In Situ Gelling Electrospun Ocular Films Sustain the Intraocular Pressure-Lowering Effect of Timolol Maleate: In Vitro, Ex Vivo, and Pharmacodynamic Assessment.

Most common intraocular pressure (IOP) reduction regimens for the management of glaucoma include the topical use of eye drops, a dosage form that is associated with short residence time at the site of action, increased dosing frequency, and reduced patient compliance. In situ gelling nanofiber films comprising poly(vinyl alcohol) and Poloxamer 407 were fabricated via electrospinning for the ocular delivery of timolol maleate (TM), aiming to sustain the IOP-lowering effect of the ß-blocker, compared to conventional eye drops. The electrospinning process was optimized, and the physicochemical properties of the developed formulations were thoroughly investigated. The fiber diameters of the drug-loaded films ranged between 123 and 145 nm and the drug content between 5.85 and 7.83% w/w. Total in vitro drug release from the ocular films was attained within 15 min following first-order kinetics, showing higher apparent permeability (Papp) values across porcine corneas compared to the drug's solution. The fabricated films did not induce any ocular irritation as evidenced by both the hen's egg test on chorioallantoic membrane and the in vivo Draize test. In vivo administration of the ocular films in rabbits induced a faster onset of action and a sustained IOP-lowering effect up to 24 h compared to TM solution, suggesting that the proposed ocular films are promising systems for the sustained topical delivery of TM.

Efficacy and safety of preoperative IOP reduction using a preservative-free fixed combination of dorzolamide/timolol eye drops versus oral acetazolamide and dexamethasone eye drops and assessment of the clinical outcome of trabeculectomy in glaucoma.

INTRODUCTION: To demonstrate that preoperative treatment for 28 days with topical dorzolamide/timolol is non-inferior (Δ = 4 mm Hg) to oral acetazolamide and topical dexamethasone (standard therapy) in terms of intraocular pressure (IOP) reduction 3 and 6 months after trabeculectomy in glaucoma patients. MATERIALS AND METHODS: Sixty-two eyes undergoing trabeculectomy with mitomycin C were included in this monocentric prospective randomized controlled study. IOP change between baseline and 3 months post-op was defined as the primary efficacy variable. Secondary efficacy variables included the number of 5-fluorouracil (5-FU) injections, needlings, suture lyses, preoperative IOP change, hypertension rate and change of conjunctival redness 3 and 6 months post-op. Safety was assessed based on the documentation of adverse events. RESULTS: Preoperative treatment with topical dorzolamide/timolol was non-inferior to oral acetazolamide and topical dexamethasone in terms of IOP reduction 3 months after trabeculectomy (adjusted means -8.12 mmHg versus -8.30 mmHg; Difference: 0.18; 95% CI -1.91 to 2.26, p = 0.8662). Similar results were found 6 months after trabeculectomy (-9.13 mmHg versus -9.06 mmHg; p = 0.9401). Comparable results were also shown for both groups concerning the classification of the filtering bleb, corneal staining, and numbers of treatments with 5-FU, needlings and suture lyses. More patients reported AEs in the acetazolamide/dexamethasone group than in the dorzolamide/timolol group. DISCUSSION: Preoperative, preservative-free, fixed-dose dorzolamide/timolol seems to be equally effective as preoperative acetazolamide and dexamethasone and has a favourable safety profile.

Assessment of the Anterior Chamber Flare and Macular Thickness in Patients Treated with Topical Antiglaucomatous Drugs.

PURPOSE: To determine the changes in the anterior chamber flare and central macular thickness (CMT) under topical antiglaucomatous therapy. METHODS: This study included 121 eyes of 73 patients and 36 eyes of 18 controls. Glaucoma patients were divided into 3 groups (timolol maleate, latanoprost, and bimatoprost). Control eyes did not receive any medications. Flare and CMT measurements were performed at baseline and follow-up visits (15th day, and 1st, 3rd, 6th, and 12th month). RESULTS: Statistically significant increases were detected in the flare values in the bimatoprost and latanoprost groups (P < 0.001, P = 0.011, respectively). Significant increases were also found in CMT values measured in these 2 groups (P < 0.001, P = 0.002, respectively). However, increased flare and CMT values were not clinically manifested as uveitis and macular edema. Flare and CMT values did not change statistically in the timolol maleate and control groups. CONCLUSIONS: Although the use of prostaglandin (PG) analogs was found to be associated with increased flare and CMT, these increases were not clinically significant. PG analog monotherapy may be safely and effectively used in the treatment of glaucoma.

