maximal response of the rat right ventricle strip, isoprenaline had to occupy 73% of the beta 1-adrenoreceptors. 6. The use of the rat right ventricle strip, a tissue with a small beta 1-adrenoreceptor reserve for isoprenaline, allows a definitive characterization of reversible (e.g. metoprolol) and irreversible (e.g. BAAM) beta 1-adrenoreceptor antagonists. It is suggested that (+/-)- and (-)-pindolol, mepindolol and bopindolol may be slowly dissociating beta 1-adrenoreceptor antagonists.

After improvement of technical equipment continuous ambulatory blood pressure monitoring is more and more used in the diagnosis of hypertension. New fully automatic systems permit a reliable registration and evaluation of 24-h blood pressure profiles. Typical circadian rhythmics of blood pressure, independent of a variability with different grades of activity, can be demonstrated in normotensive persons and also in patients with essential hypertension. Patients with secondary forms of hypertension show a nivellation or offset of circadian blood pressure rhythmics. A study was performed to examine the antihypertensive efficacy of the calcium antagonist Nitrendipine, the beta 1-adrenoceptor-selective blocker Metoprolol, the beta-blocker with intrinsic activity Mepindolol and the angiotensin converting enzyme inhibitor Enalapril in patients with mild to moderate hypertension over a period of 6 month. Continuous ambulatory blood pressure monitoring was performed before and after 6 month of therapy. 98 of 299 included patients broke off therapy, 47 of those because of side effects. Hydrochlorothiazide was given additionally if the antihypertensive effect of monotherapy was not sufficient after a period of 4 weeks. Morning blood pressure controls at the end of the treatment period showed normotensive values in all groups without significant differences between the groups before and at the end of the treatment period. The number of prescriptions of diuretics necessary to achieve normotension differed between the four treatment groups: Nitrendipine (n = 5), Metoprolol (n = 7), Mepindolol (n = 14), Enalapril (n = 20). In contrast to the morning blood pressure values the continuous 24-h blood pressure monitoring demonstrated significant differences between the therapy groups. Metoprolol turned out as most effective in lowering blood pressure and in reducing the number of systolic blood pressure peaks above 180 mmHg, but on the other hand showed the highest incidence of relative hypotension (less than 100 mmHg systolic, less than 80 mmHg diastolic). Mepindolol demonstrated a significant lower efficacy. In the Nitrendipin group least of all prescriptions of diuretics were necessary and the lowest number of hypotensive systolic blood pressure values occurred. Enalapril showed the most significant reduction of diastolic values above 100 mmHg and the lowest number of diastolic values below 80 mmHg, but the highest number of prescription of diuretics was necessary in the Enalapril group. In none of the four therapy groups a neutralisation of circadian blood pressure rhythmics was demonstrable.

Healthy males (23-29 years) volunteered as subjects. We studied the ventilatory response to carbon dioxide and to isometric exercise (50% of maximum voluntary contraction) after administration of propranolol (20 mg), mepindolol (5 mg), salbutamol (20 mg) and placebo (single dose orally). The increase of pulmonary ventilation (VE) activated by central (CO2) and reflex stimulus (hand-grip) did not differ statistically between the four drugs. Analysis of VE in terms of inspiratory drive (Vt/Ti) and timing ratio (Ti/Ttot) showed that during CO2 stimulation mepindolol and salbutamol increased VE predominantly by the increase of Vt/Ti, presumably through the direct stimulation on the respiratory center. During rebreathing, Ti/Ttot increased significantly after administration of placebo and propranolol, so VE increased by a rise of Vt/Ti and by an increase of an effective 'timing component' (Ti/Ttot). Propranolol does not modify the ventilatory response to CO2 and hand-grip when VE is analyzed in terms of Vt/Ti and Ti/Ttot.

The infusion of arachidonic acid through Langendorff-perfused guinea pig hearts in vitro for 15 min was associated with an increased PGI2 formation and release. This was a transient reaction, which showed a peak after 3-5 min and declined thereafter. Simultaneous infusion of washed human platelets (4 X 10(8)/min) stimulated the peak PGI2 formation (measured as immunoreactive 6-oxo-PGF1 alpha) but did not antagonize the inactivation of the PGI2-forming mechanism(s) in the vessel wall. The beta-adrenoceptor-blocking agent mepindolol (0.3 and 3 microgram/ml) significantly enhanced the peak release of PGI2 at 3 microgram/ml (P less than 0.05). Its major effect, however, was to inhibit the decline in PGI2 release during arachidonic acid infusion. In this case the PGI2 release during arachidonic acid infusion (area under the curve) was doubled in the presence of mepindolol at both concentrations. It is concluded that protection of vascular PGI2 formation from inactivation might be an important mechanism for the maintenance of PGI2 release in response to continuous stimuli.

