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The chiral resolution of some clinically used drugs namely metoprolol, teratolol, tolamolol, nebivolol (β-adrenergic blockers), econazole, miconazole (anti-fungal agents), cromakalim (anti-hypertensive agent) and etodolac (anti-inflammatory agent) was achieved on cellulose tris (3,5-dichlorophenylcarbamate) chiral stationary phase. The mobile phase used was 2-propanol at 0.5 mL/min with detection at 220 nm. The separation factors (α) of these drugs ranged from 1.24 to 3.90 while the resolution factors were from 1.05 to 5.0. The chiral recognition mechanisms between the racemates and the chiral selector are discussed. Copyright ­© 2003 John Wiley & Sons, Ltd.

Several β-adrenoceptor blocking agents have been evaluated for spermicidal activity using a transmembrane migration method. The rank order of potency of the active compounds was: penbutolol > (+) - propranolol > bufuralol > (—) - alprenolol > oxprenolol > metoprolol. Atenolol, pindolol, practolol, tolamolol were without activity. The observed potencies of spermicidal activity are believed to be unrelated to β-blocking activities, and we have shown that whilst they are not predictable from lipid solubility or nonspecific membrane properties of the compound alone, both these aspects appear to play a role in this pharmacological activity.

The effects of single oral doses of the cardioselective beta adrenoceptor blocking drugs, metoprolol and tolamolol, on specific airways resistance (SRaw) were compared with those of propranolol and practolol in 6 healthy volunteers and in 12 patients with bronchial asthma. Whole-body plethysmography was used to measure SRaw and the blocking potency of different antagonists assessed by the degree of inhibition of tachycardia due to exercise on a treadmill. The changes correlated with plasma drug levels. Propranolol and practolol were measured fluorometrically and metoprolol by electron-capture gas-liquid chromatography. In normal subjects, about 30% reduction in exercise-induced tachycardia resulted from single doses of 80 mg propranolol (plasma levels, 50.3, SD, 29.5 to 60.8, SD, 26 ng/ml), 250 mg practolol (plasma levels, 1.05, SD, 0.32 to 1.10, SD, 0.55 mug/ml), 100 mg metoprolol (plasma levels, 137, SD, 111 to 152, SD, 100 ng/ml), and 100 mg tolamolol. In patients, these doses of the drugs produced significant increases in SRaw. These increases were greater than those after placebo but significantly so only during the peak effect 1 hr after propranolol. Compared with changes after placebo, significant effects on SRaw were also found in 3 patients given 200 mg of tolamolol. None of the drugs had a significant effect on SRaw in normal subjects. It is concluded that metoprolol, practolol, and tolamolol may impair ventilatory function in asthmatics less than propranolol and that at high doses this difference may not be demonstrable.

Fifteen patients with angina pectoris participated in a double-blind study evaluating the effect of intravenous saline, 10 mg of intravenous tolamolol, 20 mg of intravenous tolamolol, and 10 mg of intravenous propranolol on resting and exercise heart rate and on exercise time until angina. Twenty mg of tolamolol and 10 mg of propranolol caused a similar decrease in mean resting heart rate, heart rate after a similar amount of exercise, heart rate at angina, resting product of systolic blood pressure times heart rate, and product of systolic blood pressure times heart rate at angina and were, therefore, judged equipotent. Tolamolol, 10 and 20 mg, and propranolol, 10 mg. were not followed by a significant change in mean exercise duration until angina, but there was a 25 percent increase in exercise time until angina in 4 of 15 patients (27 percent) after 10 mg of propranolol and in 3 of 15 patients (20 percent) after 20 mg of tolamolol.

The antihypertensive and renin-lowering efficacy and side effects of tolamolol, a beta adrenergic blocking drug with cardioselectivity, were examined in 10 patients with mild essential hypertension while on regular diet. Tolamol, at a dose of 300 to 900 mg per day, given over a period of 2 to 4 wk significantly decreased systolic and diastolic blood pressures in both the recumbent and standing positions. Normal blood pressure (140/90 mm Hg or less) was attained in 8 subjects. Mean heart rate and ambulatory midday plasma renin activity (PRA) decreased significantly; however, there was no significant correlation between blood pressure decrease and either the pretreatment PRA or decrease in PRA. Body weight did not change significantly. No adverse side effects were detected and no changes in the liver or renal function or in the blood count were observed. It is concluded that tolamolol is effective in lowering blood pressure and PRA in patients with hypertension.

