Metipranolol promotes structure and function of retinal photoreceptors in the rd10 mouse model of human retinitis pigmentosa.

Metipranolol is a ß-adrenergic receptor antagonist that is given orally for the treatment of hypertension and also applied topically to the cornea for treating glaucoma. It also inhibits nitrosative stress which has previously been shown to be the cause of cone photoreceptor death in retinitis pigmentosa. In this study, we tested the hypothesis that metipranolol protects photoreceptor structure and function in the mouse model rd10. At P35, compared with vehicle-treated rd10 mice in which rod degeneration was nearly complete, rd10 mice given daily subcutaneous injections of 40 mg/kg of metipranolol had reduction in markers of nitrosative stress, fewer TUNEL-positive cells, increased outer nuclear layer thickness, and substantially more staining for rhodopsin. This was accompanied by significantly higher mean scotopic and photopic electroretinogram b-wave amplitudes indicating improved photoreceptor function. At P50, metipranolol-treated rd10 mice had decreased 3-nitrotyrosine staining in the retina, increased immunostaining for cone arrestin, a marker for cone photoreceptors, and significantly higher scotopic and photopic b-wave amplitudes at the highest stimulus intensity compared with vehicle-treated mice. At P65, cone density was significantly higher in metipranolol-treated versus vehicle-injected rd10 mice. Metipranolol applied as eye drops promoted cone photoreceptor function in retinas of rd10 mice greater than subcutaneously injected metipranolol. The reduced nitrosative damage and rescue of functional loss of photoreceptors in rd10 mice suggests that metipranolol, a drug with established ocular safety and tolerability, may have potential for treating patients with retinitis pigmentosa.

Cardiovascular parameters in rat model of chronic renal failure induced by subtotal nephrectomy.

Chronic renal failure (CRF) is associated with high incidence of cardiovascular complications. To clarify pathogenesis of CRF numerous animal models have been developed. The aim of our work was to describe methodology of subtotal surgical renal ablation in rat and to characterize some biochemical and cardiovascular parameters of this animal model. Male rats underwent 5/6 surgical nephrectomy or sham operations in two steps. The following parameters were measured on day 10 and in week 10 after the surgery: plasma concentrations of creatinine and urea, blood pressure, resting heart rate, chronotropic response to atropine and metipranol, heart ventricles weight, contraction parameters and action potential duration in the left ventricle. Increased serum concentrations of creatinine and urea, decreased creatinine clearance, polyuria and alteration of the remnant kidney tissue were found in CRF rats. Changes in cardiovascular parameters identified after subtotal nephrectomy resembled alterations of cardiovascular system in uremic patients and included hypertension, elevated resting heart rate, diminished parasympathetic cardiac tone, hypertrophy of the left ventricle associated with weakened force of contraction, prolonged contraction and relaxation and shortening of action potential duration. These data suggest that the present model can be a useful tool in the study of CRF and its cardiovascular complications.

Parasympathetic regulation of heart rate in rats after 5/6 nephrectomy is impaired despite functionally intact cardiac vagal innervation.

BACKGROUND: Chronic renal failure is frequently associated with a high risk of sudden cardiac death due to dysfunction of the autonomic nervous system. The pathogenic mechanisms underlying the parasympathetic cardiac dysautonomia are not fully elucidated yet. METHODS: Chronic renal failure was induced in rats by 5/6 nephrectomy. Blood pressure, resting heart rate and plasma levels of creatinine, urea and asymmetric dimethylarginine (ADMA) were measured. To characterize the parasympathetic innervation of the heart, chronotropic responses to atropine, metipranolol and to vagal stimulation in the absence or presence of ADMA were investigated in vivo. In vitro, chronotropic and inotropic effects of carbachol and ADMA and mRNA expression of muscarinic M2 receptors, high affinity choline transporter (CHT1), vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) were assessed in the isolated cardiac tissues. RESULTS: In 5/6 nephrectomy rats, the resting heart rate was significantly higher and the parasympathetic tone, measured as the effect of atropine after administration of metipranolol was significantly lower than in control animals. Plasma ADMA levels were significantly elevated in the uraemic rats and significantly inversely correlated with the effect of atropine on the heart rate. No differences were revealed in the plasma norepinephrine concentrations, negative chronotropic responses to stimulation of the vagus nerves, chronotropic and inotropic responses to carbachol and the relative expression of M2 receptors, CHT1, VAChT and ChAT. CONCLUSION: The data suggest that cardioacceleration in chronic renal failure is caused by a diminished cardiac parasympathetic tone in the presence of a functionally intact intrinsic cardiac cholinergic signalling system.