To study the role of intrinsic sympathomimetic activity (ISA) in beta-blocker-induced changes of beta-adrenoceptors, the effects of administration of several beta-blockers for 9 days on lymphocyte beta 2-adrenoceptor density--assessed by 125iodocyanopindolol binding--were investigated in 47 normotensive volunteers. Propranolol (unselective; no ISA; 4 X 40 mg/day) increased beta 2-adrenoceptor density by 25-40%; after withdrawal beta 2-adrenoceptor density declined slowly, being still elevated for 3 days. In contrast, the unselective beta-blockers pindolol (ISA (isoprenaline = 1.0) = 0.39; 2 X 5 mg/day) and mepindolol (ISA = 0.27; 2 X 5 mg/day) decreased beta 2-adrenoceptor density by 50% and 35%, respectively, while alprenolol with weak ISA (=0.066; 4 X 100 mg/day) had no effect. Among the beta 1-selective blockers studied, celiprolol with ISA (=0.32; 1 X 200 mg/day) decreased beta 2-adrenoceptor density by 30% whereas bisoprolol without ISA (1 X 10 mg/day) had no effect. It is concluded that the ISA determines the direction and amount of beta-adrenoceptor alterations induced by beta-blockers. Furthermore, changes in human lymphocyte beta-adrenoceptors reflect subtype-selective changes in beta 2-adrenoceptors, since the beta 1-selective blocker bisoprolol without ISA--in contrast to propranolol--did not affect lymphocyte beta 2-adrenoceptors. Accordingly, the fact that the beta 1-selective blocker celiprolol with ISA decreased lymphocyte beta 2-adrenoceptors, is consistent with the hypothesis that celiprolol possesses in addition to its beta 1-antagonistic activity a beta 2-agonistic activity.

This paper describes a general approach for the therapeutic drug monitoring of 13 different beta blockers in plasma. The chromatographic system contains a cyanopropyl-bonded phase as a stationary phase in combination with a mobile phase composed of acetonitrile and phosphate buffer (pH = 3, μ = 0.05). Two modes of detection are used, namely, UV detection and fluorescence detection. The sample pretreatment is performed with a nitrile-sorbent in combination with methanol—phosphate buffer (pH = 3, μ = 0.05) or with methanol containing 0.1% propylamine as eluent. Acceptable recoveries are obtained for practolol, acebutolol, pindolol, oxprenolol, mepindolol, atenolol, propranolol, prenalterol, alprenolol, metoprolol, sotalol and nadolol. For labetalol, however, the elution recovery has to be improved. Finally, this approach is illustrated by the assay of nadolol in the plasma of patients suffering from hypertension, who had received an oral formulation of the drug.

Mepindolol is a newly developed beta-adrenergic blocking agent reported to counteract the chronotropic effect of catecholamines, with only little effect on contractility. This study was designed to assess whether or not mepindolol is effective in reducing infarct size. Accordingly, 16 rats, serving as controls, underwent coronary artery occlusion and did not receive any treatment; an additional 19 were treated with mepindolol (1 mg/kg s.c. t.i.d.) for 48 h. Finally, a third group (n = 18) underwent sham operation. Forty-eight hours later, infarct size was calculated from left ventricular creatine phosphokinase activity and found to average 52.4 +/- 7.8% (mean +/- SEM) of the left ventricle in control rats and 35.6 +/- 5.4% in treated rats (p less than 0.05). Left ventricular phospholipid content averaged 0.79 +/- 0.08 microgram P/mg protein in sham-operated rats and 0.61 +/- 0.04 microgram P/mg protein in control animals. In contrast, in mepindolol-treated rats, phospholipid concentration was 0.70 +/- 0.04 microgram P/mg protein (p less than 0.05), this suggesting a protective effect of the drug on ischemia-induced phospholipid degradation. The long-term effect of mepindolol on left ventricular hydroxyproline concentration was assessed 21 days post-coronary occlusion. Infarct size calculated by this method was 30.2 +/- 4.8% of left ventricle in 21 control animals and 18.2 +/- 4.2% in 28 treated rats (p less than 0.05), indicating that, as for the acute necrosis, the extent of scar development after coronary artery occlusion can be reduced by mepindolol.

