Oxidized cellulose microneedle patch combined with vascular embolization and local delivery of timolol maleate for hemangiomas.

Hemangiomas are superficial tumors characterized by dense vascular structures that often affect the patient's aesthetic appearance due to the obvious red appearance on the skin. Current treatments, especially timolol maleate in the form of eye drops and hydrogels, suffer from low transdermal drug delivery rates, resulting in prolonged treatment time. To address this challenge, our study introduced a soluble microneedle patch with dextran as the main material to form microcatheters for sustained delivery of timolol maleate. In addition, we proposed a vascular embolization strategy to disrupt the blood supply in hemangiomas. Oxidized cellulose (C-cellulose) was selected for its excellent hemostatic properties. We incorporated C-cellulose into dextran microneedles to facilitate thrombosis in the vascular-rich areas of hemangiomas. The innovative microneedle patch we developed can penetrate the skin to a depth of 430 µm and dissolve rapidly within 3 minutes, ensuring direct drug delivery to the subcutaneous layer. Notably, the treated skin area regained its original appearance within two hours after treatment. In addition to excellent skin permeability and rapid dissolution, these patches significantly promoted apoptosis and inhibited cell migration in mouse hemangioendothelioma EOMA cells. Our results demonstrate that this approach not only achieves significant tumor inhibition in a mouse hemangioma model, but also represents a more effective, convenient, and non-invasive treatment option. Therefore, dextran/C-cellulose/timolol maleate microneedle patch (MNs/Timolol) has broad clinical application prospects in the treatment of hemangiomas, minimizing the risk of additional damage and improving treatment efficacy.

In situ forming hydrogels based on modified gellan gum/chitosan for ocular drug delivery of timolol maleate.

In situ forming hydrogels are suitable candidates for increasing drug residence time in ocular drug delivery. In this study, gellan gum (GG) was oxidized to form aldehyde groups and in situ gelling hydrogels were synthesized based on a Schiff-base reaction between oxidized GG (OGG) and chitosan (CS) in the presence of ß-glycerophosphate. The effect of OGG and CS concentration on the physical and chemical properties of the resulting hydrogels was investigated. The FT-IR spectroscopy confirmed the chemical modification of OGG as well as the functional groups of the prepared hydrogels. The scanning electron microscope (SEM) revealed the highly porous structure of hydrogels. The obtained hydrogels indicated a high swelling degree and degradability. Also, the rheological studies demonstrated self-healing behavior, shear thinning, thixotropy, and mucoadhesion properties for the developed hydrogels. The results of in vitro and ex vivo studies showed that the timolol-loaded hydrogel with a higher amount of OGG has a higher release rate. Moreover, the MTT cytotoxicity test on bone marrow mesenchymal stem cells (BMSCs) confirmed that developed hydrogels are not toxic. The obtained results revealed that the developed hydrogels can be a desirable choice for the ocular drug delivery of timolol in the treatment of glaucoma.

Ophthalmic complication of pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare dermatological condition which may present with ocular manifestations. We report a case of recurrent cicatricial ectropion (CE) with topical beta-blocker use in the rare dermatological condition PRP. The patient underwent release of scar tissue, lateral tarsal strip and full-thickness supraclavicular skin graft for CE following immunosuppression with methotrexate for 3 months. Postoperatively, CE recurred, with skin graft shrinkage and resumption of periocular disease activity, 8 weeks following the introduction of topical timolol. The patient was referred for further immunosuppression and substitution of timolol before consideration for further surgery. PRP has a variety of potential ocular complications. Surgery has a high risk of recurrence and should be performed when the overall disease is quiescent and drugs, which could trigger reactivation, have been discontinued and/or substituted. Skin grafts should be oversized to off-set shrinkage.

[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.

The Effect of Dorzolamide-timolol Eye drop on Intraocular Pressure Change in Intravitreal Ranibizumab Injected Patients.

