Combination of available topical beta-blockers and antibiotic ointment for epidermal growth factor receptor tyrosine kinase inhibitor-induced paronychia and pseudopyogenic granulomas in Taiwan.

BACKGROUND: Painful paronychia and pseudopyogenic granuloma (PG) are common adverse drug reactions (ADRs) associated with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat non-small cell lung cancer (NSCLC). Multiple local management approaches have been tested with unsatisfactory results. We have introduced an occlusion therapy technique through which available topical drugs for longer than 2 years. METHODS: Based on the cancer registry and case management system of our hospital, from July 2019 to July 2020, we retrospectively enrolled patients with NSCLC who were treated with EGFR-TKIs and received applications of 0.5% timolol ophthalmic solution (TIMOPTOL XE 0.5%®) combined with a neomycin/tyrothricin ointment (Biomycin®) using the occlusion method to treat paronychia or PG. RESULTS: A total of 22 patients were enrolled, with a mean age of 66.5 years, most of whom were women (72.7%). Periungual lesion-related pain was reported by all patients, and periungual bleeding and PG were reported in 14% (3/22) and 64% (14/22) of patients, respectively. After the occlusion therapy application of timolol ophthalmic solution combined with neomycin/tyrothricin ointment twice daily, the overall response rate was 83.3%, including complete response in 18% (4/22) of cases and partial response in 68% (15/22) of cases. CONCLUSION: We presented an occlusion method using available topical beta-blockers and antibiotic ointment for EGFR-TKI-induced paronychia and PG in Taiwan. The result is favorable. Further randomized control trial is urgent to validate our findings.

Successful Late Treatment of Orbital Infantile Haemangiomas in Two Teenagers with Topical Transcutaneous Timolol Maleate 0.5% Alone.

We previously described the first successful treatment of deep periocular and, subsequently, orbital infantile haemangiomas (IH) with topical transcutaneous timolol maleate 0.5% (TM 0.5%) alone as the first-line treatment in the acute proliferative phase in infancy. It is not known whether orbital IH with persistent proptosis in later years, untreated in infancy, would still respond to TM 0.5% treatment as well. To our best knowledge, we here present the first reports of the successful late treatment of persistent orbital IH with topical timolol maleate 0.5% applied to the skin overlying the orbital IH in two teenagers. Case 1 was an 11-year-old girl with proptosis measuring 4 mm before and 7 mm after Valsalva manoeuvre that diminished to 1 mm after topical treatment. Case 2 was a 10-year-old girl with 2 mm (before) and 4 mm proptosis (after Valsalva) that decreased to 0 mm proptosis with topical treatment. The time to resolution was 19 months (case 1) and 13 months (case 2). The treatment dose was 3 drops of TM 0.5% applied an average of 1.94 (case 1) and two times daily (case 2). In comparison to proptosis, resolution of periorbital swelling required less treatment time. There was no recurrence of either proptosis or periorbital swelling 1 year after stopping treatment in either case. The findings indicate that beta-blockers are effective not just in the proliferative but also in the late involutional phase in older children. No adverse clinical effects were noted throughout treatment in either case. The presence of increased proptosis with a Valsalva manoeuvre predicts a significant persistent vascular compartment in the orbital IH and may thus serve as a simple predictive clinical sign of likely treatment success. We recommend that a trial with this well-tolerated treatment form is considered in persistent cases of orbital IH, especially in the presence of enhanced proptosis with a Valsalva manoeuvre.

Application of topical betaxolol to cure superficial infantile hemangioma: A pilot study.

