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PubMed1994

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.

Adult↗

PubMed1989

Cardiovascular responses to metipranolol and timolol eyedrops in healthy volunteers.

1. Intraocular pressure and cardiovascular responses to metipranolol 0.1% and 0.3% and timolol 0.25% eyedrops were measured in a balanced single dose placebo-controlled crossover study in eight healthy volunteers aged 34-58 years. 2. Timolol 0.25% and metipranolol 0.3% reduced intraocular pressure throughout the 6 h period of observation to a similar extent. Metipranolol 0.1% was marginally less effective, significantly reducing pressure up to 4 h only. 3. No drug treatment significantly altered resting heart rate or blood pressure. Timolol 0.25% significantly reduced exercise tachycardia (P less than 0.05), an effect which was not shown by metipranolol 0.1 or 0.3%. Exertional pain in the legs occurred more frequently after timolol 0.25% and metipranolol 0.3% than after metipranolol 0.1% or placebo eyedrops. 4. Octan-1-ol/pH 7.4 buffer distribution coefficients at 37 degrees C were found to be: metipranolol 5.19, timolol 0.84, indicating that metipranolol has an approximately 6-fold greater lipid solubility. 5. It is concluded that, by comparison with timolol, metipranolol in eyedrop concentrations up to 0.3%, despite its greater lipid solubility, reaches concentrations in the systemic circulation which are less likely to affect the heart.

Adult↗

PubMed1992

Metipranolol-induced adverse reactions: II. Loss of intraocular pressure control.

This paper reviews the behaviour of intraocular pressure (IOP) in glaucomatous eyes treated with metipranolol with and without drug-induced adverse reactions (ADRs). Two hundred and forty seven patients with open angle glaucoma who were receiving the three different strengths of metipranolol (0.1%, 0.3%, and 0.6%) in our Department and the 7 patients who participated in the metipranolol rechallenge trial were included in this study. Out of the 247 patients, there were 52 eyes of 29 patients who showed 78 episodes of ADRs associated with metipranolol. Forty five of these 78 episodes (57.6%) were associated with loss of IOP control. Two of the 7 eyes treated with metipranolol in the rechallenge trial showed loss of IOP control, 1 of them without any signs of ocular inflammation. We further studied all the glaucomatous eyes controlled with metipranolol 0.6% only and 22 eyes were identified with loss of IOP control but without recognisable signs or symptoms of ADR. Five other eyes in this group later developed metipranolol-induced ADRs. The possible pathophysiological mechanisms for the loss of IOP control are discussed and it is suggested that the active drug, metipranolol, could be directly implicated.

Eye Diseases↗

PubMed1992

[Are metipranolol eyedrops responsible for intraocular side effects?].

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.

Adolescent↗

PubMed1987

[Comparison of the effects of carteolol and metipranolol eyedrops on the ventilatory and cardiovascular functions in asthmatics].

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.

Adult↗

PubMed1982

Pharmacokinetics of metipranolol in normal man.

The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6-25mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of beta-blocking agents.

Administration, Oral↗

PubMed1997

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.

Administration, Topical↗

PubMed1985

A study on the ocular and extraocular pharmacology of metipranolol.

Metipranolol (Betamann) is a clinically efficacious ocular hypotensive drug and preclinical experiments were undertaken to characterize this beta-adrenoceptor antagonist. In vitro beta1- and beta2-adrenoceptor antagonism was evaluated using the guinea pig atrium and the rat uterus, respectively. The respective pA2 values were 8.3 and 8.4. Topical metipranolol, 0.3% and 0.6%, blocked both the hypotension (beta2-mediated) and the tachycardia (beta1-mediated) elicited in ganglion-blocked, conscious rabbits by isoproterenol, 0.5 microgram/kg, i.v. The Ki for displacement of 3H-dihydroalprenolol binding to rabbit iris + ciliary body homogenates was 34 nM. The effect of metipranolol, 0.3% and 0.6%, was not particularly striking on the intraocular pressure (IOP) of conscious, normotensive rabbits. However, the elevated IOP of the alpha-chymotrypsinized rabbit eye was significantly decreased (maximum reduction of 5.8 mm Hg) following the instillation of metipranolol, 0.3%. IOP recovery in conscious rabbits following hyperosmotic challenge (i.v. infusion of a 20% NaCl solution) was not decreased by a 1-h pretreatment with a 0.3% solution. In contrast, a significant reduction of 41% was elicited by a 0.6% solution. Hence, the ocular hypotensive effect of metipranolol may result from decreased aqueous humor inflow. Metipranolol, 0.6%, was devoid of effect on rabbit pupil diameter. However, corneal local anesthesia was elicited in the rabbit by both 0.3% and 0.6% solutions of the drug, the effect being more marked with the higher concentration.