PURPOSE: The objective of the study was to examine the effect of dorzolamide-timolol (DT) eye drop used before intravitreal ranibizumab (IVR) injection on intraocular pressure (IOP) change. METHODS: 50 eyes of 50 patients who received DT eye drops 1 h before IVR injection due to diabetic retinopathy and macular edema were considered Group 1, and 50 eyes of 50 patients who did not receive DT eye drops were considered Group 2. Those patients who had previously undergone intravitreal injection had intraocular surgery, and used any eye drops were not included in the study. Before the injection, IOP values were measured with a Tonopen contact handheld tonometer before the blepharostat was placed (BIOP), after the blepharostat was placed (AIOP), and at the 1st min after the injection (IIOP). RESULTS: There were 25 males and 25 females in Group 1 and 25 males and 25 females in Group 2; the mean age was 65.66 ± 9.94 years in Group 1 and 65.54 ± 7.43 years in Group 2 (P = 0.98). In Group 1, BIOP was 18.91 ± 18.91, AIOP was 21.62 ± 6.16 mmHg, and IIOP was 49.21 ± 10.95 mmHg. In Group 2, BIOP was 20.18 ± 4.19 mmHg, AIOP was 24.60 ± 4.90 mmHg, and IIOP was 49.96 ± 9.72 mmHg. IIOP-BIOP difference was 30.30 ± 9.85 mmHg in Group 1 and 29.78 ± 9.33 mmHg in Group 2 and the difference was not statistically significant (P = 0.78). In Group 1, the IIOP-AIOP difference was 27.58 ± 10.60 mmHg and in Group 2, 25.36 ± 10.46 mmHg. The difference between IIOP and AIOP was not statistically significant (P = 0.27). CONCLUSION: The use of topical DT eye drops before IVR injection does not affect the intraocular pressure change.

Infantile Sacral Region Hemangioma and Combination Treatment with Propranolol and Topical Timolol: Case Review and Reference Review.

BACKGROUND: Infantile hemangiomas (IH) are the most common vascular, benign tumors of childhood with a prevalence of 4-5%. Due to intense vasculogenesis, they proliferate during infancy, then involute at an unpredictable rate, extent of involution, and quality of residual tissue. Depending on the location, they may be associated with anomalies of other organ systems (PHACE, PELVIS syndroms). In recent decades, knowledge about hemangiomas has improved, and therefore therapeutic possibilities have improved. Today, the non-selective beta blocker-propranolol is considered the drug of first choice in the treatment of infantile hemangiomas. It is desirable to start treatment in the proliferative phase of hemangioma growth for the best possible effect. The dynamics of drug administration, time interval of dose increase and monitoring of patients during treatment vary from one Institution to another and are still the subject of discussion. OBJECTIVE: We presented the case of a child with infantile hemangioma of the lumbo-sacral region, treated with combination therapy with systemic propranolol and topical timolol, with satisfactory effect in the end. CONCLUSION: Propranolol is considered a drug with well-studied side effects and a safety profile. During 6 months of treatment, it leads to complete or almost complete withdrawal of the hemangioma. Treatment should be started in the hemangioma proliferation phase for the best possible therapeutic effect.

Efficacy and Safety of Topical Timolol for the Treatment of Infantile Hemangioma in the Early Proliferative Stage: A Randomized Clinical Trial.

