Enhanced Percutaneous Delivery of Beta-Blockers Using Thermal Resurfacing Drug Delivery System for Topical Treatment of Infantile Hemangiomas.

BACKGROUND: Infantile hemangiomas (IHs) are the most common vascular tumors in children. In the past few years, topical beta-blockers (bBs) have been reported to be an effective treatment of superficial IHs. OBJECTIVE: We sought to evaluate the clinical effectiveness and safety profile of enhanced percutaneous delivery of bBs for the treatment of IH. METHODS: A retrospective study of all cases of IHs treated with enhanced percutaneous delivery of bBs between 2018 and 2019 was performed. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. RESULTS: The study included 11 patients with a total of 11 IHs. Of the total number of IHs, 7 (63.7%) showed a good response to treatment and 4 (36.3%) had a partial response; thus all patients (100%) had good or partial response to treatment. No systemic or local adverse effects were reported. LIMITATIONS: This is an uncontrolled retrospective study. CONCLUSION: Enhanced percutaneous delivery of bBs is a safe and efficient topical therapy for IH.

DenTimol as A Dendrimeric Timolol Analogue for Glaucoma Therapy: Synthesis and Preliminary Efficacy and Safety Assessment.

In this work, we report the synthesis and characterization of DenTimol, a dendrimer-based polymeric timolol analog, as a glaucoma medication. A timolol precursor ( S)-4-[4-(oxiranylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine (OTM) was reacted with the heterobifunctional amine polyethylene glycol acetic acid (amine-PEG-acetic acid, Mn = 2000 g/mol) via a ring opening reaction of an epoxide by an amine to form the OTM-PEG conjugate. OTM-PEG was then coupled to an ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimer G3 to generate DenTimol using the N-(3-(dimethylamino)propyl)- N'-ethylcarbodiimide hydrochloride (EDC)/ N-hydroxysuccinimide (NHS) coupling reaction. MALDI mass spectrometry, 1H NMR spectroscopy, and HPLC were applied to characterize the intermediate and final products. Ex vivo corneal permeation of DenTimol was assessed using the Franz diffusion cell system mounted with freshly extracted rabbit cornea. The cytotoxicity of DenTimol was assessed using the WST-1 assay. Our results show that DenTimol is nontoxic up to an OTM equivalent concentration of 100 µM. DenTimol is efficient at crossing the cornea. About 8% of the dendrimeric drug permeated through the cornea in 4 h. Its IOP-lowering effect was observed in normotensive adult Brown Norway male rats. Compared to the undosed eye, an IOP reduction by an average of 7.3 mmHg (∼30% reduction from baseline) was observed in the eye topically treated with DenTimol (2 × 5 µL, 0.5% w/v timolol equivalent) in less than 30 min. Daily dosing of DenTimol for a week did not cause any irritation or toxicity as confirmed by the histological examination of ocular tissues, including the cornea, ciliary body, and retina.

Prospective, open-label, rater-blinded and self-controlled pilot study of the treatment of proliferating superficial infantile hemangiomas with 0.5% topical timolol cream versus 595-nm pulsed dye laser.

Topical timolol and 595-nm pulsed dye laser (PDL) are both widely used in the treatment of superficial infantile hemangiomas (IH). However, to date, there is no reliable study comparing the therapeutic outcomes between the two treatment options. We designed the present study to evaluate and compare the efficacy and safety of timolol cream and PDL in the treatment of superficial proliferating IH. Twenty-one patients with superficial IH were included in the study. Each lesion was divided into two regions; one part was treated with 0.5% topical timolol cream four times daily, and the other part was treated monthly with PDL. Both treatments were continued for 2-6 months. Five independent and blinded assessors were asked to judge the results in both the topical timolol-treated and PDL-treated parts by comparing photographs taken before and after treatment. Both treatments resulted in significant clinical improvements after 3.39 sessions in the 2-month follow up. The average visual evaluation showed that PDL had significantly better results than topical timolol (6.55 ± 2.26 to 4.98 ± 2.92, P < 0.01). No patients experienced permanent side-effects during the treatment. Our short-term study revealed that PDL had better results compared with topical timolol cream application in the treatment of superficial proliferating IH. Further studies with longer follow-up time and larger sample size are required to validate our findings.

The long-term outcomes of four alternative treatment strategies for primary open-angle glaucoma.