Assessment of the ocular response to topical beta-adrenoceptor antagonists using accommodative microfluctuations.

Power spectrum analysis of accommodative microfluctuations has identified two dominant frequency components: a low frequency component (LFC < 0.6 Hz) and a high frequency component (1.3 Hz < HFC < 2.5 Hz). Computer-driven models of accommodation and experimental manipulation of accommodative feedback loops indicate that LFCs are likely to have a functional role in monitoring retinal image contrast during sustained accommodation. In contrast HFCs have been shown to be correlated with arterial pulse frequency and consequently their characteristics can be modified by the extra- and intra-ocular vascular (and possibly CNS) effects. For example, topical instillation of the non-selective beta-antagonist timolol maleate has shown previously the ability to modify the HFC. In an attempt to clarify proposed differences between beta-adrenoceptor antagonist agents with regard to their effects on systemic and ocular vasculature, we extend the potential offered by HFCs as a non-invasive method of assessing the ocular response to beta-antagonists to the cardioselective beta-antagonist betaxolol HCl. Accommodative microfluctuations were measured using a continuously recording infrared optometer on 10 emmetropic subjects (mean age 23.9 +/- 2.3 years) who viewed a high contrast target located at a vergence of -4 D. A double-blind protocol was employed between saline and betaxolol (0.5%, 2 x 30 microliters) following corneal anaesthesia. Local and systemic effects were separated by examining the treated and untreated eyes of three subjects. Power spectrum analysis indicated that the root mean square (r.m.s.) value and power of LFCs and HFCs were equivalent for the saline and betaxolol trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of bronchial effects following topical administration of butylamino-phenoxy-propanol-acetate, an oculoselective beta-adrenoceptor blocker in asthmatic subjects.

1. Butylamino-phenoxy-propanol-acetate (BPPA) is a new topical oculoselective beta-adrenoceptor blocker for the reduction of intraocular pressure (IOP) in man. Its potency on the airways of normal subjects was identical with that of placebo. A study was carried out to determine the potential of BPPA to cause bronchoconstriction in mild asthmatics (FEV1 greater than or equal to 60% predicted) with normal IOP. 2. Twelve nonsmoking outpatients who bronchoconstricted to 0.25 or 0.50% of timolol eye drops (fall in FEV1 23.33 +/- 1.20% (mean +/- s.e. mean), range 16-30) were investigated in this double-masked, randomized, 3-period, crossover study. On three different occasions six incremental concentrations of BPPA (range: 0.1-2%; maximum cumulative concentration 4%), timolol (0.1-1%; 2%), and placebo were administered bilaterally until bronchoconstriction (decrease in FEV1 greater than or equal to 20% and in specific airway conductance (sGaw) greater than or equal to 35% simultaneously) or the maximum cumulative concentration was reached. 3. Airway response was measured as change in FEV1 and sGaw and dose-response curves to timolol, BPPA and placebo were performed. IOP was measured 3 h after the highest concentration of each study day. 4. Timolol caused dose-dependent falls in FEV1 and sGaw as well as clinical symptoms of respiratory distress in all subjects. The median cumulative concentrations of timolol required to decrease FEV1 by 20% and sGaw by 35% were 0.98% and 1.53%. Neither placebo (P greater than 0.05) nor BPPA (P greater than 0.05) caused a significant change in sGaw. A fall in FEV1 by 20% not accompanied by a simultaneous fall in sGaw by 35% was found in four subjects following BPPA and in five subjects following placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of timolol on clinical features and echocardiographic assessment of left ventricular function in hyperthyroidism.

The effect of timolol, a beta-adrenoceptor blocking drug on the clinical status, thyroid status and left ventricular function as measured by serial M-mode echocardiographic recordings was assessed in a double-blind randomised study in 18 hyperthyroid patients. A significant clinical improvement was documented after 2 weeks of timolol treatment compared with placebo. There was no evidence that timolol impaired peripheral monodeiodination of thyroxine (T4). There were significant increases in left ventricular fractional shortening (Fr. Sh.) and velocity of circumferential shortening (Vcf) as well as a significant decrease in the left ventricular systolic internal dimension (LVIDs) (all P less than 0.01) in the untreated thyrotoxic patients compared with a normal euthyroid control group. After timolol treatment (2/52) there were significant increases in LVIDs and LVIDd and a significant decrease in Vcf (all P less than 0.05). No further changes occurred after a further 2/52 treatment with carbimazole. The cardiac data suggest that both an augmented sympathetic drive and a direct effect of thyroid hormone on myocardial contractility are mediators of the haemodynamic changes in hyperthyroidism.