Chronic atropine administration diminishes the contribution of vasoactive intestinal polypeptide to heart rate regulation.

Vasoactive intestinal polypeptide (VIP) is implicated in the modulation of vagal effects on the heart rate. In this study, the impact of acute and chronic atropine administration on VIP levels in rat heart atria was investigated in relation to heart rate in the course of vagus nerves stimulation. Anaesthetised control and atropinised (10 mg/kg/day for 10 days) rats pretreated with metipranolol and phentolamine that were either given or not a single dose of atropine were subjected to bilateral vagus nerve stimulation (30 min: 0.7 mA, 20 Hz, 0.2 ms). VIP concentrations in the atria were determined after each stimulation protocol. In control rats with or without single atropine administration, the heart rate upon vagal stimulation was higher than in atropinised animals with or without single atropine dose, respectively. VIP concentrations in the control atria were significantly decreased after the stimulation; the decrease was comparable both in the absence and presence of a single dose of atropine. Compared to controls, VIP levels were significantly decreased after chronic atropine treatment and they were not further reduced by vagal stimulation and single atropine administration. Administration of VIP antagonist completely abolished the differences in the heart rate upon vagal stimulation between control and atropinised groups. In conclusion, the data indicate that chronic atropine administration affects VIP synthesis in rat heart atria and consequently it modifies the heart rate regulation.

The beta-adrenergic receptor antagonist metipranolol blunts zinc-induced photoreceptor and RPE apoptosis.

PURPOSE: To determine the effect of zinc on retinal cells at concentrations at which it is known to cause oxidative stress. Furthermore, the effects of metipranolol, known to prevent retinal damage, and of other antiglaucoma drugs were determined on zinc-injured retinal cells. METHODS: Lipid peroxidation assays were conducted on rat brain and bovine retina-retinal pigment epithelial (RPE) membrane preparations. Immunohistochemistry, immunoblot analysis and the terminal-deoxynucleotidyl transferase dUTP-linked nick-end labeling (TUNEL) procedure determined the effects of zinc with or without trolox or metipranolol on photoreceptor death in situ. The effect of treatments on cultured RPE cells was analyzed using cell viability assays, immunoblot analysis, and the TUNEL procedure. RESULTS: Zinc-induced lipid peroxidation of rat brain and bovine retina-RPE membranes, although the effect of the latter was of a (twofold) greater magnitude. Both effects, however, were similarly attenuated by metipranolol, desacetylmetipranolol, and trolox. Antiglaucoma drugs other than metipranolol had no effect. Intraocular injection of 150 microM zinc and treatment of cultured RPE cells with zinc led to mainly photoreceptor apoptosis and apoptotic death of RPE cells (50% death at 18 microM rising to 10% at 50 microM), respectively. Zinc-induced apoptosis of cultured RPE cells and photoreceptors were attenuated only by metipranolol and trolox. CONCLUSIONS: The combined data suggest that oxidative injury to RPE cells and photoreceptors may be caused by elevated levels of zinc in diseases such as age-related macular degeneration (AMD) and that metipranolol may act as an efficacious antioxidant to blunt this process.

The interaction of beta-adrenoceptor blocking drugs with platelet aggregation, calcium displacement and fluidization of the membrane.

beta-Adrenoceptor blocking drugs interfere with adenosine diphosphate-stimulated platelet aggregation. Alprenolol, exaprolol, Kö 1124 and propranolol inhibited the aggregation, metipranolol decreased the extent and rate of aggregation significantly. Atenolol potentiated the aggregation measured by amplitude significantly. The interaction of beta-adrenoceptor blocking drugs with aggregation correlated with the displacement of calcium ions from binding sites in isolated platelets and the fluidization of the whole platelets and isolated platelet membrane as measured with electron spin resonance of the spin probe. The most potent were highly liposoluble drugs alprenolol, exaprolol, metipranolol and propranolol which increased the calcium displacement and membrane fluidity, the least active was atenolol decreasing these phenomena. The inhibition by beta-adrenoceptor blocking drugs of stimulated platelet aggregation is rather a result of unspecific than specific receptor interaction.