BACKGROUND: Beta-blockers have gradually become an attractive option for the treatment of infantile hemangiomas. Topical application is preferred to oral administration because of their potential systemic adverse effects. The aim of this study is to investigate the effect of betaxolol in treating superficial infantile hemangioma. METHODS: Seventy-four infants admitted to the First Affiliated Hospital of Xinjiang Medical University from 2018 to 2019 were observed and recorded. Variables such as color, size, tension, and thickness were recorded monthly and evaluated using visual analog scales. Multi-factor analysis of variance with repeated measurements and the non-parametric Kruskal-Wallis H test were used to compare clinical effectiveness across the different groups. RESULTS: After 6 months of treatment, 33.78% (25/74) showed excellent results, 55.41% (41/74) had good responses, 8.11% (6/74) had moderate responses, and 2.70% (2/74) had poor responses. Local discomfort and systemic complications were not found. There was no significant difference in gender and location of occurrence among groups (p > 0.05), and the effect of topical application of betaxolol was optimum in the children aged 0-3 months (p = 0.002). None of three age groups had statistically significant difference in heart rate and blood pressure after accepting treatment (1 month, p = 0.618; 4 months, p = 0.138; 6 months, p = 0.757). CONCLUSIONS: Our study showed that topical administration of betaxolol was effective and well tolerated for superficial infantile hemangiomas, particularly in the early proliferative stage. However, its safety and efficacy need further research.

Comparison of the efficacy and safety of lasers, topical timolol, and combination therapy for the treatment of infantile hemangioma: A meta-analysis of 10 studies.

Topical timolol and lasers are widely used for the treatment of infantile hemangioma (IH), and they can replace propranolol as the first-line treatment of IH. We aimed to investigate the efficacy and safety of topical timolol alone or lasers plus topical timolol versus lasers alone for the treatment of IH using a meta-analysis. We searched the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases. A more conservative random effect model meta-analysis technique was used to analyze the efficacy and adverse reactions of timolol and lasers. Ten RCTs with a total of 979 patients with IH were included in this meta-analysis. Treatment with topical timolol alone was as effective as lasers in treating IH (risk ratio [RR] = 0.99, p = 0.94), with similar adverse events. The difference was not statistically significant (RR = 1.67, p = 0.14). Combined treatment with topical timolol and lasers showed a favorable response rate compared with treatment with either lasers (RR = 1.23, p = 0.01) or topical timolol (RR = 1.35, p = 0.001) alone. Furthermore, compared to topical timolol alone, the combined treatment indicated similar risks of adverse events (RR = 0.70, p = 0.38) but fewer risks of adverse events (RR = 0.39, p = 0.004) compared to lasers alone. This meta-analysis provided evidences that a combined treatment with topical timolol and lasers might be more effective than a single treatment strategy in infants with IH, and with no significant increase in adverse reactions. The combination of topical timolol and laser therapy might be the preferred choice for the treatment of IHs.

Reversible Corneal Decompensation Caused by a Topical Dorzolamide/Timolol Fixed Combination After Descemet Stripping Automated Endothelial Keratoplasty.

PURPOSE: The purpose of this study was to report a case of acute corneal endothelial decompensation caused by a topical dorzolamide/timolol fixed combination (DTFC) after Descemet stripping automated endothelial keratoplasty. METHODS: A 75-year-old woman who was referred to our hospital with a chief complaint of visual disturbance in the right eye after cataract surgery. Anterior segment optical coherence tomography identified an extensive defect in Descemet membrane. The patient subsequently underwent uneventful Descemet stripping automated endothelial keratoplasty surgery for persistent corneal edema. Two weeks after surgery, she had been prescribed topical DTFC twice daily to control elevated intraocular pressure. On the day she started using the eye drops, the patient noticed an acute deterioration of visual acuity. Severe corneal edema was detected at follow-up 5 days later. RESULTS: The topical DTFC was stopped immediately. Thereafter, the corneal edema improved gradually, and there was a reduction in corneal thickness. CONCLUSIONS: Topical DTFC should be used with caution after corneal endothelial transplantation because of the possibility of iatrogenic corneal endothelial dysfunction.

Effectiveness and safety of 0.5% timolol solution in the treatment of pyogenic granuloma: A randomized, double-blind and placebo-controlled study.

