[Topical application of hypotensive drugs for the prevention of intraocular pressure elevation after intravitreal injections of anti-VEGF drugs]. / Mestnoe primenenie gipotenzivnykh preparatov s tsel'yu profilaktiki povysheniya urovnya vnutriglaznogo davleniya posle intravitreal'nykh in"ektsii anti-VEGF-preparatov.

The management protocol for patients with neovascular age-related macular degeneration (nAMD) involves multiple intravitreal injections (IVI) of anti-VEGF drugs. The ability to reduce the peak intraocular pressure (IOP) rise is greatly important in clinical practice. PURPOSE: This study evaluates the effect of topical hypotensive drugs on the short-term IOP rise after IVI of anti-VEGF drugs in patients with nAMD. MATERIAL AND METHODS: The prospective study included 80 patients with newly diagnosed nAMD. Before the start of treatment, the patients were divided into 4 groups of 20 people each: 1st - controls, who received no prophylactic drugs, in the 2nd, 3rd and 4th groups local instillations of one drop of hypotensive drugs brinzolamide 1%, brinzolamide-timolol, brimonidine-timolol were performed in the conjunctival sac twice: 1 day before the injection (at 20:00) and on the day of the injection 2 hours before the manipulation (at 08:00), respectively. IOP was measured in each patient using ICare Pro non-contact tonometer before injection, as well as 1 min, 30 and 60 min after injection. RESULTS: Prophylactic use of hypotensive drugs was associated with a significant decrease in IOP immediately after IVI compared to the same parameter in the 1st group (p<0.001), the maximum decrease in IOP values was observed when using a fixed combination of brimonidine-timolol by 12.1 mm Hg compared to the controls (p<0.001), the combination of brinzolamide-timolol reduced IOP by 8.5 mm Hg (p<0.001), brinzolamide 1% led to the smallest decrease in IOP - by 5.1 mm Hg (p<0.001). CONCLUSION: Study patients that received instillations of brimonidine-timolol combination of one drop into the conjunctival sac 1 day before the injection and on the day of the injection showed the maximum decrease in IOP compared to patients of the other groups.

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.

Beta-adrenergic glaucoma drugs reduce lymphatic clearance from the eye: A sequential photoacoustic imaging study.

Our study aims to determine whether the beta-adrenergic system is involved in the regulation of lymphatic drainage from the eye. For this purpose, we assessed the effect of 2 topical beta-adrenergic blockers, timolol and betaxolol, commonly used as glaucoma drugs, on lymphatic clearance of albumin from the aqueous humor to neck lymph nodes. Adult mice were treated with either topical timolol, a non-selective ß-blocker, 0.5% (n = 8), or topical betaxolol, a selective ß1-adrenergic blocker, 0.5% (n = 6) twice daily for 14 days and compared to respective control groups (n = 5 and n = 7). Changes in lymphatic clearance from the eye were assessed using a quantitative in vivo photoacoustic imaging approach. In all subjects, right eye and neck lymph nodes were longitudinally assessed by sequential photoacoustic imaging just prior to near-infrared dye injection into the anterior chamber of the eye, and 20 min, 2 and 4 h after injection. Repeat measurements of mean pixel intensities (MPIs) of right eyes and nodes were performed at all timepoints. The areas under the curves (AUC) were calculated and the AUC of the treated-group was compared to that of controls using the Mann-Whitney U test. The slopes of MPI of each region of interest over time were compared using the linear mixed model after adjusting for IOP decrease after treatment and other parameters such as sex and body weight. In the timolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.003), and significant decrease in slope of MPI compared with controls (P = 0.0025). In the betaxolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.02), and significant decrease in slope of MPI compared with controls (P = 0.0069). Topical treatment with timolol and betaxolol reduced lymphatic clearance of albumin from the aqueous humor to the neck lymph nodes. This finding may be relevant for the management of secondary glaucomas and inflammatory eye disease in which the clearance of accumulated proteins and antigen from the eye is important to disease recovery and sight protection. This study suggests that the beta-adrenergic system plays a role in the regulation of lymphatic clearance from the eye.

Ocular timolol as the causative agent for symptomatic bradycardia in an 89-year-old female.

Bradycardia can present with variations of severity from asymptomatic to life threatening. In this paper we present the case of an 89-year-old female presenting with symptomatic bradycardia for whom the cause was found to be ophthalmic timolol which she had been taking for four years. Prompt recognition of potential causes of bradycardia is essential for correct selection of treatment and disposition.