Clinical pharmacologic investigations with carvedilol, a new beta-blocker with direct vasodilator activity.

Carvedilol (BM 14.190) has been shown to have beta-adrenergic blocking and vasodilating activity. By means of digital plethysmography, the threshold for vasodilation was ascertained at a dose of 2.6 mg iv infused over 1 hour. The oral threshold dose was established at about 15 mg, with a linear increase in response (r = 0.78) up to 76.5 mg. This dose increased blood flow to the forearm by reduction of arterial resistance. Although venous capacity was not changed, postural symptoms in three subjects could also be indicative of venous involvement. Carvedilol, 50 mg, reduced exercise heart rate for about 10 hours.

A single dose of three different ophthalmic beta-blockers antagonizes the chronotropic effect of isoproterenol in healthy volunteers.

The systemic effect of three beta-blocking eyedrops was compared in a placebo-controlled, double-blind trial in 12 healthy male volunteers. Each subject received successively each treatment in random order at weekly intervals. The eyedrops administered were as follows: 0.5% timolol, 2% carteolol, 0.6% metipranolol, and placebo. We evaluated the intraocular pressure and systemic beta-blockade 3 hours after a single administration of one eyedrop in each eye. The systemic beta-blocking effect was evaluated by the isoproterenol sensitivity test, that is the dose of isoproterenol required to increase resting heart rate by 25 bpm (I25). Each beta-blocking eyedrop antagonized the chronotropic effect of isoproterenol. I25 for placebo was 3.1 +/- 0.5 micrograms, for metipranolol 5.2 +/- 0.9 micrograms (P less than 0.005), for timolol 10.9 +/- 1.9 micrograms (P less than 0.001), and for carteolol 39.6 +/- 5.4 micrograms (P less than 0.0005). Each treatment significantly decreased the intraocular pressure: metipranolol 3.6 +/- 0.4 mm Hg (P less than 0.001), timolol 2.44 +/- 0.4 mm Hg (P less than 0.01), and carteolol 2.38 +/- 0.48 mm Hg (P less than 0.01) compared with placebo. The resting heart rate and blood pressure were not influenced by the treatments. Even though the results might be different in the case of an earlier or a later time of evaluation or chronic administration, we believe that the isoproterenol sensitivity test may be used to evaluate the systemic effect of beta-blocking eyedrops.

Metipranolol blunts nitric oxide-induced lipid peroxidation and death of retinal photoreceptors: a comparison with other anti-glaucoma drugs.

PURPOSE: To determine the effect of the nitric oxide donor sodium nitroprusside (SNP) on rat retinas and to see whether detrimental changes could be attenuated by known antiglaucoma drugs. METHODS: SNP was injected into the rat eye and retinas were analyzed by the terminal-deoxynucleotidyl transferase dUTP-linked nick end labeling (TUNEL) procedure and by immunohistochemistry. In some instances, retinal homogenates were analyzed by immunoblot for proteins associated with either photoreceptors or with cell death. Analysis of lipid peroxidation in retinal homogenates was by the thiobarbituric acid reactive species (TBARS) formation RESULTS: SNP caused an increase in the number of retinal photoreceptors labeled for DNA breakdown by the TUNEL procedure and for caspase-3 and Bcl-2. After intravitreal injection of SNP, breakdown of poly(ADP-ribose) polymerase and an increase in the level of active forms of caspase-3 and Bcl-2 were detected. Furthermore, photoreceptor-specific rhodopsin kinase was reduced. SNP also stimulated formation of TBARS in retinal homogenates, occurring to a greater extent in retinas from young Royal College of Surgeons rats lacking photoreceptor degeneration. This supports the view that the photoreceptors are the prime target for SNP. Significantly, of several antiglaucoma drugs tested only metipranolol and its active metabolite, desacetylmetipranolol, blunted the SNP-induced retinal changes. CONCLUSIONS: Of all antiglaucoma drugs tested, only metipranolol was able to attenuate SNP-induced lipid peroxidation and activation of apoptosis in photoreceptors. Because oxidative injury has been implicated in the pathogenesis of certain ocular diseases, these findings could prove to be of clinical significance.

Ocular metipranolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in glaucoma and ocular hypertension.