On oral administration, the non-selective beta-adrenoceptor blocking drugs (+/-)-bufuralol, (-)-bufuralol, propanolol, oxprenolol, pindolol and alprenolol produced hypotensive responses in the conscious cat; (+)-bufuralol was without effect. The selective beta-adrenoceptor blocking drugs practolol and atenolol had no effect on blood pressure but tolamolol elicited a hypotensive response. All the drugs tested reduced the tachycardia due to intravenous isoprenaline in the conscious cat; however, not all doses of these drugs reduced blood pressure. (+)-Bufuralol was devoid to beta-adrenoceptive blocking activity. Only tolamolol reduced the pressor response to i.v. phenylephrine in the conscious cat, indicating that alpha-adrenoceptive blocking activity may contribute to its hypotensive action. The results suggest that beta-adrenoceptive blocking activity is necessary for the hypotensive responses of these drugs. However, for the different drugs, there was no correlation between peripheral beta-adrenoceptive blocking activity and hypotensive response.

Trains of electrical stimuli were applied to the ventricular epicardium in pentobarbital-anesthetized dogs. The trains, delivered during the absolute refractory period via Walton-Brodie strain gauge arches, resulted in a highly localized potentiation of ventricular contractile force. The magnitude of the potentiation was directly related to the intensity of the trains. The positive inotropic response of either ventricle to trains of stimuli was abolished following chronic cardiac denervation or beta-adrenergic blockade with tolamolol, indicating that the response was probably mediated by the excitation of local sympathetic nerve fibers. Following the elimination of adrenergic influences, a slight negative inotropic response to trains of stimuli was observed in some animals. Administration of atropine blocked the negative inotropic response. When the adrenergic system was intact the administration of atropine resulted in a significant augmentation of the positive inotropic response of both ventricles to trains of stimuli. Thus in addition to norepinephrine release, it also appeared that electrical stimulation of the ventricles resulted in activation of local parasympathetic fibers with subsequent release of acetylcholine.

Long-term ingestion of tolamolol led to severe poikiloderma with microscopic features similar to those of premycosis.

Summary: Blood pressure variability in patients on beta-blockers. The direct arterial blood pressure was monitored over 24 hours in unrestricted untreated patients in order to obtain the average pressure and standard deviation over 24 hours. The standard deviation was taken as the index of variability of pressure. In eight subjects the study was repeated three months after commencement of treatment with a beta-adrenergic blocking agent (tolamolol, 300 mg/day). In these subjects tolamolol resulted in a fall in mean blood pressure from 107 to 92 mmHg (P < 0.05) and a fall in heart rate from 82 to 70 beats per minute (P ≤ 0.01). The variability in blood pressure, however, was unaffected by treatment.

In a clinical study comparing the cardiocirculatroy effects of intravenous tolamolol to those of propranolol, tolamolol, 16 mg, induced similar reduction in resting heart rate as 8 mg propranolol in 16 coronary patients. Tolamolol did not disturb cardiac pump performance and exerted less negative inotropic action than propranolol as assessed by mechanical contractility indices. Myocardial beta-one chronotropic and inotropic stimulation by exogenous epinephrine was blocked equally by tolamolol and propranolol. Tolamolol exerted less systemic vascular beta-two blockade than propranolol as assessed by the peripheral resistance and vasopressor responses to epinephrine infusion. Tolamolction than propranolol and is thereby suitable for careful extension of beta blockade therapy to certain patients with pulmonary and ventricular dysfunction.

