Treatment of central serous chorioretinopathy with beta-blocker metipranolol.

AIM: The purpose of this study was to evaluate the effect of the systemically administered betablocker metipranolol on the course of central serous chorioretinopathy (CSC). METHODS: A prospective double-blind study involving 48 patients with a first attack of CSC not exceeding two weeks and who agreed to the follow-up ophthalmology examinations every week. The group was divided into a metipranolol group (n=23), receiving 10 mg of drug twice per day and a placebo group (n=25). The outcome measure was time in weeks from drug intervention (metipranolol vs. placebo) to reattachment of macula neuroepithelium. RESULTS: There was no statistically significant difference in duration of CSC in patients who used metipranolol and those who used placebo (P=0.341). CONCLUSIONS: In a prospective double-blind study, we found no effect of the betablocker metipranolol on the duration of central serous chorioretinopathy.

Novel pluronic-chitosan micelle as an ocular delivery system.

Pluronic micelles were prepared for ophthalmic delivery by incorporation of ethyl acetate as a dispersion agent and their surfaces were modified by chitosan to improve their bioavailability. The micelles disperse well in the solution and have a core-shell like structure with a particle size ranging from 93 to 181 nm for drug unloaded, 123-232 nm for drug-loaded, and a zeta potential between 6.1 and 9.2 mV, indicating very suitable use as ophthalmic carrier. The in vitro serum stability tests indicate the particle size of the micelles was very stable during the serum absorption. The turbidity test reveals that the prepared micelles were very stable under phosphate buffered saline environment, which can prevent the blurred vision. The loading efficiency of metipranolol in micelles can be as high as 83%. Finally, the in vitro and in vivo studies indicate the pluronic micelles modified by chitosan have sustained release behavior and good pharmacological response. As the results, the pluroic-chitosan micelles system provides a potential opportunity in decreasing frequency of administration and improving patient compliance for ocular drug delivery.

Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension: focus on beta-adrenergic blockade.

Glaucoma and ocular hypertension are highly prevalent conditions in individuals over the age of 40 and are commonly seen together in patients with cardiovascular disease. Many of the antiglaucoma medications, when systemically absorbed, affect the sympathetic and parasympathetic nervous systems of patients and can cause cardiovascular toxicity. Such adverse effects are frequently associated with the long-term use of potentially toxic agents in elderly people, who are most prone to chronic eye disease. Moreover, patients may not associate their symptoms with the topical eye medications, and consequently may not report adverse drug effects. Drug-drug interactions can also occur when patients are taking medications for both cardiovascular disease and glaucoma. This review focuses on beta-adrenergic blockers as topical antiglaucoma medications and other topical antiglaucoma drugs. The systemic toxicity of these agents is reviewed, along with the possible drug interactions. Brief mention is also made of other antiglaucoma medications used alone and in combination with topical beta-blockers.

Comparison of the effects of 0.5% timolol maleate, 2% carteolol hydrochloride, and 0.3% metipranolol on intraocular pressure and perimetry findings and evaluation of their ocular and systemic effects.

PURPOSE: To compare the effects of 0.5% timolol maleate, 2% carteolol, and 0.3% metipranolol on intraocular pressure (IOP) in 45 patients with primary open-angle glaucoma (POAG) and ocular hypertension. A secondary goal of this study was to evaluate the ocular and systemic side effects of these medications. METHODS: Measurements of IOP were taken at baseline (pretreatment) and 2, 6, and 12 hours after instillation on treatment days 15, 30, 60, and 90. Mean sensitivity (MS) and mean defect (MD) values of perimetry before and after treatment and the effects of the three beta blockers on serum lipid profiles were determined. Ocular and systemic side effects were recorded. RESULTS: The most prominent IOP lowering effect was noted with metipranolol at 2 and 6 hours on day 15, and with timolol maleate at 12 hours on day 15 and at all hours of the subsequent days on which measurements were taken. Timolol maleate produced a significant decrease in IOP at 12 hours on day 15 compared with carteolol. There was not a statistically significant difference between the MS and MD values on perimetry before and after treatment for any treatment. There was a statistically significant decrease in levels of total cholesterol and high-density lipoprotein (HDL) cholesterol and a significant increase in triglyceride levels; these changes were observed for all treatments. CONCLUSION: The effects of the three medications were not statistically different from each other in terms of IOP reduction and visual field changes. Careful monitoring of blood lipid levels is necessary with long-term treatment with beta blockers, because these agents reduced serum levels of HDL and total cholesterol while increasing triglycerides. Such changes in lipid levels could lead to increased incidence of complications, particularly in patients with atherosclerosis or coronary heart disease.