Metipranolol is a non-selective beta-adrenoceptor blocking agent used for the topical treatment of elevated intraocular pressure in patients with chronic open angle glaucoma or ocular hypertension. In double-blind comparative studies of up to 4 months duration, metipranolol 0.1 to 0.6% produced comparable reductions in intraocular pressure to timolol 0.25 to 0.5% and levobunolol 0.5%, lowering pressure by about 20 to 29% from baseline. Metipranolol has been well tolerated by most patients, producing only minor changes in objective measurements of ophthalmic status and systemic parameters. Similarly, subjective ophthalmic complaints have been minimal although reports of initial stinging or burning upon instillation have occurred. Further published reports, in which larger numbers of patients are treated over extended periods, are needed to confirm the drug's apparent long term comparative efficacy. Studies of ocular metipranolol to date are encouraging, and the drug demonstrates a lasting intraocular pressure reducing effect with good tolerability. Thus, ocular metipranolol provides a viable alternative to ocular timolol and levobunolol in the topical treatment of chronic open angle glaucoma or ocular hypertension.

Metipranolol and propranolol: no CNS effects of a single oral dose.

Effects of single oral doses of the beta-blocking drugs propranolol (40 mg) and metipranolol (Disorat, Boehringer, Mannheim, FRG, 5 and 20 mg), in comparison with placebo, on mental performance and psychophysiological measures were investigated in a double-blind crossover study comprising 12 healthy volunteers. Effects were evaluated using a battery of highly reliable and sensitive computerized indices of mental performance and a comprehensive range of psychophysiological measures. Propranolol and metipranolol had no effects on mental performance, in contrast to findings in a previous study for bunitrolol (Stresson, Boehringer, Ingelheim, FRG). There were marked effects on some autonomic functions; dose-dependent for heart rate and heart rate response, and dose-independent for blood pressure and finger tremor. In the previous study bunitrolol had no effect on tremor and blood pressure and a less marked effect on heart rate. The lack of psychotropic effects for metipranolol and propranolol as compared to bunitrolol cannot be predicted from pharmacokinetic properties or peripheral effects of the three drugs, arguing for the need for systematic screening using psychometric and psychophysiological methods of current and new beta-blocking drugs. A comparison between the effect of propranolol given in a single oral dose and findings in a previous study with repeated administration suggested that the differences in effect profile between acute and chronic administration of the drug are small.

The effect of renin and aldosterone inhibition by beta-adrenergic blockade on the response to the new diuretic azosemide.

The effect of repeated Azosemide infusions (20 mg in 500 ml 5% glucose for one h) on urine volume and electrolyte excretion, and on the activity of the renin-angiotensin-aldosterone system (RAAS) was studied in a group of 15 patients with benign essential hypertension before and during treatment with the beta-adrenergic blocker Trimepranol. Azosemide alone had a marked but short-lasting diuretic and natriuretic effect. Repeated administration on three consecutive days led, however, to a progressive decrease in the natriuretic effectiveness of Azosemide, associated with an increase in plasma renin activity (from 0.413 o.032 to 1.631 0.438 pmol/l). Treatment with Trimepranol 20 mg/day enhanced and prolonged the diuretic and natriuretic response to Azosemide concomitantly with a reduction of its stimulatory effect of RAAS. There results suggest that stimulation of the RAAS might be responsible for the diminishing effectiveness of repeated Azosemide infusions and that the stimulation could be, at least partly, inhibited by a beta-blocker Trimepranol, resulting in a greater diuretic and natriuretic effect of Azosemide.

Differences among beta-adrenoceptor blocking drugs in modifying platelet aggregation and arachidonic acid liberation under thrombin stimulation.

The dose-dependent inhibition of thrombin stimulated platelet aggregation due to beta-adrenoceptor blocking drugs followed the rank order of potency: propranolol greater than alprenolol greater than metipranolol and correlated with arachidonic acid (3H-AA) liberation. Atenolol which slightly potentiated stimulated aggregation increased also the liberation of 3H-AA from membrane phospholipids of isolated platelets. Stimulation of platelets resulted in decreased 3H-AA incorporation into phosphatidylcholine, phosphatidylinositol and phosphatidic acid and increased incorporation into phosphatidylethanolamine and phosphatidylserine. Alprenolol, metipranolol and propranolol enhanced the incorporation of 3H-AA into phosphatidylcholine of stimulated platelets.