Beta-adrenergic blocking agents are widely used to treat disorders of cardiac rhythm and rate, angina, and hypertension. Propranolol is the most widely used β-adrenergic blocking agent in this country. Because of its nonselective β-adrenergic blocking effect, propranolol may be associated with significant bronchoconstriction in asthmatic subjects and in some patients with chronic obstructive pulmonary disease. Since tolamolol, a new β-adrenergic blocking agent, has cardioselectivity in animals, we studied asthmatic subjects for six hours on three separate days in a double-blind crossover comparison of oral therapy with 40 mg of propranolol, its β-adrenergic blocking equivalent dose of tolamolol (50 mg), and a high dose of tolamolol (100 mg). AD three dosages had equipotent effects on heart rate and systolic pressure. The 50-mg dose of tolamolol had no effect on pulmonary function over six hours; however, both propranolol (40 mg) and the 100-mg dose of tolamolol had equivalent deleterious effects on airway resistance and on rates of expiratory flow. We conclude that the cardioselectivity of tolamolol is dose-limited but is present at the dosage of 50 mg, which is equivalent to the usual antiarrhythmic β-adrenergic blocking dose of propranolol (40 mg).

The anti-anginal activity of a new beta-blocking agent, tolamolol, was investigated in an open study. Seventeen patients ( fourteen males, three females) from two centres were given tolamolol in doses varying from 150 mg to 800 mg daily for periods of between one and thirty-four weeks. Records were made of the number of attacks of angina and of the consumption of sublingual glyceryl trinitrate ( GTN). Blood pressure and heart rate were monitored together with possible side-effects and the results of routine laboratory tests. There was an over-all reduction in anginal attack rates and the number of GTN tablets used, although these did not reach statistical significance in the small numbers concerned. Heart rate and blood pressure were similarly reduced. Side-effects were of mild severity and were tolerated or disappeared with continued treatment.

1 Four groups of patients with previously untreated essential hypertension in WHO stage I were treated either with timolol (n = 16), or prazosin (n = 13) or prazosin plus tolamolol (n = 12), or labetalol (n = 15). 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial brachial BP were recorded at rest in the supine and sitting position and during steady-state work at 50, 100 and 150 W before treatment and after 1 yr on drug therapy. 3 All regimes induced significant decrease in arterial BP at rest as well as during exercise. 4 BP reduction was achieved through different haemodynamic mechanisms. In the timolol group BP reduction was associated with a marked decrease in heart rate and cardiac output but no decrease in total peripheral resistance. In the prazosin group there was a significant decrease in total peripheral resistance at rest as well as during exercise. During exercise the cardiac index was higher than before treatment. In the groups treated with prazosin plus tolamolol or labetalol alone the changes were rather similar. There was a significant decrease in total peripheral resistance at rest, supine and during exercise. Heart rate was decreased, but much less than by the use of a pure β-blocker alone. Due to a compensatory increase in stroke volume, particularly during muscular exercise, the cardiac index was reduced much less than in the group treated with timolol. 5 The results indicate that the haemodynamic long-term effects of labetalol differ from those seen after long-term therapy on prazosin or β-adrenoceptor blockers and resemble those seen after combined treatment with both α- and β-adrenoceptor blockers. 6 The clinical significance of these differences is briefly discussed.

The effects of five beta-adrenoreceptor blocking agents and placebo during twice daily sustained therapy were compared in 23 patients with stable, exertional angina pectoris. The study was double blind in design, and each drug was prescribed for a period of one month in a random fashion. The number of anginal attacks and consumption of glyceryl trinitrate tablets during the one month period were significantly reduced by a similar degree during therapy with all five beta blocking drugs in comparison to the placebo (P less than 0.01). Exercise tolerance, when assessed 12 hours after a previous dose had been given and 1 hour after the morning dose was given, also improved by a similar degree with all five drugs in comparison to the placebo (P less than 0.01). The increase in exercise duration was associated with a significant reduction in the S-T segment depression, heart rate, systolic blood pressure, and the product of heart rate and systolic blood pressure, with each of the five drugs--effects markedly different from those obtained with the placebo (P less than 0.01). These data show that noncardioselective (propranolol and oxprenolol) and cardioselective (practolol, metoprolol and tolamolol) agents, as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective antianginal agents during sustained therapy. Furthermore, twice daily therapy with any of these drugs was effective in the management of patients with angina pectoris.

The effect of psychologic stress on cardiac vulnerability was examined in 10 conscious dogs. The repetitive extrasystole threshold was employed as a measure of susceptibility to ventricular fibrillation. Instrumental aversive conditioning constituted a stressful environment. The repetitive extrasystole threshold decreased by nearly 50 percent during 3 days in which the animals were exposed to the stressful environment. When Tolamolol hydrochloride, a cardioselective beta adrenoceptor blocking agent, was administered before a stress session, the repetitive extrasystole threshold was unaltered from the control value. Thus, stress-evoked changes in cardiac vulnerability are mediated through the sympathetic nervous system.