Introduction Pyogenic granulomas are benign vascular lesions of the skin and mucosa which are often a source of concern because of their recurrent bleeding even with minimal trauma. Current treatment for pyogenic granuloma is ablative; no medical therapy is standardized to date. Timolol, due to its vasoconstrictive effect, vascular growth factor inhibition and apoptosis promotion properties, is a potential therapeutic option. Objectives: To assess the effectiveness and safety of topical timolol in the treatment of pyogenic granulomas. Methods A two-centre, double-blind and placebo-controlled trial (Registration CTRI/2019/04/018581) was conducted. Patients of either sex were recruited with pyogenic granuloma lesions of less than eight weeks duration. Topical treatment with 0.5% timolol or matching glycerin placebo was continued for six weeks. Changes in color, size, bleeding tendency, physicians' and patients' global assessments and adverse events were assessed. Results Forty subjects were randomized between the two groups which were comparable in age, sex, duration of illness and baseline lesion size.Significant improvement was noted with timolol, with color change from first follow-up onwards and lesion size reduction from second follow-up onward. Patients' assessment of bleeding tendency also showed imrovement from the second visit onward. Between-group comparison showed significant difference with respect to percentage reduction in size (timolol 40.9%, placebo 3.4%; P = 0.002). Rescue treatment (electrosurgery) was required in five patients on placebo and in one in the timolol group (P = 0.182). Complete resolution occurred in 2 (10%) patients with timolol and in no patients on placebo (P = 0.231). Limitations: We observed effects of treatment for only six weeks. Conclusion Topical timolol may be a treatment option for early pyogenic granulomas but complete resolution is unlikely in six weeks. Studies of longer duration are required to assess resolution and recurrence rates.

Risk factors for periorbital dermatitis in patients using dorzolamide/timolol eye drops.

This study assessed the clinical risk factors for periorbital dermatitis (PD) after using dorzolamide/timolol eye drops in a total of 1282 glaucoma patients. Both the PD(+) group and the PD(-) group were evaluated using clinical data such as age, sex, dosing duration, presence of benzalkonium chloride (BAK) in the formulation, ocular surgery history (e.g. cataract or glaucoma operations), height, weight, personal history of systemic hypertension, smoking, alcohol consumption, intraocular pressure, best-corrected visual acuity (BCVA), central corneal thickness, axial length, and visual field index (VFI). Univariate analyses showed that shorter dosing duration, higher rate of BAK-included cases, worse BCVA, worse VFI, more systemic hypertension history, and more ocular surgery history were more associated with the PD(+) group than the PD(-) group. The BAK(-) group showed a lower PD rate than the BAK-included group, which was supported by the Kaplan-Meier analysis (log-rank test, p = 0.0014). Multivariate analyses revealed that the probability of PD increased by 8 times if they had a history of ocular surgery and increased by 2.3% when the VFI decreased by 1% (Cox's hazard regression test, p < 0.001). Therefore, a preservative-free dorzolamide/timolol can benefit the subjects for those who had ocular surgery or who have worse VFI.

Twelve-month efficacy and safety of omidenepag isopropyl, a selective EP2 agonist, in open-angle glaucoma and ocular hypertension: the RENGE study.

PURPOSE: To assess the long-term safety and efficacy of omidenepag isopropyl (OMDI) 0.002% (a first-in-class, selective, non-prostaglandin, prostanoid EP2 receptor agonist), alone or administered concomitantly with timolol 0.5%, in patients with open-angle glaucoma (OAG, including normal-tension and exfoliation glaucoma) or ocular hypertension (OHT). STUDY DESIGN: Open-label, multicenter, Phase 3 study (NCT02822729). METHODS: Patients aged ≥ 20 years, with OAG or OHT, and a baseline diurnal intraocular pressure (IOP) ≥ 16- < 22 mmHg (Group 1) or ≥ 22- ≤ 34 mmHg (Groups 2 and 3) were enrolled. All patients (N = 125) received OMDI 0.002% once daily. Group 3 also received timolol 0.5% twice daily. IOP was measured at baseline and at Weeks 2, 4, 8, 12, 26, 40, and 52. RESULTS: Significant reductions in mean diurnal IOP from baseline occurred at every visit (P < 0.0001). Mean ± SE diurnal IOP reduction at Week 52 was -3.7 ± 0.3 mmHg (Group 1), -5.6 ± 0.5 mmHg (Group 2), and -8.4 ± 0.6 mmHg (Group 3). Most adverse events (AEs) were mild, and no serious treatment-related AEs were reported. Conjunctival hyperemia (incidence: monotherapy [Groups 1 and 2], 18.8%; concomitant [Group 3], 45.0%) and macular edema (ME)/cystoid macular edema (CME) (incidence: monotherapy, 11.8%; concomitant, 15.0%) occurred most frequently. All treatment-related ME/CME cases occurred in pseudophakic eyes and responded to standard-of-care treatment and study drug discontinuation. CONCLUSIONS: In this study, OMDI 0.002%, alone or administered concomitantly with timolol 0.5%, resulted in sustained IOP reduction over 52 weeks in patients with OAG or OHT. Concomitant treatment resulted in increased efficacy and increased incidence of conjunctival hyperemia.