Animals↗

PubMed1992

Metipranolol-induced adverse reactions: I. The rechallenge study.

Previously unreported adverse drug reactions can be difficult to detect and it may be even more difficult to establish a cause and effect relationship, particularly if the adverse reactions mimic naturally occurring disease. In a previous paper we reported 29 patients with granulomatous anterior uveitis, blepharoconjunctivitis, periorbital dermatitis, marginal keratitis and elevation in intraocular pressure (IOP), suspected to be caused by metipranolol (Glauline). With the approval of the District Ethics Committee 7 of those patients were rechallenged with metipranolol 0.3% compared to timolol maleate 0.5% in a double blind trial. The 7 metipranolol treated eyes developed an adverse reaction within 14 days. Metipranolol (Glauline) has been conclusively proven to cause granulomatous anterior uveitis, blepharoconjunctivitis and elevation in IOP, adverse effects never previously reported with any of the ophthalmic topical beta-blockers. The multidose preparations of metipranolol (Glauline) in all three strengths 0.1%, 0.3% and 0.6% and the single dose minim preparation of metipranolol 0.6% have now been withdrawn from clinical use in the United Kingdom.

Aged↗

PubMed2006

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.

Adrenergic beta-Antagonists↗

PubMed1977

Experiments in animals on the pharmacological effects of metipranolol in comparison with propranolol and pindolol.

The beta-blocking agent 1-(4-acetoxy-2,3,5-trimethylphenyloxy)-3-isopropylamino-propan-2-ol (metipranolol) was compared with propranolol and pindolol. The beta-blocking activity on isoproterenol induced tachycardia was determined in rabbits (ED250bpm). The following doses in microgram/kg i.v. were required to produce the same inhibition: 410 propranolol; 160 metipranolol; 130 pindolol. When intrinsic sympathomimetic activity was determined in reserpinized rats metipranolol was found to produce less than 10% of the increase in heart rate induced by a standard isoproterenol dose (1 mg/kg i.p.), whereas propranolol caused less than 20% and pindolol ca. 60%. The membrane stabilising activity, determined by the elevation of the fibrillation threshold (ED delta100muA) in rabbit hearts, was found to be greatest with propranolol (0.98 mg/kg i.v.) and least with metipranolol (1.68 mg/kg), with pindolol occupying an intermediate position (1.10 mg/kg). The cardioprotective action to hypoxia stress of metipranolol in rats was found to be the best, requiring a dose of only 5 microgram/kg i.p. compared with values of 28 microgram/kg for pindolol and 250 microgram/kg for propranolol. These results show that metipranolol has a high beta-sympatholytic activity which is not accompanied by either marked intrinsic activity or membrane-stabilising properties. The relatively marked cardioprotective action, which is probably due to a metabolic action, is particularly noteworthy.

Adrenergic beta-Antagonists↗

PubMed1991

Influence of the strength, drop size and viscosity of metipranolol eye drops on the concentration of the substance in human aqueous humour.

Concentrations of metipranolol were determined in the aqueous humour of patients undergoing cataract surgery. At 30 min before the operation, patients were given 20- or 30 microliters drops of 0.1% or 0.3% metipranolol solutions with a viscosity of 7.5 cP or drops (20 or 30 microliters) of a 0.3% solution with a viscosity of 1.5 cP. Samples of the aqueous humour were obtained at the beginning of the cataract operation, and desacetyl-metipranolol content was determined by means of gas chromatography and mass spectroscope. The Wilcoxon signed-rank test and Jonckheere's method were used for evaluation of the results. A 3-fold increase in the strength of metipranolol was associated with an approx. 8-fold increase in the concentration of metabolite found in the aqueous humour. Drop size had no apparent effect on the concentration of this substance in the aqueous humour, but viscosity had a significant influence when large drops were applied. An increase in the amount of metipranolol applied as eye-drops was associated with an increase in the intraocular concentration of the metabolite.

Administration, Topical↗

PubMed1997

Metipranolol-associated nongranulomatous anterior uveitis.

PURPOSE: To describe the findings in a patient with a nongranulomatous anterior uveitis, presumed to be induced by metipranolol. METHOD: A 69-year-old woman developed bilateral, nongranulomatous, anterior uveitis while undergoing treatment with metipranolol 0.3% for primary open-angle glaucoma. Four months after resolution of the initial episode, the patient was challenged with metipranolol 0.3% in the right eye. RESULT: On reinstituting metipranolol 0.3%, the patient once again developed a unilateral, nongranulomatous, anterior uveitis in the challenged eye. CONCLUSION: Metipranolol 0.3% eyedrops, used to treat primary open-angle glaucoma, appear to cause a nongranulomatous anterior uveitis.