We compared the immediate effects of five beta-adrenoreceptor-blocking agents in 16 patients with stable angina pectoris. Acute dose-response studies showed that all five drugs improved exercise tolerance and reduced ST-segment depression, heart rate and blood pressure by a similar degree in comparison with a placebo (P less than 0.01). Near maximum improvement in exercise tolerance occurred when the acute cumulative oral dose had reached 160 mg for propranolol and oxprenolol, 200 mg for metoprolol and tolamolol and 400 mg for practolol. When these drugs were administered as a single doses, increase in walking time before the development of angina and reduction in ST-segment depression, heart rate and systolic blood pressure all occurred within one hour and persisted for eight hours--effects markedly different from the response to a placebo (P less than 0.01). These data show that non-cardioselective agents (propranolol and oxprenolol), cardioselective agents (practolol, metoprolol and tolamolol), as well as drugs with intrinsic sympathomimetic activity (oxprenolol and practolol), were equally effective in the treatment of angina pectoris.

SummaryThe antihypertensive response and side-effects of prazosin ('Peripress') as the sole therapy, as well as in combination with a beta-blocking agent, were studied in 37 outpatients with moderate to severe essential hypertension. About half of the patients had a known history of hypertension, duration 1 to 17 years. Original starting dosage regimen for prazosin was 1 mg + 2 mg daily; however, due to initial adverse reactions in a few patients, it was later reduced to 0.5 mg twice daily. Maintenance dosage of the beta-blocking agent was 160 mg to 320 mg propranolol daily or tolamolol in anticipated equipotent dosage of 200 mg to 400 mg daily.In a group of 17 patients treated with prazosin alone there was an early fall in blood pressure, seen at 1 to 2 weeks' control, with a further mean total reduction of 19/11 mmHg, in the sitting position, after 12 weeks. Seven of these patients, although presenting a mean reduction of 24/15 mmHg, were still not satisfactorily controlled. After combination with the b...

The peripheral vasodilator and β2-adrenergic blocking activity of 17 β-adrenoceptor antagonists were evaluated in the perfused dog hindlimb to determine whether a decrease in vascular resistance might contribute to their antihypertensive properties. The antagonists produced either a transient decrease in hindlimb perfusion pressure followed by either a sustained increase or a decrease in limb resistance with increasing doses. These effects were independent of the ability of the compounds to block vascular β2-receptors. (±)-, (+)-Propranolol, (-)-alprenolol, bunitrolol, IPS-339, butoxamine, tolamolol, RMI-81968, labetalol and penbutalol produced transient dose-related reductions in hindlimb perfusion pressure (20–60 mm Hg). The greatest transient decrease in limb resistance was observed with penbutalol and IPS-339, but the transient vasodilator response following i.a. labetalol was more sustained than any of the compounds tested. Timolol and nadolol were devoid of acute vasodilator activity. A sustained de...

1. [3H, 14C]Tolamolol was well absorbed after oral administration to mice, rats, guinea-pigs, rabbits and dogs. 2. The major route for excretion of radioactivity by mice, rats and guinea-pigs was the faeces; in rabbits the major route was the urine. Dogs excreted similar amounts of radioactivity by both routes. Biliary excretion of radioactivity by the rat and guinea-pig was demonstrated. 3. Tolamolol was extensively metabolized by all five species. The major metabolite in mice, rats, guinea-pigs and rabbits was the product of hydroxylation of the tolyl ring, which was excreted as such as the glucuronide and sulphate conjugates. 4. In the dog the major metabolite was the acid resulting from hydrolysis of the carbamoyl group. This acid was also excreted by the rabbit, but was only a minor metabolite in the other species studied.

1. The effects of prazosin administered alone or in combination were studied in thirty patients between August 1974 and March 1975. 2. All patients had previously received treatment for hypertension with other agents, for from 2 months to 10 years. All thirty patients had refractory hypertension which had not responded satisfactorily to other treatment. 3. Patients were treated initially with prazosin; polythiazide, or polythiazide plus tolamolol, were added when necessary. 4. A satisfactory blood pressure response to prazosin alone, or prazosin in dual or triple combination therapy, occurred in all thirty patients. 5. Prazosin was well tolerated.