PURPOSE: To evaluate the long-term effects and costs of four treatment strategies for primary open-angle glaucoma compared to usual care. METHODS: Cost-effectiveness analyses with a lifelong horizon were made from a societal perspective. Data were generated with a patient-level model based on discrete event simulation. The model structure and parameter estimates were based on literature, particularly clinical studies on the natural course of glaucoma and the effect of treatment. We simulated heterogeneous cohorts of 3000 patients and explored the impact of uncertainty with sensitivity analyses. RESULTS: The incremental cost-effectiveness ratio (ICER) of initial treatment with a prostaglandin analogue compared with a ß-blocker was €12.931 per quality-adjusted life year (QALY) gained. A low initial target pressure (15 mmHg) resulted in 0.115 QALYs gained and €1550 saved compared to a gradual decrease from 21 to 15 mmHg upon progression. Visual field (VF) measurements every 6 rather than 12 months lead to health gains at increased costs (ICER €173,486 per QALY gained), whereas measurements every 24 months lead to health losses at reduced costs (ICER €21,516 per QALY lost). All treatment strategies were dominant over 'withholding treatment'. CONCLUSIONS: From a cost-effectiveness point of view, it seems advantageous to aim for a low intraocular pressure in all glaucoma patients. The feasibility of this strategy should therefore be investigated. Additionally, the cost-effectiveness outcomes of initiating monotherapy with a prostaglandin analogue and reducing the frequency of VF testing may be acceptable.

Timolol tópico en el tratamiento de rosácea eritematotelangiectásica: ensayo clínico randomizado doble ciego / Topical timolol in the treatment of erythematotelangiectatic rosacea: double blind randomized clinical trial

Introducción: La rosácea es un síndrome inflamatorio crónico frecuente que afecta principalmente la zona centrofacial. El subtipo más común, la rosácea eritematotelangiectásica (RET), no cuenta con un tratamiento efectivo demostrado. Estudios in vitro han propuesto que el factor de crecimiento endotelial (VEGF) podría tener un rol clave en la génesis de la rosácea al inducir angiogénesis. El uso exitoso de betabloqueadores orales (propanolol) y tópicos (timolol) en el hemangioma de la infancia abrió las puertas al estudio de la inhibición de la angiogénesis como principal objetivo terapéutico de las patologías vasculares benignas. Debido a que este subtipo de rosácea y los hemangiomas podrían presentar una etiopatogenia similar, se propone el estudio del efecto del timolol en este subtipo de rosácea. Metodología: Ensayo clínico randomizado doble ciego. Se reclutaron 67 pacientes con RET desde septiembre a diciembre de 2011. Se asignó un grupo con timolol tópico al 1 por ciento en base oil free y otro sólo con base oil free. Todos los pacientes recibieron instrucción y tratamiento estándar consistente en un limpiador, hidratante y protector solar. Nuestro outcome primario fue la diferencia de reducción del grado de eritema a las 12 semanas con colorímetro CR 200 de Minolta, y fue analizado según intención de tratar. Se evaluaron además las diferencias en las características clínicas, demográficas, el tamaño de las telangiectasias, la calidad de vida, evaluación subjetiva del tratamiento por el paciente, la adherencia a tratamiento y las reacciones adversas. Resultados: No hubo diferencia significativa en el grado de eritema a las 12 semanas de tratamiento entre los grupos, lo que permite rechazar la hipótesis diagnóstica. Tampoco se encontró diferencia alguna en los otros parámetros estudiados.

Introduction: Rosacea is a common chronic inflammatory syndrome that mainly affects the midface area. The most common subtype, Erythematotelangiectatic rosacea (ETR) has no proven effective treatment. Studies in vitro have suggested that vascular endothelial growth factor (VEGF) may have a key role in the pathogenesis of rosacea inducing angiogenesis. The successful use of oral (propanolol) and topical (timolol) betablockers in the childhood hemangioma conducted to the study of inhibition of angiogenesis as a main therapeutic target of benign vascular pathologies. Because this subtype of rosacea and hemangiomas share a similar pathogenesis, we proposed to study the effect of timolol in this subtype of rosacea. Methodology: Double blind randomized clinical trial. We recruited 67 patients with ETR from September to December of 2011. Two groups were assigned one with 1percent topical timolol oil free based and the other group used only the vehicle. All patients also received education and standard treatment consisting of a cleanser, moisturizer and sunscreen. The primary outcome was the difference in reducing the degree of erythema at week 12, and was evaluated through the Minolta CR 200 colorimeter and analyzed by intention to treat. Secondary outcomes were differences in clinical and demographic characteristics of the patients, the size of telangiectasias, quality of life, subjective evaluation from the patient, adherence to treatment and adverse reactions. Results: No significant difference was seen in the reduction of erythema degree at week 12 allowing us to reject the hypothesis. There were also no difference in all the other parameters. Conclusion: The present study shows that the use of topical timolol its not superior to placebo in reducing the degree of erythema or any of the variables analyzed. This study shows that topical timolol not constitute a possible treatment in ETR.