Early conjunctival changes following treatment with metipranolol and preservatives are not reversible with dexamethasone.

BACKGROUND: Topical medication for the treatment of glaucoma alters the cellular and extracellular composition of the superficial and deep conjunctival layers. We sought to determine whether, after short-term use of metipranolol with preservatives, subsequent application of steroids or metipranolol without preservatives affects these conjunctival changes. METHODS: Rabbits received topical metipranolol over a period of 6 months. For the following 2 months, one group received metipranolol without preservatives, and another group steroids. For controls, animals were treated with preservatives only or metipranolol with preservatives for 6 months. Superior bulbar conjunctiva was examined by light microscopy, immunohistochemistry, and transmission electron microscopy. RESULTS: On light microscopic and immunohistochemical examination of conjunctival specimens from all groups, there was an increase of subepithelial collagen deposition in all treated groups. Treatment with steroids or preservative-free metipranolol did not alter the initial effects. By electron microscopy, additional extracellular matrix changes were seen as well as degenerative changes of tissue fibroblasts. CONCLUSION: The animal model used was able reliably to produce conjunctival changes following antiglaucomatous therapy. The changes seen were early changes, because there was no increase of inflammatory cells. Steroids did not significantly affect the changes. The beneficial effect of steroids used prior to glaucoma surgery remains controversial.

Effects of beta-blockers association with pilocarpine on rabbit intraocular pressure and heart rate.

The effect of 7-days BID (twice in a day) or TID (three times in a day) administration of the eye-drop combinations of timolol and pilocarpine (0.5% and 2%, respectively), metipranolol and pilocarpine (0.1% and 2%, respectively) or placebo on intraocular pressure (IOP) and heart rate (HR) of conscious rabbits were studied in order to assess the pharmacological potency of the combinations and their heart side effects. TID administration of both pharmacological combinations was followed by similar decrease of IOP as measured over 24 h (at 4.00 and 20.00 h). After the BID administration, a reduction in IOP was observed only twice with the timolol-pilocarpine combination. In contrast, a constant reduction in IOP was seen with the metipranolol-pilocarpine combination. Furthermore, the TID administration of the timolol-pilocarpine combination exerted a decrease of IOP that appeared to be more pronounced than that observed after the BID administration of the same combination, while no difference was found between the TID and BID administration of the metipranolol-pilocarpine treatment. Heart rate, when measured after 7 days of treatment, appeared to be constantly decreased only in the group of animals which received the TID administration of timolol-pilocarpine combination. The present results suggest that the BID or TID administration of metipranolol-pilocarpine combination was fully effective in reducing IOP without influencing HR. The timolol-pilocarpine association appeared to be fully active in reducing IOP only under the TID administration schedule. However, this rate of administration was followed by a constant reduction of HR. Thus, on a dose basis the metipranolol-pilocarpine combination appeared to be more effective in reducing IOP and less effective in inducing bradycardia than the timolol-pilocarpine association.

Topical ophthalmic beta-adrenergic blockade for the treatment of glaucoma and ocular hypertension.

Since the late 1970s, topical beta-adrenergic blockers have been the drugs of choice in treating ocular hypertension and associated glaucoma. The currently available drugs are timolol, betaxolol, levobunolol, metipranolol, and carteolol. All reduce intraocular pressure by decreasing the production of aqueous humor. Although these drugs are applied locally in the eye, they may enter the general circulation and reach concentrations high enough to cause systemic effects, including alterations in heart rate and rhythm, bronchoconstriction, dyslipidemia, and central nervous system abnormalities. Interactions with other drugs may also occur. Ocular beta- blockers differ in beta 1-selectivity (betaxolol is beta 1-selective, whereas the other drugs are nonselective) and in intrinsic sympathomimetic activity (ISA) or partial agonist properties (only carteolol possesses ISA). These differences give betaxolol and carteolol potential advantages in minimizing certain side effects. The advantage of betaxolol vis-à-vis systemic side effects is more clearly established than that of carteolol. Further systematic study is needed to determine what advantages, if any, are conferred by the presence of ISA.