The electrophysiologic effects of tolamolol (UK-6558-01), a beta-adrenergic blocking agent, were studied in 13 patients by means of intracardiac electrograms and the extrastimulus method. Tolamolol (4 to 30 mg. intravenously) resulted in : (1) prolongation of sinus cycle length (SCL) in all patients (p less than 0.01); (2) prolongation of sinus escape time (SET) in 11 of 13 patients (p less than 0.001); (3) prolongation of A-V nodal conduction time during sinus rhythm in 1i of 13 patients (p less than 0.001); (4) onset of A-V nodal Wenckebach block at longer paced cycle lengths in 10 of 11 patients (p less than 0.001); (5) prolongation of the functional refractory period (FRP) of the A-V node in 11 of 11 patients (p less than 0.001); and (6) prolongation of the effective refractory period (ERP) of the A-V node in 10 of 10 patients (P less than 0.001). Tolamolol had no effect on His-Purkinje system (HPS) conduction time in any patient, including 3 patients with abnormal H-V intervals. Because of the marked increase in A-V nodal conduction time encountered by premature atrial depolarizations, the relative and effective refractory periods of the HPS could not be determined in any patient after tolamolol. Atropine (0.5 or 1.0 mg. intravenously) significantly reversed the effects of tolamolol on: sinus cycle length (4 of 5 patients); sinus escape time (3 of 3 patients); A-V nodal conduction time (4 of 5 patients); and A-V nodal refractioriness (5 of 5 patients).

Bioavailability of capsule and tablet formulations of tolamolol were compared by measuring plasma concentration of tolamolol and reduction in maximum exercise heart rate over a period of twelve hours in eight healthy subjects in a two-way cross-over study. Tolamolol was absorbed more rapidly from capsules than from tablets; this did not result in any significant difference in the reduction in maximum exercise heart rate between the two formulations. There was no significant difference between area under curve of reduction in exercise tachycardia and area under-curve of plasma concentration of tolamolol for the two formulations. Reduction in maximum exercise heart rate was related to logarithm of plasma concentration of tolamolol between two and twelve hours after both formulations.

The pharmacological methods used to assess the intrinsic sympathomimetic activity (ISA) of beta-blockers are discussed. The clinical relevance of ISA to respiratory function, peripheral resistance and cardiac function is reviewed. It appears doubtful whether ISA is always of predominant clinical significance and an alternative explanation is offered for many clinical effects observed with certain beta-blockers, e.g. pindolol, oxprenolol, tolamolol, metoprolol, etc. Some effects of these beta-blockers resemble those of labetalol, a new drug with both alpha and beta-blocking activity. Some clinical effects of certain beta-blockers are more likely to be due to alpha-blocking activity than to their ISA.

Forty-two patients with angina pectoris have completed a randomized, double-blind trial comparing tolamolol 100 mg and 200 mg with propranolol 80 mg, practolol 100 mg, and placebo, all given three times a day. Tolamolol 200 mg thrice daily was found to be equivalent to propranolol 80 mg thrice daily in anti-anginal efficacy. Anginal attack rates and trinitrin consumption were significantly reduced by all active treatments as compared with the placebo but tolamolol and propranolol were the most effective. Tolamolol 200 mg thrice daily was most effective in reducing blood pressure, while propranolol was most effective in reducing the resting heart rate. All treatments except the placebo significantly increased the amount of exercise which could be performed before angina appeared (exercise work), while tolamolol 200 mg thrice daily significantly reduced Robinson9s index when compared with all other active agents. The degree of S-T segment depression induced by exercise was significantly lessened by both tolamolol and propranolol but not by practolol or placebo. There was no difference in patient preference between tolamolol and propranolol but tolamolol at both dose levels was preferred to practolol. Both tolamolol and propranolol are potent adrenergic beta-receptor antagonists and equal in anti-anginal efficacy but tolamolol has the advantage of being cardioselective. It is superior to practolol.