Prophylactic anti-glaucoma therapy in dogs with primary glaucoma: A practitioner survey of current medical protocols.

AIM: To examine the use of prophylactic anti-glaucoma medications in the normotensive fellow eye in dogs with unilateral overt primary glaucoma by veterinary ophthalmology clinicians. METHODS: A survey of veterinary ophthalmology clinicians was distributed over two international list serves servicing veterinary ophthalmologists, trainees, and individuals whose practice consisted primarily of ophthalmic patients. The survey was developed following analysis of historical and currently available medical options for control of intraocular pressure and for neuroprotection. RESULTS: Responses from 199 veterinary ophthalmology clinicians were evaluated. While a large variety of topical anti-hypertensive drugs and protocols were used, the most commonly used medications were aqueous humor production suppressors such as dorzolamide 2.0% ophthalmic solution, timolol 0.5% ophthalmic solution, and a combination product containing both drugs. Latanoprost 0.005% ophthalmic solution was used infrequently for prophylaxis by comparison. The majority of respondents do not use concurrent anti-inflammatory medications (61.22%), although a sizeable minority used prednisolone acetate, dexamethasone, or ketorolac as prophylactic treatment. Systemically administered ocular anti-hypertensive agents were rarely used. Only 40% of respondents used neuroprotectant agents; the most commonly prescribed were the calcium channel blocker amlodipine and the nutraceutical Ocu-Glo™. Recommended intervals between re-examination by the clinician ranged from one month to one year, with most re-evaluations occurring every 3 to 6 months. The majority of respondents recommended more frequent assessments of IOP at intervals between once monthly and once every 3 months. CONCLUSIONS: Data analysis of medical therapy for the normotensive fellow eye of dogs previously diagnosed with primary glaucoma suggests that there is a great need for well-designed, prospective, controlled, multi-center studies to determine which protocols have the greatest efficacy in delaying an overt attack in the previously normotensive eye in dogs with a genetic predisposition to glaucoma. Prospective studies utilizing a carbonic anhydrase inhibitor such as dorzolamide and a prostaglandin analogue such as latanoprost would be reasonable as these two drugs are widely used in the treatment of overt glaucoma and would allow for an exploration of the impact of different mechanisms of action of lowering IOP on the pathophysiology of primary glaucoma.

Ocular Intracameral Pharmacokinetics for a Cocktail of Timolol, Betaxolol, and Atenolol in Rabbits.

The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics of three ß-blocker agents after intracameral (ic) injection into the rabbit eyes. Aqueous humor samples were collected and analyzed using LC-MS/MS to determine drug concentrations. Pharmacokinetic parameters were obtained using a compartmental fitting approach, and the estimated clearance, volume of distribution, and half-life values were the following: atenolol (6.44 µL/min, 687 µL, and 73.87 min), timolol (19.30 µL/min, 937 µL, and 33.64 min), and betaxolol (32.20 µL/min, 1421 µL, and 30.58 min). Increased compound lipophilicity (atenolol < timolol < betaxolol) resulted in higher clearance and volume of distributions in the aqueous humor. Clearance of timolol and betaxolol is about 10 times higher than the aqueous humor outflow, demonstrating the importance of other elimination routes (e.g., uptake to iris and ciliary body and subsequent elimination via blood flow).

Randomised controlled trial: Can topical timolol maleate prevent complications for small superficial infantile haemangiomata in high-risk areas?

BACKGROUND: To define the role of topical timolol maleate (TTM) in the treatment of infantile haemangiomata (IH). METHODS: In this single-centre randomised controlled trial, we included all <1-year-old infants within a 13-month period presenting with small (<2 cm) superficial IH located at high-risk areas (i.e. tip of ears, tip of nose, eyelids, acral areas, facial areas, scalp, neck, buttocks, perineum and axilla). Patients either received 12 months of 0.5% TTM solution (study group) or watchful waiting (control group). The primary outcome was IH with development of complications that required additional interventions. The secondary outcomes included side effects of TTM and change in IH size. RESULTS: Forty-two children were eligible to the study. Patients who received TTM were noted to have significantly fewer complications than the control group (4.2% versus 29%, odds ratio 9.58 [95% confidence interval: 1.01-91.62], p = 0.04). Mean IH volume percentage reduction was significantly more for the TTM group and no-TTM group at 3, 6 and 12 months. CONCLUSIONS: TTM is an effective and safe treatment option to reduce complications, IH volume and the need for further intervention for infants with small superficial IH located at high-risk areas. IMPACT: There is a lack of reliable signs to predict ulceration, disfigurement and other complications for high-risk IH. Treatment options range from watchful waiting to early systemic treatment, with TTM a novel and promising treatment. The exact role of TTM remains unanswered due to a lack of evidence-based research. TTM is effective and safe for infants with superficial IH of <2 cm in high-risk areas. Early TTM use on IH can reduce complications, IH volume and the need for further treatment.