Ocular macro- and microcirculation after topical application of clonidine and metipranolol.

We investigated the effect of clonidine (Isoglaucon, an alpha-agonist) and metipranolol (Betamann, a beta-antagonist) on the blood flow in the ophthalmic artery and the anterior uvea of 40 young, healthy volunteers (mean age, 23.5 +/- 2 years) in a prospective, randomized simple blind study. The blood flow in the iris and ciliary body was detected by laser-Doppler flowmetry (bpm, 403a; TSI; wavelength, 780 nm; power, < 1.6 mW). The blood flow in the ophthalmic artery was measured by pulsed Doppler sonography (4 MHz, EME). The blood pressure, pulse respiration, and intraocular pressure (IOP) were recorded. Vascular resistance (RF) was calculated by the equation RF = (RRmean--IOP)/blood flow. Group 1 was treated with a single drop of Betamann (3 mg/ml) applied topically, and group 2 was treated with Isoglaucon (2.5 mg/ml). Measurements were made before and 30 min after application. Both drugs significantly lowered the IOP by about 7% (P = 0.01). Clonidine did not affect the blood velocity in the ophthalmic artery. In group 2 (metipranolol) we found a significant increase in the blood velocity in the ophthalmic artery during the diastolic period (from 11.0 +/- 3.7 to 11.9 +/- 2.2 cm/s, P = 0.05). Both clonidine and metipranolol decreased the iridal blood flow [clonidine, from 9.3 +/- 3.9 to 7.6 +/- 3.1 (flux), P = 0.05; metipranolol, from 7.5 +/- 2.9 to 6.5 +/- 2.6 (flux), P = 0.05]. Vascular resistance in the iris increased under the effect of clonidine (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the efficacy of various metipranolol-pilocarpine combinations in patients with ocular hypertension and primary open-angle glaucoma.

We compared the ocular hypotensive effects of four fixed-dose metipranolol-pilocarpine combinations in nineteen ocular hypertensive subjects and glaucoma patients. Each patient was tested with all of the study medications: vehicle alone, 0.1% metipranolol HCl + 2% pilocarpine HCl, 0.1% metipranolol HCl + 4% pilocarpine HCl, 0.3% metipranolol HCl + 2% pilocarpine HCl, and 0.3% metipranolol HCl + 4% pilocarpine HCl, in a single dose, randomized, double-masked, cross-over placebo-controlled trial. In addition, another eight age and baseline intraocular pressure (IOP)-matched subjects received 0.1% or 0.3% metipranolol HCl, while a similar group of 14 volunteers received 2% or 4% pilocarpine HCl. A two week washout period was instituted between the various groups of treatments. All four metipranolol-pilocarpine combinations were more effective than placebo or either medication alone in reducing the average IOP for up to 8 hours (p < 0.05 for each treatment group). Metipranolol HCl 0.3%, regardless of the pilocarpine concentration, demonstrated the most significant IOP lowering effect, reducing the IOP by 4.9 mm Hg or about 20% from baseline. However, 0.1% metipranolol HCl in combination with 4% pilocarpine HCl was found almost as effective with a 18.5% reduction in IOP from baseline, but a shorter duration of action. In conclusion, all metipranolol-pilocarpine combinations were more efficacious than either medication alone in a single-dose trial. Additional multiple-dose studies are needed to determine the long-term effectiveness and tolerance of combining 0.3% metipranolol HCl with either 2% or 4% pilocarpine HCl.

Design of new formulations for topical ocular administration: polymeric nanocapsules containing metipranolol.

To investigate the potential of polymeric nanocapsules for ocular delivery of beta-blockers, several formulations of polyisobutylcyanoacrylate and polyepsiloncaprolactone nanocapsules containing metipranolol base were developed. These formulations differed in the polymer forming the coating and in the type and volume of the oil encapsulated. Analysis of particle-size distribution, electrophoretic mobility, and loading efficiency of the nanocapsules revealed that the type of oil is the most important factor influencing these properties. From the in vitro release studies, we concluded that drug diffusion through a dialysis membrane is delayed as a consequence of the encapsulation process. However, the release profiles were not influenced by the polymeric coating, suggesting that drug release from these systems is governed mainly by the partition of the drug between the oily core and the aqueous release medium. Nevertheless, despite the inability of the polymer coat to control the release of the drug, its contribution to the stabilization of the emulsion was noted. Finally, the suitability of these formulations for ophthalmic administration was investigated. Although the pharmacologic response was not affected by the encapsulated metipranolol compared with the commercial eye drops, a drastic reduction of the drug's systemic side effects was observed.