1. The average blood pressure over 24 h and its variability were measured in eight unrestricted subjects before and after commencing therapy with a new β-adrenoreceptor-blocking agent, tolamolol. 2. The drug caused a fall of 15±6 mmHg in mean arterial pressure and heart rate fell by 13 beats/min. The variation in blood pressure and heart rate over 24 h was unchanged after treatment.

The efficacy of tolamolol, a cardioselective beta adrenergic blocking agent, was evaluated in the treatment of cardiac arrhythmias in 27 patients. Nineteen patients had supraventricular arrhythmias and eight had ventricular arrhythmias. Evaluation was by doulbe-blind randomized trial in 23 patients. Tolamolol was effective in reducing ventricular rate in 17 (85 percent) of 19 patients with supraventricular arrhythmias and resulted in conversion to sinus rhythm in 2 of the 17. The mean ventricular rate in 17 patients decreased from 135 to 102/min 10 minutes after initiation of administration of tolamolol and gradually decreased further to 93/min after 60 minutes. Reduction in ventricular rate was sustained for 2 hours of monitoring undergone by all patients and for 4 and 6 hours monitoring in two subgroups. Among the eight patients with ventricular ectopic beats, tolamolol reduced their frequency in four patients and had no effect in four. Six patients had chronic obstructive pulmonary disease and experienced no adverse clinical effects on respiratory function in association with administration to tolamolol. Untoward effects occurred in 10 patients, including hypotension in 3, 1 of whom required vasopressor therapy. Other side effects were sedation, nausea, dyspnea and warmth in the chest, all of which were mild and transient, requiring no treatment. Cardioselective beta adrenergic blockade with tolamolol was highly effective in controlling ventricular rate in supraventricular arrhythmias and reduced the frequency of ventricular ectopic beats in half of the small group of patients with this arrhythmia. It is particularly applicable in patients with obstructive pulmonary disease in whom cardiac beta adrenergic blockade is indicated. Hypotension is an important potential side effect.

In a placebo controlled double-blind study in six healthy male volunteers the effects of single oral doses of 100 mg and 200 mg of tolamolol on plasma concentrations of prolactin, growth hormone and luteinising hormone were investigated. In a second placebo controlled single-blind study in a further six healthy male volunteers the effects of single oral doses of 200 mg tolamolol and 160 mg propranolol on the same plasma hormone concentrations were compared. A dose dependent increase in plasma prolactin concentration was demonstrated after tolamolol. The increase in plasma prolactin concentration was not evident after propranolol. Plasma growth hormone and luteinising hormone concentrations were not significantly changed by either propranolol or tolamolol.

The efficacy and toxicity of tolamolol and methyldopa in hypertensive patients has been compared by a dose-titrated, double-blind, cross-over study. Thirteen patients completed the trial. Within the dose ranges investigated (tolamolol - 300 mg/day - 900 mg/day; methyldopa - 750 mg/day - 2250 mg/day)both drugs produced significant falls in laying and standing, systolic and diastolic blood pressures. Although the hypotensive effects of methyldopa were more marked than tolamolol, these only achieved conventional (P less than 0.05) levels of significance for lying blood pressure. There were no objective changes in haematological or biochemical indices during treatment with either drug, but patients complained of tiredness, weak limbs and mouth dryness significantly more during methyldopa treatment, than during either placebo or tolamolol therapy.

1 Twelve men with untreated essential hypertension in WHO stage I were studied on an outpatient basis to evaluate the haemodynamic long-term effects of a combination of prazosin and a β-adrenoceptor blocker, tolamolol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intra-arterial brachial pressure were recorded at rest in a supine and sitting position and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with the combination of prazosin (dose 3-6 mg daily) plus tolamolol (150-300 mg daily) for 7-12 months and the haemodynamic study was repeated. 4 The blood pressure was reduced approximately 18% at rest and during exercise. The pressure reduction was due to a combination of reduction in cardiac index and total peripheral resistance. During hard exercise the cardiac index was almost unchanged, the pressure reduction being almost entirely due to reduction in total peripheral resistance. The heart rate was reduced significantly, but less than what is seen by β-adrenoceptor-blockers alone. 5 One subject demonstrated the `first dose reaction' of prazosin with syncope. During the study tolamolol was withdrawn from clinical trials due to possible side-effects in long-term high dose studies in animals. After the haemodynamic study was completed, tolamolol was replaced by timolol without changes in the blood pressure. 6 The combination of prazosin and a β-adrenoceptor blocking drug is very effective in most patients with mild and moderate essential hypertension. The blood pressure reduction is due to a combination of reduction in total peripheral resistance and in cardiac index, the latter being only slightly decreased during severe muscular exercise.