Adrenergic beta-Antagonists↗

PubMed1994

Metipranolol-associated granulomatous iritis.

PURPOSE: Topical metipranolol therapy for primary open-angle glaucoma has been associated with anterior granulomatous uveitis in the United Kingdom. We studied granulomatous uveitis reactions to topical metipranolol 0.3% therapy for primary open-angle glaucoma in two patients in the United States. METHODS: Two patients, aged 71 and 81 years, were given topical metipranolol 0.3% therapy for primary open-angle glaucoma. RESULTS: Both developed granulomatous uveitis. The iritis was associated with an increase in intraocular pressure in both patients and resolved on discontinuation of the drug. One patient was inadvertently rechallenged with metipranolol, and the iritis recurred. CONCLUSIONS: Topical metipranolol 0.3% therapy may be associated with the development of granulomatous uveitis and a paradoxical increase in intraocular pressure.

Aged↗

PubMed1991

A clinical trial of metipranolol, a noncardioselective beta-adrenergic antagonist, in ocular hypertension.

In randomized, double-masked fashion, 24 volunteers with ocular hypertension received 0.3% or 0.6% metipranolol, a noncardioselective beta blocker; or placebo twice daily to both eyes for six weeks. Intraocular pressure (mean +/- SEM) was reduced (P = .01) in the metipranolol-treated patients (baseline measurement, 25.9 +/- 0.5 mm Hg to 18.1 +/- 1.2 mm Hg at six weeks, 0.6% concentration; baseline measurement, 27.1 +/- 0.4 mm Hg to 21.6 +/- 1.5 mm Hg at six weeks, 0.3% concentration). Intraocular pressure was not markedly changed in placebo-treated patients. Outflow facility was unaltered two hours after instillation of metipranolol at study week 2 compared to baseline measurement. Aqueous humor flow rates were reduced (P = .02) 20% after 0.6% or 0.3% metipranolol instillation and were unchanged after placebo administration compared to baseline measurement. Mean systolic blood pressure, diastolic blood pressure, and pulse rate were not markedly altered. Metipranolol reduces intraocular pressure by suppressing aqueous humor flow rates.

Aged↗

PubMed1991

Metipranolol-associated granulomatous anterior uveitis.

This paper presents for the first time documented evidence, clinical details, and photographic illustrations of metipranolol-associated granulomatous anterior uveitis in 26 eyes of 15 patients being treated for glaucoma. There were 56 episodes of granulomatous anterior uveitis, all associated with large (mutton-fat) keratic precipitates, flare, cells, and 'white eyes' (except in seven episodes). In 30 (53.6%) of these episodes there was loss of control of intraocular pressure. Metipranolol 0.6% was implicated in 54 of the 56 episodes and metipranolol 0.3% in the remaining two. Fifty-one other cases of metipranolol-associated granulomatous anterior uveitis have so far been reported from other parts of the country to the Committee on Safety of Medicines. As a result multidose metipranolol in 0.1%, 0.3%, and 0.6% strengths has been withdrawn from clinical use in the United Kingdom. The pathogenesis of this adverse drug reaction is uncertain.

Aged↗

PubMed1986

[Local subjective tolerance of levobunolol and metipranolol in a double-blind comparative study in patients with increased intraocular pressure].

We evaluated the ocular comfort of 0.5% levobunolol hydrochloride and 0.6% metipranolol hydrochloride ophthalmic solutions in a randomized, double-masked, paired-comparison clinical trial. The drugs were given twice daily for 7 days to 16 patients with open-angle glaucoma or ocular hypertension. Patients rated comfort in terms of the severity of burning and/or stinging. For both drugs, the severity rating of ocular discomfort was low, averaging between 1 and 2 on a scale of 0-10. At initial and follow-up visits, the mean severity rating of burning or stinging with metipranolol was 2, slightly greater than the mean score of 1 with levobunolol. At 55% (26 of 47) of the patient visits, the patients rated levobunolol as more comfortable than metipranolol. Metipranolol (Betamann; Mann) was rated as more comfortable than levobunolol at only 9% (4 of 47) of the patient visits. The duration of burning and stinging was also rated as longer lasting with metipranolol treatment than with levobunolol (Vistagan; Pharma-Allergan) treatment. Although little ocular discomfort was reported for either drug, the majority of the patients tested rated levobunolol the more comfortable of the two drugs.

Clinical Trials as Topic↗

PubMed1988

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.

Glaucoma↗