Recalcitrant trametinib-induced paronychia treated successfully with topical timolol in a pediatric patient.

Paronychia has been described as a side effect in patients undergoing treatment with MEK (mitogen activated protein kinase enzyme) inhibitors. It is usually a recurrent condition that can have a significant impact in the quality of life. Topical beta blocker treatment has been described as an effective therapy in antineoplastic-induced pyogenic granulomas and in antineoplastic-induced paronychia. We describe the first case treated with topical timolol for a trametinib-induced paronychia in a pediatric patient that allowed to continue the third line antineoplastic therapy for his glioma.

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.

Validation of a More Reliable Method of Eye Drop Self-Administration.

SIGNIFICANCE: We propose an alternative method for eye drop self-administration. Similar IOP reductions were found with this method compared with clinician instillation. The alternative method of self-administration potentially benefits patients who have trouble successfully instilling drops. PURPOSE: The purpose of this study was to validate the efficacy of an alternative method of drop instillation. METHODS: This study is a randomized controlled crossover clinical trial. Thirty participants were recruited. A drop of 0.5% timolol maleate was instilled into subject's eye on two separate visits. On one visit, eye drop instillation was by a trained clinician, and on the other, self-instillation using an alternative method was used. The order was randomly chosen. Intraocular pressure was measured before drop instillation and 2 hours after drop instillation. The investigator was masked during measurement, and an observer recorded the IOP measurements. RESULTS: Mean ± SD IOP measurement before 0.5% timolol maleate instillation measured 13.89 ± 2.29 mmHg. An average reduction 3.75 ± 2.36 mmHg was found with clinician administration, and an average reduction of 3.32 ± 2.31 mmHg was recorded with the new method. No significance was found in IOP reduction between two groups P < .45. Percent reduction was 25.17 ± 16.21% and 24.38 ± 16.31% in clinician instillation and alternative instillation method group, respectively. No significant difference was found. This percentage reduction was similar to previously reported studies. No reported cases of eye infection or irritation were found in any case, within a 3-month follow-up period. CONCLUSIONS: We have proposed a more reliable method for instillation that provides a larger area for instillation and lessen the risk of contamination and patient's fear for eye drops. Similar efficacy was found compared with that of having a clinician directly administer the drop. This alternative method could potentially benefit patients who require topical eye drop therapy and result in increased compliance.

Use of Topical Timolol Maleate as Re-Epithelialization Agent for Treatment of Recalcitrant Wounds of Varying Etiologies.

Background: Chronic wounds remain a challenge for the clinician and healthcare system. It is therefore vital for additional therapies that target steps involved in wound recalcitrance. Recently, topical timolol has shown promising results for use in wound healing. Objective: The goal of this study was to assess timolol's effectiveness in healing wounds of varying etiologies. Methods: This multi-center series took place from 2016¬­2019 at the wound healing centers at the University of Miami Health System and the Veterans Affairs Northern California Healthcare. We identified all wound patients who received treatment with topical timolol maleate 0.5% for at least 4 weeks after failing previous treatments. Timolol drops at a dose of 1 drop per cm2 of wound area were instilled with dressing changes twice a day, once a day, every other day, or continuous application. Once they began the study, they stopped all concurrent therapies aside from standard of care. Healing outcomes were classified into 3 categories: healed, defined as complete re-epithelialization of the wound and closure, improved, defined as decreasing wound size area (WSA), and worsening, defined as increasing WSA. Results: We identified 39 patients, 32 males and 7 females that had a total of 55 chronic wounds of varying etiologies. Thirty-four of the wounds had completely healed, 15 wounds improved in WSA, 4 wounds were unchanged in WSA, and 2 wounds worsened in WSA. Conclusions: In line with our previous experience, we found topical timolol to be a safe, cost-effective, and efficacious treatment for recalcitrant wounds of varying etiologies.

Allergic contact dermatitis caused by timolol eyedrop application for classic Kaposi sarcoma.