Pharmacokinetic and physiological variables were measured in six healthy subjects after intravenous and oral administration of tolamolol. 2. After intravenous injection of tolamolol (20 mg), there was a biphasic decline both in plasma concentration and attenuation of maximum exercise tachycardia. First and second phase half-lives of plasma concentration were 7 min and 2.5 h respectively. WReduction of maximum exercise tachycardia declined from 32 beats/min at 2 h to 19 beats/min at 8 hours. Clearance of tolamolol from blood ranged from 0.8-1.41 min-1. 3. After the oral administration of tolamolol (100 mg), the average volume of distribution was 220.1 and plasma concentration half-life 1.8 hours. After ten eight-hourly doses of 100 mg there was no accumulation of tolamolol and the half-life of plasma clearance was unchanged. 4. Hydroxytolamolol was detected in plasma in two of six subjects after oral tolamolol. 5. There was a significant positive correlation between reduction in maximum exercise heart rate and logarithm of plasma concentration of tolamolol after both oral and intravenous administration.

1. The beta-adrenergic blocking potencies of practolol, ICI 66082, tolamolol, acebutolol, H 93/26, H 87/07, pindolol and Ro 3-4787 were compared with that of propranolol, on human and rat adipocytes. 2. A good correlation was found between the potencies on adipocytes of the two species but not between our results and literature data on antagonism of isopernaline tachycardia in the anaesthetized cat. 3. The results indicate that differences between adrenergic beta-receptors in heart and adipose tissue may be detected using cardioselective beta-adrenergic receptor blocking agents.

SummaryIt has been suggested that reversal of stress-induced tachycardia by beta-adrenergic blockade might be of benefit in the treatment of phobias. This was tested in a double-blind cross-over trial by exposing 22 female volunteers with spider or snake phobias to their phobic object 1 ½ hours after administration of either tolamolol 200 mg, diazepam 10 mg or placebo. Although tolamolol abolished the stress-induced tachycardia, it had no beneficial behavioural or subjective effects. In contrast, diazepam, which had no significant effect on heart rate, improved behavioural performance. Subjective measures were more influenced by order effect than by medication.

Tolamolol was administered in a “double-blind” study to fifteen hypertensive patients by dose-titration against arterial blood pressure. Mean steady-state plasma tolamolol concentrations (Css) were determined for each patient from the area under the plasma concentration — time curve during a dosage interval whilst patients were receiving optimal tolamolol doses. No significant correlation was observed between daily tolamolol dose and Css; the relationship between fall in lying mean arterial pressure and Css also failed to reach conventional levels of statistical significance, but Css was observed to be correlated with the fall in standing pressure. The results suggest that plasma concentrations in excess of 200 ng/ml may be required to achieve an effective hypotensive response with the drug.

The effect of tolamolol 50-300 mg three times daily in the treatment of 30 patients with mild–severe hypertension was studied. The duration of therapy in the majority of cases was 3-6 months. There was a highly significant reduction of mean blood pressure (p < 0·001) for the group as a whole. Overall, 61% of patients became normotensive or showed a reduction in severity of hypertension. In the majority of cases, this improvement occurred within the first four weeks of therapy. There was no postural hypertension. Apart from one patient with Prurigo Besnier who developed asthma, another patient who developed severe headache and a third patient who stopped treatment without giving a reason, treatment was well tolerated and there were no other serious side or toxic effects.

The renal heamodynamic effects of a single i.v. administration of tolamolol were studied in 9 hypertensive subjects. No change of GFR and ERPF was observed after tolamolol, while urine output decreased and urine creatinine concentration increased. A reduction of the heart rate was confirmed. Blood pressure was unchanged.

Urticaria with systemic effects occurred in a patient being treated with propranolol and was reproducible upon rechallenge with the drug; Successful beta-adrenergic blocking therapy was achieved using a new agent, tolamolol, with no evidence of any adverse effects.