A European perspective on costs and cost effectiveness of ophthalmic combinations in the treatment of open-angle glaucoma.

PURPOSE: Efficacy, safety, and cost implications are important considerations when choosing an ophthalmic treatment. Fixed-combination glaucoma medications containing brimonidine 0.2% and timolol 0.5%, or dorzolamide 2% and timolol 0.5%, were compared with brimonidine 0.2% and dorzolamide 2% that were used as adjunctive therapy to timolol 0.5%. METHODS: A literature review was conducted to determine the outcome parameters of intraocular pressure reduction and tolerability after 3 months of use of brimonidine or dorzolamide, each together with timolol as a fixed-combination or in concomitant therapy. Modelled cost-minimization and cost-effectiveness analyses were performed to investigate the economic consequences of ophthalmic therapy with brimonidine, dorzolamide, and timolol from a societal perspective. RESULTS: The literature review found that brimonidine and dorzolamide used as fixed combinations with timolol as well as in adjunctive therapy to timolol were equally effective and safe. Furthermore, in the European countries studied, the fixed combination of brimonidine/timolol represented a less costly option when compared to the fixed combination of dorzolamide/timolol evaluated over both a 3-month and a 12-month horizon. CONCLUSIONS: Brimonidine used as a fixed-combination therapy with timolol provided better cost value than dorzolamide/timolol in all the countries studied. For most countries, the fixed combination of brimonidine and timolol also provided better cost value than adjunctive therapy with brimonidine, which was more cost effective than adjunctive therapy with dorzolamide.

Ocular powder: dry topical formulations of timolol are well tolerated in rabbits.

PURPOSE: Although eye drops are the most common form of ocular drugs, they have several limitations. Drug absorption into the eye is, in general, less than 5%, addition of preservatives is often necessary, and many drugs cannot be formulated as eye drops. Formulating ocular drugs as powder may solve these problems. The aim of this study was to investigate ocular irritation in rabbits following powder administration. METHODS: Timolol maleate (TM) powder was administered to pigmented lop rabbits. Both pure TM powder and freeze-dried with PVP-polymer (2.4% of mass) were tested in 1.0- and 0.1-mg doses. Additionally, 4 rabbits received 0.1 mg of the pure powder 3 times a day for 8 d. Redness of the bulbar conjunctiva and the amount of discharge was rated from photographs (0-3 points, randomized and masked evaluation). The 8-d experiment additionally included examination with a slit lamp and examination of hematoxylin-eosin stained sections of eyes with light microscopy. RESULTS: No serious or irreversible signs of irritation were noted. Doses of 1.0 mg were more irritating than 0.1-mg doses. There was no detectable difference in irritation between pure or freeze-dried powder. Slit-lamp examination, surface photographs and histology showed a negligible difference between drug and control eyes following the 8-d experiment. CONCLUSIONS: The results suggest that 0.1 mg of timolol powder does not irritate the eye and that testing topical timolol powder in humans is feasible.

Daytime diurnal curve comparison between the fixed combinations of latanoprost 0.005%/timolol maleate 0.5% and dorzolamide 2%/timolol maleate 0.5%.

PURPOSE: The diurnal efficacy and safety of the fixed combinations of latanoprost/timolol given once daily vs dorzolamide/timolol given twice daily in primary open-angle glaucoma or ocular hypertensive patients. DESIGN: A double-masked, two-centre, crossover comparison. RESULTS: In 33 patients, the mean diurnal IOP (0800-2000, measured every 2 h) for latanoprost/timolol fixed combination was 17.3+/-2.2 mmHg and for dorzolamide/timolol, the fixed combination was 17.0+/-2.0 mmHg (P = 0.36). Additionally, there was no statistical difference for individual time points following a Bonferroni correction. A bitter taste was found more frequently with the dorzolamide/timolol fixed combination (n = 6) than the latanoprost/timolol fixed combination (n = 0) (P = 0.040), while the latanoprost/timolol fixed combination demonstrated more conjunctival hyperaemia (n = 9) than the dorzolamide/timolol fixed combination (n = 2) (P = 0.045). One patient was discontinued early from the dorzolamide/timolol fixed combination due to elevated IOP. CONCLUSION: This study suggests that the daytime diurnal IOP is not statistically different between the dorzolamide/timolol fixed combination and latanoprost/timolol fixed combination in primary open-angle glaucoma and ocular hypertensive patients.

Latanoprost, a prostaglandin analog, for glaucoma therapy. Efficacy and safety after 1 year of treatment in 198 patients. Latanoprost Study Groups.