[Are metipranolol eyedrops responsible for intraocular side effects?]. / Verursachen Metipranololhaltige Augentropfen intraokulare Nebenwirkungen?

Metipranolol is a beta-blocker that has been used in ophthalmology and in systemic therapy for about 10 years. Reports about reversible uveitis under the product Glauline (metipranolol-containing eye drops) in England were the reason for extensive studies with metipranolol-containing eye drops produced with different methods. Analytical studies concerning the influence of irradiation sterilization on the drug containers, studies on the toxicity of the ophthalmic drug on tissue cultures, and prospective and retrospective clinical studies on 2,800 glaucoma patients were performed. Irradiation sterilization leads to the formation of free radicals on the surface of the containers and, depending on the radiation dose, to a decrease in the pH of the drug solution. In prospective studies involving 1,516 glaucoma patients, no intraocular side effects due to metipranolol-containing eye drops were found. In the retrospective examination including 1,306 glaucoma patients, 19 cases of uveitis were found. Thirteen cases of recurring iritis were diagnosed, which had already been observed before the onset of glaucoma therapy. In 2 cases the iritis led to secondary glaucoma and was treated with metipranolol. In 2 cases glaucoma was treated with pilocarpine (and dipivefrin) and metipranolol concomitantly. One case of rubeosis iridis was incorrectly classified as iritis. One case is possibly related to metipranolol despite the assessment to the contrary by the ophthalmologist in question. Following the results of these studies, an accumulation of cases of uveitis caused by metipranolol can be excluded.

[Self-care in the prevention of sudden cardiac death]. / Prevence náhlé koronární smrti svépomocí.

In acute myocardial infarction a third up to half of death registered within the first month occur in the first hour of the onset of attack most frequently because of ventricular fibrillation. Immediate self administration of drugs stabilizing electrically the heart may prevent it. On the basis of experiments in dogs and in rats flunitrazepam (Rohypnol tabl. 1 mg), tramadol (Tramal caps. 50 mg) and the beta blocker metipranolol (Trimepranol tabl. 10 mg) were selected for clinical trial on high risk patients. As the chosen combinations of drugs were not yet tested in view of possible interactions, we studied their effect on circulation and cardiovascular reflexes in eight healthy volunteers. When the drugs were absorbed from the mouth mucosa, the decrease in the heart rate during deep breathing was observed already 15 minutes after the intake of drugs. The subjects started to feel relaxed; later on they had pleasant feelings and felt sleepy. There were no undesirable changes in the heart rate or blood pressure. In the three drug combination with metripranolol, the decrease in the heart rate was more marked. The tests in volunteers were without any undesirable effects and both combinations may, therefore, be given to selected high risk subjects, e g. convalescents from myocardial infarction. Randomized trial to prove the preventive effect already started.

Amlodipine in patients with stable angina pectoris treated with nitrates and beta-blockers. The influence on exercise tolerance, systolic and diastolic functions of the left ventricle.

The effects of 5 and 10 mg of amlodipine and of placebo were compared in 21 patients with stable angina pectoris and multivessel coronary artery disease. The blind comparison was performed by means of bicycle ergometry and stress echocardiography using esophageal stimulation of the left heart atrium. All patients subsequently received placebo, amlodipine 5 mg and 10 mg for 2 weeks. In bicycle ergometry both doses of amlodipine in comparison with placebo significantly lowered the ST segment depression in lead V5 and prolonged the time to onset of angina. The exercise duration was significantly prolonged only after 10 mg of amlodipine. In stress echocardiography 10 mg of amlodipine significantly improved ejection fraction and reduced wall motion score during stimulation and increased peak velocity of relaxation of left ventricular posterior wall at rest and immediately after stimulation. In the patients with left ventricular end-diastolic pressure < or = 20 mmHg, amlodipine reduced the ratio of peak transmitral flow velocity in atrial contraction to that in early diastole (A/E) at rest and shortened deceleration time at rest and immediately after stimulation. Amlodipine in patients with stable angina pectoris significantly improved the exercise tolerance and the function of the left ventricle in a dose-dependent way. Amlodipine was well tolerated.