On the relationship between the inhibition of thrombin stimulated aggregation and thromboxane formation in isolated platelets treated with beta-adrenoceptor blocking drugs.

Thromboxane B2 (TXB2) formation in isolated, thrombin-stimulated rat platelets was time dependent and appeared after 5 s of incubation. Beta-adrenoceptor blocking (BAB) drugs inhibited thrombin-stimulated TXB2 formation in the following rank order of potency: metipranolol approximately alprenolol approximately propranolol > oxprenolol > practolol. Atenolol was ineffective in inhibiting TXB2 production in stimulated platelets. The inhibition of thrombin-stimulated TXB2 formation by BAB drugs correlated with their inhibitory effect on thrombin-stimulated platelet aggregation, arachidonic acid liberation from membrane phospholipids and with their membrane fluidization. The higher was the liposolubility of the beta-adrenoceptor blocking drugs investigated, the higher was their inhibition of stimulated TXB2 formation. Hydrophilic, selective atenolol and practolol revealed slight or no inhibitory effect on stimulated thromboxane production.

Cationic amphiphilic drugs and platelet phospholipase A(2) (cPLA(2)).

The aim of the study was to verify and compare the effect of cationic amphiphilic drugs (CAD) from different pharmacological groups on activation of platelet phospholipase A2 (PLA2)--the essential enzyme of arachidonic pathway in blood platelets. Beta-adrenoceptor-blocking (BAB) drugs inhibited platelet aggregation in the rank order of potency: propranolol>alprenolol>metipranolol>atenolol. The higher the inhibition of arachidonic acid (AA) liberation by BAB drugs, the higher the inhibition of aggregation. Similarly did the H1-histamine antagonists bromadryl (BRO) and dithiaden (DIT) as well as the antimalarial chloroquine (CQ) show antiplatelet effect in vitro in the rank order of potency: DIT>BRO>CQ. Dose-dependent inhibition of aggregation was followed by the inhibition of AA liberation from membrane phospholipids of platelets stimulated either at the receptor site (thrombin) or by a stimulus bypassing membrane receptors (Ca2+ ionophore A23187). The rank order potency for inhibition of stimulated 3H-AA liberation from membrane phospholipids was: (a) for BAB drugs: propranolol>alprenolol>metipranolol, (b) for other drugs: DIT>BRO>CQ. The investigated drugs' interference with stimulated liberation of AA showed nonspecific inhibition of platelet cytosolic PLA2 (cPLA2) by these drugs at intracellular level. The results revealed that besides the inhibition of cyclooxygenase pathway and receptors for adenosine diphosphate (ADP) and glycoproteins Gp IIbIIIa, the interaction of drugs with cPLA2 may represent a further site for antiplatelet action.

Topical ophthalmic beta blockers may cause release of histamine through cytotoxic effects on inflammatory cells.

AIM: To evaluate the effects of beta blockers used in ophthalmology on the release of histamine from mixed cell preparations containing human leucocytes and basophils. METHODS: A mixed leucocyte and basophil preparation was obtained from venous blood of healthy non-atopic volunteers. Cell preparations were then incubated with betaxolol, metipranolol, timolol, or carteolol. After incubation for 1 hour the histamine content of the supernatant was analysed by automated fluorometric analysis. Cell viability was tested by measuring lactate dehydrogenase (LDH) concentrations. RESULTS: Betaxolol and metipranolol in concentrations between 10(-2) M and 10(-3) M liberated histamine from human blood cells in a dose dependent manner. Carteolol and timolol had no effect on histamine at these concentrations. At the same concentrations LDH was also detected in the supernatants of cell suspensions incubated with metipranolol or betaxolol. CONCLUSIONS: Betaxolol and metipranolol induce substantial histamine release from human leucocytes, probably as a result of their cytotoxic effect.

Acute effect of metipranolol on the retinal circulation.