A randomized, controlled, split-face study of topical timolol maleate 0.5% eye drops for the treatment of erythematotelangiectatic rosacea.

BACKGROUND: Centrofacial erythema associated with telangiectasis is the most common presentation of rosacea, known as erythematotelangiectatic rosacea (ETR). However, successful management of these symptoms remains challenging. AIM: The purpose of this study was to evaluate the efficacy and safety of topical timolol maleate eye drops 0.5% for ETR. METHODS: In this randomized, single-center, single-blind, placebo-controlled split-face study, 16 patients with mild-to-moderate ETR who presented at West China Hospital between January 2019 to September 2020 were randomized to receive either topical timolol maleate eye drops 0.5% to one side of their face daily for 28 days and normal saline to the other side of the face. Patients were assessed with both the Clinician Erythema Assessment (CEA) and Patient Self-Assessment (PSA) at the 28-day follow-up appointment. Subjective assessment was performed by asking participants to grade their sensation of warmth and burning. RESULTS: The sides treated with timolol demonstrated a significant improvement in both the CEA and PSA at the 28-day assessment. Patients reported a significant difference in warmth and burning sensations. The only adverse reaction was worsened redness on both sides of the face at Day 1 in one patient. CONCLUSIONS: In this small study, the application of topical timolol maleate was safe and effective for the treatment of ETR.

Repurposing Ophthalmologic Timolol for Dermatologic Use: Caveats and Historical Review of Adverse Events.

Ophthalmic timolol solution is increasingly being repurposed as a topical therapeutic for a variety of dermatologic diseases, including pyogenic granulomas, infantile hemangiomas, and chronic wounds. There are no published guidelines or protocols for use in these indications in adults, and the dermatologic community may not be familiar with adverse events that have been extensively documented relating to its ophthalmic use. We review the evidence available relating to adverse events to topical timolol use to evaluate its safety in dermatologic applications and to alert clinicians to screening and monitoring that is needed when repurposing this drug for dermatologic use. The majority of serious adverse events associated with ophthalmic timolol were reported in the first 7 years of use, between 1978 and 1985, of which most common were cardiovascular and respiratory events, but also included 32 deaths. The available evidence suggests that ophthalmic timolol safety profiling may have been incomplete prior to widespread use. Recent clinical trials for dermatologic indications have focused on documenting efficacy and have not had rigorous monitoring for potential adverse events. Topical timolol may be safe and effective for the treatment of various dermatologic conditions in patients whose medical histories have been carefully reviewed for evidence of pre-existing cardiac or pulmonary disease and are monitored for potential adverse events. Despite the wide use of timolol in ophthalmologic practice, safe dermatologic repurposing requires recognition of the potential for facilitated systemic absorption though the skin and appreciation of its history of adverse events.

The effect of 0.5% topical timolol cream on regression of superficial infantile haemangioma in the involuting phase: a prospective, randomized, self-controlled study.