Reduction of cardiovascular side effects associated with ocular administration of metipranolol by inclusion in polymeric nanocapsules.

A new formulation of metipranolol base for ophthalmic administration was developed consisting of a colloidal suspension of polyepsiloncaprolactone nanocapsules with an oily core (Migliol 840) in which the drug is dissolved. Physicochemical properties of the nanocapsules show that the polymer coating around the oily droplets causes an important reduction of the droplet size, with no significant modification of the surface charge noted. When this formulation was administered to rabbits, a reduction of intraocular pressure similar to that seen with commercial eye drops was observed. Nevertheless, the evaluation of the cardiovascular side effects clearly showed lower conjunctival absorption of the encapsulated drug compared with the commercial drops. The direct (bradycardia) and the indirect evaluation (based on the study of the influence on the hypotensive and positive chronotropic effects of isoprenaline) showed that blockage of beta-adrenoreceptors was reduced greatly by the topical administration of the new formulation.

[New treatment possibilities of progressive school myopia]. / Neue Behandlungsmöglichkeiten progredienter Schulmyopie.

It is reported about the experience of stopping the progredience of the myopia of pupils by lowering the intraocular pressure by a beta-blocker (Metipranolol). Our observation bases on twenty patients, eighteen of whom didn't show any increase of the refraction during the treatment. With this brief communication we want to propose further verification of our results.

[The effect of long-term administration of metipranolol on passive diastolic properties of the hypertrophic ventricle]. / Vplyv dlhodobého podávania metipranololu na pasívne diastolické vlastnosti hypertrofovanej komory.

In the course of adaptation of the rabbit heart to volume load passive diastolic properties of the hypertrophic ventricle and myocardium were changing significantly. On day 30 following perforation of the aortic valve stiffness of the ventricle was reduced, yet normalized ventricular stiffness and myocardial stiffness were increased. These changes were prevented by beta adrenergic blockade during development of adaptation of the heart to volume load. Although ventricular stiffness was reduced, normalized ventricular stiffness and myocardial stiffness remained at the level of control values. The demonstrated effect of beta adrenergic blockade on passive diastolic properties of the ventricle and myocardium may be of value in preventing heart failure due to chronic hemodynamic load. (Tab.3,Ref.15.).

Influence of the concentration of metipranolol eye drops on the drug concentration in human aqueous humour.

The concentration of the metabolite of the beta-blocker metipranolol was determined in the aqueous humour of 89 cataract patients. At 1, 2 or 5 h before surgery, they received one drop (30 microliters) of a 0.1% or 0.3% solution of the drug. At 1, 2 or 5 h after the application of 0.1% metipranolol eye drops, desacetyl-metipranolol concentrations of 624.55, 235.29 and 88.02 ng/ml, respectively, were measured. At the same intervals after the instillation of 0.3% metipranolol eye drops, the respective values of 1289.20, 1120.88 and 327.36 ng/ml were found. The metabolite concentration in the eye drops and the values measured show no consistent correlation.

Doubled-masked three-period crossover investigation of metipranolol in control of raised intraocular pressure.

Metipranolol is a non-cardioselective beta adrenergic blocking drug used in the treatment of glaucoma. 56 patients with intraocular pressure between 30-49 mm hg were randomised to one of six treatment regimens for a 12 week period. Each patient received each concentration for 4 weeks and intraocular pressures were checked every two weeks. Using a worst and an average eye approach, mean initial intra-ocular pressures were 35.8 and 35.0 mm hg respectively. The mean fall in intra-ocular pressure after 4 weeks treatment ranged from 12.8 (0.1%) to 14.1 mm hg (0.6%) for average eyes (n = 56), and from 13.4 to 16.7 mm hg for worst eyes. These differences were not statistically significant (p greater than 0.05-p greater than 0.5). Increasing the concentration had no significant effect on pressure. Reducing the concentration had no effect except in patients who changed from 0.6% to 0.1%, when there was a mean rise of approximately 2 mm hg, p less than 0.02. The incidence of stinging varied from 19% of attendances on 0.1%, to 63% on 0.6%. We recommend the use of the 0.1% strength since all three significantly lower intra-ocular pressure but the higher concentrations are more expensive, cause more stinging, and are no better at lowering intra-ocular pressure.