A preliminary study of the adsorption and release of preservatives by contact lenses and collagen shields.

PURPOSE: We evaluated the adsorption and release of preservatives and a beta-blocking agent (metipranolol) by three different contact lens materials and two collagen shields. METHODS: We recorded the ultraviolet absorption spectra of these materials before, during, and after extended exposure to pharmaceutical preparations of artificial tears, beta-blocking eye drops, and a contact lens cleaning solution. The presence of preservatives and active ingredients was demonstrated by thin layer chromatography. RESULTS: Significant differences were observed depending on the nature of the absorbant materials and the preservatives. Soft lenses showed the greatest affinity for benzalkonium chloride and metipranolol but also readily released them. CONCLUSIONS: This preliminary study points out that rinsing with a sodium chloride isotonic solution without preservatives has an important place in daily contact lens care.

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.

Disposition kinetics and concentration-effect relationship of metipranolol in patients with cirrhosis and healthy subjects.

The disposition kinetics and heart rate reducing effect of deacetylmetipranolol (DMP), the active form of the beta-adrenoreceptor blocking agent metipranolol (MP), administered as a single 40 mg oral dose have been compared in 6 patients with cirrhosis and 6 healthy volunteers. The mean maximal DMP concentration was significantly higher and the time to reach the peak level shorter in the patients compared to the healthy subjects. There was also a significantly higher AUC of DMP, a shorter half-life of the rapid phase of the decline in DMP concentrations, a smaller central compartment and lower apparent DMP clearance in patients. A correlation with the albumin level was observed in cirrhotics for individual values of apparent DMP clearance (r = 0.92) and AUC (r = -0.89). The maximal reduction in heart rate was recorded in patients at plasma DMP levels which were already significantly lower than the peak levels. Median inhibitory concentrations (IC50) and maximum possible heart rate reductions (delta HRmax), obtained by fitting individual plots of the plasma DMP concentration-effect relationship to the inhibitory Emax model in the postdistributional phase of DMP disposition were significantly higher in cirrhotics than in healthy subjects. It is conjectured that down-regulation of adrenoreceptors due to chronic sympathetic activation in hepatic cirrhosis contributes to decreased sensitivity to the reduction in heart rate following a single dose of the beta-blocker.

[Kinetics of metipranolol in patients with chronic kidney failure and during hemodialysis]. / Kinetika metipranololu u nemocných s chronickým selháním ledvin a v prubehu hemodialýzy.

The authors investigated the metipranolol plasma concentration in seven patients with renal failure after a single dose of 20 mg of the preparation (2 tablets of Trimepranol) by the oral route during haemodialysis and on days without dialysis, and evaluated also the effect of dialysis on selected pharmacokinetic constants. Although there was a great individual variability of plasma concentrations of metipranolol, these concentrations were at the end of dialysis lower than during the corresponding interval between dialyses. The mean values of the area beneath the concentration curve, the velocity elimination constants, the half-life of elimination and total clearance indicate a certain dialysability of metipranolol. During the practical application of these conclusions it is, however, important to consider the effect on blood pressure and cardiac rhythm resp. by changes of volume and the composition of the extracellular fluid caused by haemodialysis.

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.

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.

Pharmacokinetics and pharmacodynamics of conventional and controlled-release formulations of metipranolol in man.

The pharmacokinetics and beta-adrenoceptor blocking effects of conventional and sustained-release metipranolol have been studied in 6 healthy male volunteers given a single oral dose of 40 mg. Plasma drug concentrations determined by TLC and a radioreceptor assay, and the inhibition of exercise-induced tachycardia, were monitored for 48 h. Relevant amounts of active metabolites other than deacetylmetipranolol were not found. Compared to conventionally formulated metipranolol, the controlled-release product had a prolonged mean residence time (10.7 vs 5.5 h), the peak drug concentration was halved and the time to peak drug concentrations was delayed. Relatively constant plasma concentrations (cideal = 6.5 ng/ml) and a clinically significant reduction of exercise-induced tachycardia were maintained throughout a 24 h dosing interval. An individual deacetylmetipranolol plasma concentration-effect relationship was evaluated using the Emax model. Mean parameters were Emax 26% and C50 2.9 ng/ml.

High-performance liquid chromatography of deacetylmetipranolol in plasma.

A sensitive high-performance liquid chromatographic method with electro-chemical detection is developed for the determination of deacetylmetipranolol (DMP), an active metabolite of beta-sympatholytic drug metipranolol (MP). DMP is extracted from the plasma after basifying with dichloromethane. After evaporation, the residue is reconstituted in the mobile phase, injected onto the reversed-phase ODS column and chromatographed at 50 degrees C. The sensitivity of the method is 2 ng of DMP in 1 ml plasma. Pindolol, another beta-blocking agent is used as internal standard. The method is used for a pharmacokinetic investigation of MP in healthy volunteers and in the patients with liver cirrhosis.

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.