AIM: To assess the effect of topical and systemic application of a beta adrenergic receptor blocker on retinal haemodynamics. METHODS: 24 healthy subjects were included in this double masked, randomised, placebo controlled crossover study. Metipranolol, a non-selective beta adrenergic receptor blocking agent was used as test drug. In all subjects arm-retina time, arteriovenous passage time, arterial mean dye velocity, the arterial vessel diameters, and capillary flow velocity were quantified from digital video fluorescein angiograms. RESULTS: A significant effect was observed on the arteriovenous passage time (p < 0.05), the arterial mean dye bolus velocity (p < 0.05), and capillary blood velocity (p < 0.05), but not on the arterial vessel diameter. The arterial mean dye bolus velocity and capillary blood velocity increased after application of the test drug (topical and systemic). In tandem with this a decrease of the arteriovenous passage time was observed. The perfusion pressure increased after topical application and remained unchanged after systemic application of metipranolol. CONCLUSIONS: This study shows that systemic as well as topical application of metipranolol leads to increased retinal blood flow velocities. The implications of these results for treatment with beta adrenergic receptor blockers is not clear. However, in view of these data it is very unlikely that treatment with metipranolol has a negative effect on retinal blood flow.

Pharmacological evaluation of new alkylesters of 4-[(2-hydroxy-3-alkylamino)propoxy]phenylcarbamic acids with beta-adrenolytic properties.

The basic relationship between the chemical structure and pharmacological activities of new alkylesters of 4-[(2-hydroxy-3-alkylamino)propoxy]phenylcarbamic acids were evaluated. The efficiency of compounds was compared with those of metipranolol and practolol, respectively. The majority of 4-substituted derivatives of aryloxypropanolamines have shown antiisoprenaline (beta-adrenolytic) and local anesthetic (membrane stabilizing) activities. The values of LD50 and/or partition coefficients have not differed significantly when compared with those of standard metipranolol.

[Metipranolol 0.1%: effect of a single dose on the nycthemeral pressure curve in an eye with chronic primary open-angle glaucoma]. / Métipranolol 0.1%: l'effet d'une dose unique sur la courbe tensionnelle nycthémérale d'un oeil porteur d'un glaucome chronique primitif à angle ouvert.

A double blind randomised study was made to compare the efficiency in decreasing intra ocular pressure of Metipranolol 0.1% or 0.3% versus placebo in three groups of 15 patients with chronic open angle glaucoma with or without visual field defects. The results demonstrate that Metipranolol 0.1% significantly lowers the intra ocular pressure in comparison with placebo. But this lowering is less that the one with 0.3% and is markedly reduced after 9 hours. The action of Metipranolol 0.3% is more durable and is still observed at 24 hours with a drop of nearly 20% in comparison with the initial intra ocular pressure. In the three groups, no significant variation of pulse and arterial pressure could be noticed during this 24 hours study.

[Comparison of the effects of carteolol and metipranolol eyedrops on the ventilatory and cardiovascular functions in asthmatics]. / Comparaison des effets des collyres au cartéolol et au métipranolol sur les fonctions ventilatoire et cardiovasculaire de l'asthmatique.

Systemic effects of two topical B adrenergic blocking agents, carteolol and metipranolol, recently introduced in the treatment of open angle chronic glaucoma, were investigated in two groups of 10 asthmatic patients, according to a controlled trial device. Saline eye drops as placebo, then, 30 mn later beta blocker eye-drops, were instillated at usual dose. Heart rate, systolic and diastolic blood pressure, vital capacity (VC) and expiratory outflow (FEV1), were checked every 15 mn during 90 mn. They did not vary under placebo. After carteolol and metipranolol, heart rate decreased more than 10% in 7 out of 10 patients in each group (extreme individual changes: -16.7 and -25.0%). Bradycardia was always sino atrial. FEV1 was lowered in 3 patients with carteolol and in 6 with metipranolol (extreme individual values: -32.3 and -31.8%). If time is not taken in consideration, the lowest values were -8.6 +/-4.6% with carteolol and -17.9 +/- 3.3% with metipranolol. CV was reduced only in 1 patient under carteolol and 2 patients under metipranolol. Systemic blood pressure remained unchanged. 7 patients complained of ocular pain when metipranolol was instillated. Comparison of both ocular topics shows that metipranolol lowers heart rate and FEV1 more than carteolol, which has a sympathomimetic intrinsic activity. These two drugs have the same clinical efficiency. Our results point out the risks outcoming from their systemic diffusion, and the absolute necessity to comply with the general rules of good use of beta blockers, even with eye drops, mainly the contra-indications and the strict adjustment of individual doses.