Topical timolol has been shown to be effective on treatment of Kaposi sarcoma. We present the case of a 72-year-old man with classic Kaposi sarcoma on upper limbs, treated with topical timolol 0.5% twice a day with a pruritic eruption on areas of application.

Psoriasis precipitated by timolol eye drops. A series of eight cases.

Induction of psoriasis following administration of beta blocker containing eye drops has rarely been documented. We report eight cases of psoriasis triggered by timolol eye drops. Since the clinical and histopathological features of this drug reaction are indistinguishable from those of idiopathic psoriasis, a thorough drug history should be taken in all patients, especially elderly ones, with recent onset of psoriasis.

The effects of topical dorzolamide 2% and brinzolamide 1%, either alone or combined with timolol 0.5%, on intraocular pressure, pupil diameter, and heart rate in healthy cats.

OBJECTIVE: To investigate the effects of topical dorzolamide 2% q8h and brinzolamide 1% q8h, administered either alone (A and B, respectively) or in combination with topical timolol 0.5% q12h (C and D, respectively), on the circadian pattern of intraocular pressure (IOP), the pupil size, and heart rate in healthy cats. METHODS: In this prospective, randomized, double-blinded study, 10 healthy, adult cats were randomly assigned to one of four groups and the eye to be medicated was randomly assigned. IOP, pupil diameter, and heart rate were measured at 3-hour intervals. A 5 days' adjustment period was followed by a 5 days' placebo (baseline) period. Then, all groups of cats received all four treatments (A-D) according to a Latin square-based rotating schedule. Five days' medication periods were alternated with 3 days' washout periods. RESULTS: Mean baseline IOP was 13.6 ± 2.7 mm Hg. All treatments resulted in a statistically significant decrease in mean IOP in the treated eye: A: -2.33 mm Hg (95% CI: -2.71, -1.94), B: -1.91 mm Hg (95% CI: -2.30, -1.53), C: -2.36 mm Hg (95% CI: -2.74, -1.97), and D: -2.37 mm Hg (95% CI: -2.76, -1.98) and the nontreated eye: A: -0.19 mm Hg (95% CI: -0.28, -0.11), B: -0.18 mm Hg (95% CI: -0.27, -0.10), C -0.31 mm Hg (95% CI: -0.40, -0.23), and D: -0.24 mm Hg (95% CI: -0.32, -0.15). Timolol resulted in an additional, significant decrease in IOP of 4% and 5%, respectively, compared to A and B, and in mild bradycardia and miosis. CONCLUSIONS: Topical administration of dorzolamide 2% and brinzolamide 1% q8h significantly decreased IOP in healthy cats. Supplemental timolol 0.5% eye drops q12h resulted in an additional, statistically significant reduction of IOP.

Influence of timolol, benzalkonium-preserved timolol, and benzalkonium-preserved brimonidine on oxidative stress biomarkers in the tear film.

PURPOSE: The objective of this study was to investigate the influence of topical preservative-free timolol, benzalkonium chloride(BAC)-preserved timolol, BAC-preserved timolol, and BAC-preserved brimonidine on total protein concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response, and Oxidative Stress Index (OSI) in the tear film. METHODS: The patients were divided into four groups: group C (n = 25)-control group-subjects who did not use topical antiglaucoma medications, group T (n = 17)-patients using topical preservative-free timolol, group T + BAC (n = 24)-patients using topical BAC-preserved timolol, and group BR + BAC (n = 19)-patients using topical BAC-preserved brimonidine. RESULTS: The SOD, CAT, and GPx activities as well as AOPP, TOS, and OSI were found to be higher in the tear film of patients treated with BAC-preserved topical timolol or brimonidine in comparison with patients treated with preservative-free timolol or patients who did not use antiglaucoma topical medications. CONCLUSIONS: This indicates that using BAC-preserved topical medications increases oxidative stress in the tear film and may, in the long-term, contribute to the clinical presentation of dry eye disease.

Intractable Ocular Diseases and Treatment Progress.

In recent years, with the aging of the population and the frequent use of electronic devices, many eye diseases have shown a linear upward trend, such as dry eye disease, glaucoma, cataract, age-related macular degeneration, and diabetic retinopathy. These diseases are often chronic and difficult to cure. Based on the structure and barrier of the human eye, this review describes the pathogenesis and treatments of several intractable eye diseases and summarizes the advanced ocular drug delivery systems to provide new treatment ideas for these diseases. Finally, we also look forward to the prospect of RNAi therapy in the treatment of eye diseases.