A highly sensitive and specific column liquid chromatographic assay with electrochemical detection was developed for hydrolysed bopindolol, an active metabolite of bopindolol (Sandonorm) in human plasma. The pre-chromatographic sample preparation involved Extrelut column clean-up followed by liquid extraction of the organic extract into dilute acetic acid. Separation was on a Nucleosil ODS 3-microns column at 40 degrees C, with a phosphate buffer-methanol mobile phase. Detection was performed at +450 mV with an ESA electrochemical detector. Mepindolol was used as internal standard and quantitation was based on peak-area ratios. Total analysis time was 14 min per sample. The recovery rate of the assay was at least 70% for both compounds. A detection limit as low as 25 pg/ml, starting with 1 ml of plasma, was achieved. The day-to-day reproducibility and accuracy, checked with quality-control samples, demonstrated the reliability of this assay used by different analysts, on different chromatographic systems and over a long period of time.

A method for determining the plasma concentration of the β-receptor blocking agent mepindolol by high-performance liquid column chromatography (paired-ion chromatography) and electrochemical detection is described. Pindolol is used as an internal standard and the detection limit after extraction of 1 ml of plasma is less than 1 ng of mepindolol. Reproducible results can be obtained with relative standard deviations from replicate analyses of 5 ng/ml plasma samples within ± 4.7%. The method is also suitable for quantification of plasma pindolol levels with mepindolol as an internal standard.

beta-adrenoceptor blocking agents are widely used as treatment of essential hypertension. We studied the action of a new non cardioselective beta-adrenoceptor blocker, mepindolol, comparing its effects on blood pressure, blood lipids and platelet aggregation with those of a cardioselective beta-adrenoceptor blocker, atenolol. Blood pressure fell significantly in the patients treated with both drugs. Triglycerides rose non-significantly only in volunteers treated with mepindolol. We did not find any significant changes in cholesterol, free fatty acids, lipoproteins and platelet aggregation.

Abrupt withdrawal of β-adrenoceptor antagonists may lead to “rebound-effects”. To study the mechanism underlying this phenomenon, the effects of the nonselective β-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte β2-adrenoceptor density — assessed by (±)-[125I]-iodocyanopindolol (ICYP) binding — and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23–35 years. 1. Propranolol treatment (4×40 mg/day) increased the density of β2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment β2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. β2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to β2-adrenoceptors was not changed during or after treatment. 2. Mepindolol treatment (2×5 mg/day) caused a 30% decrease of β2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas β2-adrenoceptor density was still after 4 days significantly diminished. TheKD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. 3. Alprenolol treatment (4×100 mg/day) led to a rapid fall in PRA, but did not significantly affect β2-adrenoceptor density. 4. It is concluded, that the ISA may play an important role in modulating β2-adrenoceptor density and hence tissue responsiveness to β-adrenoceptor stimulation. Propranolol (no ISA) caused increase in β2-adrenoceptor density still persisting after withdrawal, which might explain the “propranolol rebound-effect”. Since β-adrenoceptor antagonists with ISA did not increase, but rather decrease β2-adrenoceptor density, such “rebound-effects” may not occur after rapid cessation of drug treatment.

Five patients with a creatinine clearance of 14 to 37 ml/min/1.73 m2 were each given an oral dose of 10 mg of the beta-blocker mepindolol sulphate (Corindolan). In addition, two dialysis patients received the same dose either during hemodialysis or on a dialysis-free day. Plasma levels of mepindolol were measured by a sensitive, specific HPLC method. Mepindolol was rapidly absorbed in all the patients. The maximum plasma level of 35 +/- 8 ng/ml was reached after 1.4 +/- 0.5 h. The half-life of disposition was 4.0 +/- 1.5 h. The area under the plasma concentration-time curve was 237 +/- 84 ng X h/ml. The data obtained were no different from those found in normal healthy volunteers.

The effect of calculation stress on hemodynamic parameters and plasma adrenalin and noradrenalin was studied in two groups of 6 male subjects, before and during beta-Blockade. One group received propranolol 15 mg i.v. and the other received mepindolol sulphate 0,5 mg i.v. There was an increase in heart rate, cardiac output and blood pressure during mental stress. A significant increase in plasma adrenalin but not in noradrenalin occurred at the same time. The stress-induced rise in HR but not that in blood pressure could be prevented by beta-receptor blockage with propranolol and mepindolol sulfate. The peripheral resistance (PR) and diastolic blood pressure in stress were even higher after propranolol than in the control study. Propranolol had no effect on the increased adrenalin concentration during stress, but it was prevented by mepindolol sulfate. There was no correlation between the increase in HR and that in adrenalin during stress, but the HR in stress and the HR reaction to infused isoproterenol were highly correlated.