BACKGROUND: Infantile haemangiomas are the most common benign tumours affecting infants. Over time, the tumours may involute to some extent. However, sequelae, such as telangiectasia or fibrofatty tissue, often occur following this condition, which may cause disfigurement and influence patients' psychosocial development. OBJECTIVE: This prospective, randomized, self-controlled study aimed to assess the effects of topical timolol (0.5%) on involuting infantile haemangiomas. MATERIALS & METHODS: Each involuting superficial infantile haemangioma (n = 29) was randomly divided into two regions; one region was treated with topical timolol (0.5%) cream, three times daily, and the other region was untreated. The comparative treatments continued for three months. Five independent assessors, blinded to the treatment regimen, judged the treated and untreated regions by comparing photographs before and after treatment. RESULTS: The topical timolol-treated tumour sections showed no difference compared with the untreated sites (p = 0.355) after three months of treatment, and by the end of the treatment, the untreated lesions showed significant differences relative to pre-treatment (p<0.001). CONCLUSION: Topical timolol was not observed to have any effect on the regression of infantile haemangiomas in the involuting phase.

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.

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.

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.

The effectiveness and safety of topical ß-receptor blocker in treating superficial infantile haemangiomas: A meta-analysis including 20 studies.

AIMS: To evaluate the effectiveness and safety of topical ß-receptor blocker in treating superficial infantile haemangiomas (SIH) and compare the effectiveness and safety of topical ß-receptor blocker against other therapies. METHODS: A search of the literature using PubMed, Embase, Cochrane Review database, China National Knowledge Infrastructure and Wanfang were performed to identify the studies that estimated the effectiveness and safety of topical ß-receptor blocker in treating SIH, the fixed-effect or random-effects meta-analytical techniques were applied to assess the outcomes. RESULTS: Twenty studies, involving 2098 patients, were included to conduct this analysis. Topical propranolol and topical timolol were discovered to be as effective as oral propranolol in treating SIH (propranolol, odds ratio [OR] = 0.486, 95% confidence interval [CI] 0.165, 1.426, P = .189; timolol, OR = 0.955; 95%CI 0.700, 1.302; P = .769), and topical timolol was more effective than topical imiquimod (OR = 2.561; 95%CI 1.182, 5.550; P = .017), observation (OR = 18.458; 95%CI 5.660, 60.191; P < .001) and topical saline solutions (OR = 19.193; 95%CI 8.837, 41.683; P < .001) in treating SIH. The comparison between topical propranolol and oral propranolol led to no discovery of significant difference in the incidence of adverse effects (OR = 1.258; 95%CI 0.471, 3.358; P = .647). Compared with oral propranolol, topical timolol was associated with fewer incidences of adverse effects (OR = 0.191; 95%CI 0.043, 0.858; P = .031). No significant difference in the incidence of adverse effects was found when topical timolol and topical imiquimod were compared (OR = 0.077; 95%CI 0.005, 1.206; P = .068). CONCLUSION: This meta-analysis provided evidence that topical ß-receptor blockers (propranolol and timolol), especially timolol, may replace oral propranolol as a first-line treatment for SIH.

Comparative evaluation of Latanoprostene Bunod, Timolol Maleate, and latanoprost Ophthalmic Solutions to assess their safety and efficacy in lowering intraocular pressure for the management of Open-Angle Glaucoma

OBJECTIVES: Timolol maleate has been reported to be a safer intraocular pressure (IOP) lowering treatment than latanoprost. The United States Food and Drug Administration approved latanoprostene bunod, a nitric oxide-donating prodrug of latanoprost, for lowering IOP. This study compared the safety and efficacy of latanoprost, latanoprostene bunod, and timolol maleate in patients with open-angle glaucoma. METHODS: Patients who received latanoprost eye drops once daily in the evening were included in the latanoprost Ophthalmic Solutions (LP) cohort (n=104). Those who received latanoprostene bunod eye drops once daily in the evening were included in the Latanoprostene Bunod (LB) cohort (n=94). Those who received timolol eye drops twice daily were included in the Timolol Maleate (TM) cohort (n=115). All treatments were administered to the affected eye(s) for 3 months. Informed Consent has been taken from each participant before the trial. RESULTS: At the end of 3 months of treatment, latanoprost, latanoprostene bunod, and timolol were all successful in reducing IOP. The LB cohort had the highest reduction in IOP, compared to the LP and TM cohorts. All treatments had some common adverse ocular effects. CONCLUSION: Latanoprostene bunod was superior to latanoprost and timolol for the treatment of open-angle glaucoma.