PURPOSE: To determine efficacy and safety of latanoprost, a prostaglandin analog for glaucoma, during 1 year of treatment. METHODS: After baseline measurements, 0.005% latanoprost was topically applied once daily for 12 months in patients from Scandinavia, the United Kingdom, and the United States who had elevated intraocular pressure (IOP). Diagnoses included ocular hypertension, chronic open-angle glaucoma, exfoliation syndrome, and pigment dispersion syndrome. Treatment was masked for the first 6 months and open-label during the second 6 months. RESULTS: Of the 272 patients initially enrolled, withdrawals were due to inadequate IOP control (1%), increased iris pigmentation (5%), other ocular problems (3%), systemic medical problems (3%), and nonmedical reasons (14%). Latanoprost significantly (P < 0.0001) reduced diumal IOP from 25.3 +/- 3.0 mmHg (mean +/- standard deviation) at baseline to 17.4 +/- 2.7 mmHg (32% reduction) at 12 months in the 198 patients who completed 1 year of treatment. The IOP reduction was maintained at a consistent level throughout the 12 months without evidence of drift, and was not affected by sex, age, race, or eye color. Overall, latanoprost caused a possible or definite increase in iris pigmentation in 12% of the 272 patients, all of whom had multicolored irides at baseline. One half of these patients with increased pigmentation withdrew before completing 1 year of therapy. Visual field, optic disc cupping, visual acuity, refractive error, conjunctival hyperemia, aqueous flare, anterior chamber cellular response, lens examination, blood pressure, heart rate, blood tests, and urinalysis were not appreciably altered. CONCLUSION: Latanoprost safely and effectively reduces IOP for 1 year in patients of diverse nationalities, providing further evidence for its usefulness in chronic glaucoma therapy.

[Severe anaphylactic shock with heart arrest caused by coffee and gum arabic, potentiated by beta-blocking eyedrops]. / Choc anaphylactique grave avec arrêt cardiaque au café et à la gomme arabique, potentialisé par un collyre bêta-bloquant.

The case of a male patient who experienced four allergic accidents after drinking coffee is reported. Two serious anaphylactic reactions with cardiac arrest occurred after a continuous treatment with beta-blocking eye drops (timolol) was prescribed. Dual sensitivation to coffee and to the gum arabic coating roasted coffee beans was demonstrated by skin prick tests and by human basophil degranulation tests. Occupational allergy to green coffee has been widely described, but food sensitization to these two allergens has not yet been reported. This case also draws attention to the risk, inherent in beta-blockers, of immuno-allergic reactions. These drugs produce a loss of compensatory cardiovascular mechanisms and make those who take them resistant to the conventional treatment of anaphylactic shocks, which explains the serious accidents that occurred in this patient. The authors stress the usefulness of a thorough investigation for food allergy to a rare allergen in patients with idiopathic anaphylaxis.

Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial.

We conducted a randomized, double-masked, long-term clinical trial to determine whether topical timolol therapy was effective in delaying or preventing the onset of glaucomatous damage in moderate-risk ocular hypertensive subjects. In 62 patients, one eye was chosen randomly to receive timolol therapy twice daily while the fellow eye received placebo. During the course of the study, the mean +/- SD difference in intraocular pressure between the timolol-treated and the placebo-treated eyes was 2.3 +/- 2.6 mm Hg. Reproducible visual field loss developed in 4 timolol-treated eyes and 10 placebo-treated eyes. Progressive optic disc cupping was noted in 4 timolol-treated and 8 placebo-treated eyes. Using a computerized image analysis system, the mean +/- SD increase in optic disc pallor during the course of the study was 0.86% +/- 2.4% in the timolol-treated eyes as opposed to 1.80% +/- 3.6% in the placebo-treated eyes. This study provides evidence that lowering intraocular pressure by medical treatment reduces the incidence of glaucomatous damage in ocular-hypertensive individuals.

Oral and topical adrenergic beta-receptor blockers in glaucoma treatment. A multicenter study.

In a long-term multicenter open randomized study of 103 patients with glaucoma or intraocular hypertension, oral propranolol combined with 2% pilocarpine was compared with 0.5% topical timolol also combined with 2% pilocarpine, with respect to the effects on intraocular pressure and other signs of glaucoma. The results showed that the hypotensive effects were highly significant and equal for both treatments. There were no significant differences between the 2 groups in the amount of cupping of the nerve head or the visual field defects developing during treatment. An additive hypotensive effect was recorded when both propranolol and timolol were combined with pilocarpine, which indicates the development of tolerance to both beta-blockers. Pulse rate and blood pressure were moderately reduced in both groups, both significantly more so in the propranolol group. The investigation indicates that when combined with pilocarpine the 2 adrenergic beta-receptor blockers are equally effective. We believe that oral propranolol can improve drug compliance in the treatment of glaucoma.