Sixteen healthy volunteers of a mean age of means = 26.4 years took part in a driving simulator test in an eightfold crossover study under double-blind conditions. The additional influence of alcohol was tested acutely after a single administration of 2 mg lormetazepam, a new, highly effective derivative from the benzodiazepine class, 10 mg mepindolol sulphate, a new betablocker without sedating properties, and 10 mg diazepam. All drugs were compared with placebo and the test was performed 1, 2 and 3 hours after oral intake. The aim was to investigate particularly the risks relevant in road traffic caused by simultaneous intake of these substances with alcohol. For this purpose, besides the driving simulator, an accurate reaction test ( WDG ) and self-rating scales were used, the latter in order to assess subjective stress and anxiety levels. Lormetazepam, due to its strong sedating property, showed a reduction in driving performance and an increase in reaction time and pulse rate as compared with placebo, and these effects were highly potentiated by alcohol. Mepindolol sulphate expectedly reduced pulse rate when compared with placebo, otherwise there were no significant differences. Diazepam, when compared with placebo, like lormetazepam caused a reduction in driving performance and reaction capacity and an increase in pulse rate, but intensity and duration of this effect were less than with lormetazepam and did not reach statistical significance. No significant potentiating effects were observed after the additional application of alcohol. Language: en

In order to investigate the effects of beta–blockade on haemodynamic response to stress, 2 groups of volunteers received either propranolol or mepindolol sulphate under basal conditions and under the stress of mental arithmetic. In control conditions, increases occurred in heart rate (HR), cardiac output (CO) and systolic and diastolic blood pressure in response to calculation stress. Stress–induced increases in HR and CO were significantly reduced by propranolol. Systolic blood pressure during calculation stress under propranolol was slightly less than in control conditions. However, diastolic blood pressure under stress was higher with propranolol than in the control study. Mepindolol sulphate also reduced HR and CO under calculation stress but it produced no significant change in diastolic pressure. A significant increase in plasma adrenaline occurred under stress. The level was not altered by propranolol but was reduced to less than 50% of the untreated stress value by mepindolol. Since beta–blocking agents suppress an increase in heart rate in stressful situations but either fail to prevent or even potentiate increased diastolic pressure, their use in patients without hypertension should be reserved for those showing pathological stress reactions. They do not appear to be indicated for the management of stressful situations in general.

Transdermal drug delivery has been applied to various agents in an effort to decrease the frequency of drug administration and increase the patients compliance. In our study, we demonstrated that transdermal application of a s-blocker (20 mg mepindolol) in patients with essential hypertension led to effective blood pressure lowering effect within 1 week (160.1 ±6.1 mm Hg/95.8 ± 8.3 mm Hg vs 136.8 ± 7.2 mm Hg/84.3 ± 5.0 mm Hg; Ρ < 0.05). A controlled study of transdermal versus oral s-blocker administration in hypertensives is necessary before this new therapeutic system is introduced in antihypertensive treatment. Am J Hypertens 1988; 1:199S-200S

This study compares the sympathetic nervous system response to graded exercise in normotensive and essential hypertensive subjects with and without beta-adrenergic blockade. Blood pressure (BP), heart rate, and plasma norepinephrine (NE), epinephrine (E), and dopamine (DA) were measured just before starting the exercise (Pre-Ex), in the submaximal exercise (Sub-max),and after 8 minutes rest (Post-Ex). On placebo, Sub-max induced in both normotensives and hypertensives a similar increase in NE and E plasma levels. Plasma DA remained unchanged. Propranolol in controls and propranolol or mepindolol in hypertensives didn't modify significantly: 1) Pre-Ex plasma levels of E, NE, and DA; 2) response at Sub-max in controls; 3) plasma E and DA in hypertensive patients. In hypertensives on beta-blockade, submaximal exercise elicited a greater increase in plasma NE. Values for plasma NE in patients on propranolol were 1135 +/- 229 pg/ml higher than those obtained in the same patients on placebo (p less than 0.001). On mepindolol, the plasma NE increment was higher than that on placebo (p less than 0.05), but lower than that on propranolol (p less than 0.01). In controls, propranolol did not significantly modify BP at Pre-Ex or its response to exercise, whereas systolic and diastolic BP were significantly lower at Pre-Ex, Sub-max, and Post-Ex in hypertensives. On beta-blockade, heart rate decrease in Pre-Ex, Sub-max, and Post-Ex were not different in controls and hypertensives. The differences found on beta blockade would indicate that the effects of beta blockers are not identical in normotensive and hypertensive subjects.