Treatment of Children Hemangiomas.

Introduction: Hemangiomas are the most common benign tumors in infancy and the uncontrolled increase in size can cause serious complications, requiring treatment in specialized centers. Despite their high frequency and possible complications, there is currently no consensus on optimal treatment. The strategy may vary from simple observation to the involvement of several medical, radiological and surgical specialties, requiring both pharmacological and surgical treatment. Aim: The current study analyzes the results of the treatment of hemangiomas performed in a tertiary hospital in Romania, in order to compare the data with those in the recent literature. Methods: In our retrospective study we analyzed the data of 142 patients treated in our tertiary hospital for a period of approximately 2 years. Demographics, localization of hemangiomas, duration of hospitalization and treatment, and complications were statistically analyzed. Results: We achieved favourable outcomes in over 80-90% of cases by combining propranolol treatment with bleomycin injections, topical application of timolol and surgical excision, depending on the location and complexity of the hemangioma, and the age of the patient. Conclusions: The goal of hemangioma therapy is to stop hemangioma growth in its tracks, and has to provide relief and reassurance to patients and families. Such therapies might consist of combinations of drugs given concurrently or perhaps sequentially to target cells that are most active in the proliferating phase.

Interventions for infantile haemangiomas of the skin: abridged Cochrane systematic review and GRADE assessments.

BACKGROUND: Infantile haemangiomas (IH) are soft swellings of the skin that occur in 3-10% of infants. When haemangiomas occur in high-risk areas or when complications develop, active intervention is necessary. OBJECTIVE: To update a Cochrane Review assessing the interventions for the management of IH in children. METHODS: We searched for randomized controlled trials in CENTRAL, MEDLINE, Embase, LILACS, AMED, PsycINFO, CINAHL and six trials registers up to February 2017. We included 28 trials (1728 participants) assessing 12 interventions. RESULTS: We downgraded evidence from high to moderate/low for issues related to risk of bias and imprecision. Oral propranolol (3 mg kg-1 daily) probably improves clinician-assessed clearance vs placebo [risk ratio (RR) 16·61, 95% confidence interval (CI) 4·22-65·34; moderate quality of evidence (QoE)]; we found no evidence of a difference in terms of serious adverse events (RR 1·05, 95% CI 0·33-3·39; low QoE). We found the chance of reduction of redness may be improved with topical timolol maleate (0·5% gel applied twice daily) when compared with placebo (RR 8·11, 95% CI 1·09-60·09; low QoE). We found no instances of bradycardia or hypotension for this comparison. CONCLUSIONS: Our key results indicate that oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harm.

EFFICACY OF ADJUVANT TOPICAL DORZOLAMIDE-TIMOLOL IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION REFRACTORY TO ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY.

PURPOSE: To evaluate the efficacy of adjuvant topical dorzolamide-timolol in patients with neovascular age-related macular degeneration unresponsive to anti-vascular endothelial growth factor therapy. METHODS: This retrospective, interventional study included 15 patients with neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor. Patients used topical dorzolamide-timolol twice daily in the neovascular age-related macular degeneration eye and received anti-vascular endothelial growth factor therapy at each visit, with the same fixed interval and agent as before the addition of dorzolamide-timolol. Central macular thickness, maximal subretinal fluid height, and maximal pigment epithelial detachment height were measured at baseline and every visit. RESULTS: The mean follow-up period was 17.2 ± 5.5 weeks. The mean central macular thickness decreased from 383.5 µm at baseline to 298.3 µm at the final visit (P = 0.041). The mean maximal subretinal fluid height decreased from 105.0 µm at baseline to 58.3 µm at the final visit (P = 0.021). Complete resolution of subretinal fluid was observed in 3 of 11 subretinal fluid-type eyes. There was no significant change in the maximal pigment epithelial detachment height. The mean logarithm of the minimum angle of resolution visual acuity decreased from 0.61 (20/81 Snellen) at baseline to 0.66 (20/91 Snellen) at final visit, which was not significant (P = 0.314). The mean intraocular pressure decreased significantly from 14.9 mmHg at baseline to 12.3 mmHg at the final visit (P = 0.005). CONCLUSION: The use of adjuvant topical dorzolamide-timolol was effective in decreasing central macular thickness and subretinal fluid in patients with neovascular age-related macular degeneration refractory to continual fixed-interval intravitreal anti-vascular endothelial growth factor therapy, but did not result in functional improvement in this short-term study.