The haemodynamic effects of a β-receptor blockade with mepindolol-sulphate and propranolol were studied under basal conditions and under an increasing dose of isoproterenol in 6 subjects aged between 25 and 30 years. Special attention was paid to possible differences between the two substances as regards their affinity for the various β1 and β2 -receptors. The cardiac output (HMV) was determined with the aid of the Swan-Ganz-thermodilution method, the blood pressure was measured wet. The results led to the following conclusions: A decrease in the heart rate (HR) occurs under basal conditions after propranolol, but not after administration of mepindolol-sulphate. The lack of an effect of mepindolol-sulphate on the HR at rest can be explained by its intrinsic activity. A reduction of the stroke volume (SV) occurs under basal conditions after propranolol, whereas no effect on the SV was observed under mepindolol-sulphate. Three properties of mepindolol-sulphate are responsible for this lack of effect on the S V, namely its only slight quinidine-like effect compared with propranolol, its intrinsic activity and its only slight affinity for the inotropism receptors at the heart. An infusion of isoproterenol leads to a decrease in the pulmonary capillary pressures (Pc pressures). This effect can be competitively suppressed both with propranolol and with mepindolol-sulphate. This effect has been explained by the fact that isoproterenol leads to dilatation of the venous capacity vessels as a result of stimulation of the β2 -receptors in the periphery. Blockade of the β2 -receptors can prevent this dilatation. The affinities of propranolol for the frequency and inotropism receptors at the heart and for the β2 -receptors in the peripheral vessels are of the same magnitude. In contrast to this, the affinity of mepindolol-sulphate for the inotropism receptors at the heart is considerably less than for the frequency receptors and the β2 -receptors in the periphery.

The concentrations of mepindolol in plasma and milk of five breastfeeding mothers were determined after 1 and 5 daily doses of mepindolol sulphate 20 mg. In the newborns plasma levels were measured once on the first and fifth days of the study. The mean maternal plasma concentration of mepindolol 2 h after administration was 52 ng/ml both after 1 and 5 doses; in the milk 18 and 22 ng/ml the corresponding concentrations were. The average plasma/milk drug concentration ratio was 2.6 +/- 1.6. Plasma levels in the newborn were below the detection limit of 1 ng/ml, except for one baby in whom 2 and 5 ng/ml, respectively, were found 4 h after one and five maternal doses.

The effect of a single dose of beta-blocker (5 or 10 mg mepindolol) during a written examination was investigated in two double-blind studies (N : 49 and 55 students, respectively). The question was whether the beta-blocker would in comparison to placebo diminish examination anxiety and improve the performance of highly complex tasks, while leaving the performance of less complex tasks unchanged. A reduction in examination anxiety after beta-blocker intake could not be demonstrated with a multi-level test model (which included the parameters self-rated anxiety, motor behaviour, task performance and physiology), although pulse rates were lowered significantly. An improvement in performance could not be observed, while - by the same token - the performance was not impaired by the beta-blocker. A hypothesis according to which a beta-blocker has an anxiolytic effect and improves performance, dependent on the level of habitual examination anxiety, was tested post hoc, but could not be confirmed. Ten of the subjects treated with 10 mg mepindolol, complained of different side effects, including dizziness, fatigue and headache.

Pharmacokinetics of the new s-receptor blocking agent mepindolol sulphate (CorindolanR) were investigated in rats and rabbits with special reference to effects which cannot be studied in man. Autoradiography after i.v. injection and distribution studies after oral dosing showed that in the rat these is no specific tissue accumulation of drug or metabolites either after single or multiple administration Mepindolol passes the blood-brain and placental barriers and achieves concentrations in the brain double those in the plasma, and in the liver of the foetus equal to that in the plasma of the mother. Renal excretion of mepindolol could be influenced by the urinary pH value. Acidic urine enhanced the elimination and basic urine retarded excretion of drug and metabolites.

The beta-blocking potencies of mepindolol and pindolol were determined in guinea pig right atria (heart rate) and paced left atria (contractile force) in vitro. Neither agent showed selectivity for blocking rate responses induced by isoproterenol. The pA2 (95% confidence interval) values determined for mepindolol against rate and force responses induced by isoproterenol were 9.96 (9.91-10.01) and 9.52 (9.44-9.60), respectively, and for pindolol, 9.20 (9.15-9.25) and 8.85 (8.76-8.94). Mepindolol was approximately 6.5 times as potent as pindolol. The present evidence does not support the hypothesis of subpopulations of beta-receptors subserving inotropic and chronotropic responses.