Importance: Treatment of infantile hemangioma (IH) with topical timolol in the first 2 months of life (early proliferative phase) may prevent further growth and the need for treatment with oral propranolol. To our knowledge, no studies have determined whether beginning early treatment with timolol for IH is better than in other proliferative stages. Objective: To evaluate the efficacy and safety of timolol maleate solution, 0.5%, for the early treatment of IH in infants younger than 60 days. Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, phase 2a pilot clinical trial included patients aged 10 to 60 days with focal or segmental hemangiomas (superficial, deep, mixed, or minimal/arrested growth). Patients were randomly assigned to treatment with topical timolol maleate solution, 0.5%, or placebo twice daily for 24 weeks. Changes in lesion size (volume, thickness) and color were evaluated from photographs taken at 2, 4, 8, 12, 24, and 36 weeks. Vital signs and adverse effects were recorded at each visit. The study was carried out from November 2015 to January 2017, and data analyses were completed in September 2019. Main Outcomes and Measures: The primary outcome of complete or nearly complete IH resolution and the secondary outcomes of changes in lesion thickness, volume, and color were evaluated by a blinded investigator. Results: Of the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days; 55 (80%) were female; and 51 (74%), 11 (16%), 6 (9%), and 1 (1%) had superficial, mixed, abortive, or deep IHs, respectively. The IHs were localized, segmental, or indeterminate in 60 (87%), 7 (10%), and 2 (3%) patients, respectively. The IHs were located on the head and/or neck (n = 23 [33%]) or other body sites (n = 46 [67%]). The study was completed by 26 of 33 (79%) patients receiving timolol and 31 of 36 (86%) receiving placebo. There were no significant differences between timolol and placebo for complete or nearly complete IH resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37). The odds ratio of complete or almost complete response vs no response at week 24 was 1.33 (95% CI, 0.45-3.89). There were no between-group differences in IH size (volume, thickness). An improvement in color was observed at week 4 in the timolol group, and timolol was well tolerated with no systemic adverse effects. Conclusions and Relevance: In this randomized clinical trial, results demonstrated that topical timolol is well tolerated for the treatment of early proliferative IH but provides limited benefit in lesion resolution when given during the early proliferative stage. Trial Registration: EudraCT Identifier: 2013-005199-17.

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.

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.

Efficacy of Timolol in a Novel Intranasal Thermosensitive Gel for Hereditary Hemorrhagic Telangiectasia-Associated Epistaxis: A Randomized Clinical Trial.

Importance: Other than nasal moisturizers, no standard-of-care medical therapy exists for epistaxis in hereditary hemorrhagic telangiectasia (HHT). With epistaxis as the greatest cause of morbidity in patients with HHT, there is a need to identify effective topical therapies. Objective: To determine the efficacy and safety of an intranasal timolol thermosensitive gel vs placebo thermosensitive gel in treating HHT-associated epistaxis. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial was conducted from October 29, 2019, to May 20, 2020, at a tertiary care center. A total of 27 patients with HHT and moderate-to-severe epistaxis were recruited and included in this prespecified analysis: 14 in the timolol group and 13 in the placebo group. Inclusion criteria included (1) age 18 years or older, (2) clinical or genetic diagnosis of HHT, (3) screening Epistaxis Severity Score (ESS) of 4 or greater and 2 or more nosebleeds cumulatively lasting at least 5 minutes per week, (4) stable epistaxis pattern over the preceding 3 months, and (5) no change in epistaxis treatment or nasal hygiene regimen in the preceding month. Exclusion criteria included (1) contraindications to systemic ß-blocker administration, (2) use of medications interacting with timolol, (3) use of antiangiogenic medications in the last month before recruitment, and (4) use of anticoagulants, antiplatelets, or fibrinolytic therapies within the last month. Interventions: Novel thermosensitive intranasal timolol (0.1%) gel vs placebo thermosensitive gel applied twice daily to each nostril for 8 weeks. Main Outcomes and Measures: The primary outcome was the median change in ESS and percentage of participants reaching the minimal clinically important difference in ESS. Secondary outcomes were changes in Clinical Global Impression-Severity and Clinical Global Impression-Improvement scores, Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia, and hemoglobin level. Results: Of 27 participants randomized (median [range] age, 55 [20-76] years; 14 women [52%]; 25 White [93%]), a total of 23 patients with HHT completed the primary outcome measure. Within the timolol gel and placebo gel groups, respectively, the median change (range) in ESS was 2.32 (0.22 to 5.97) vs 1.96 (-0.91 to 5.98), and 9 of 11 (82%) vs 9 of 12 (75%) participants experienced a clinically meaningful improvement in ESS. Twenty-two of the 23 participants (96%) reported improvement via the Clinical Global Impression-Improvement score, with 81% vs 58% of participants reporting reduced severity of epistaxis in the timolol vs placebo group, respectively. Of participants completing the Nasal Outcome Score for Epistaxis in HHT at follow-up visit, 7 of 10 (70%) in the timolol group achieved a clinically important difference vs 5 of 10 (50%) in the placebo group. There was no change in hemoglobin level between or within groups. Zero participants in the placebo group and 2 of 13 (15%) in the timolol group withdrew because of adverse events. Conclusions and Relevance: Thermosensitive gel, alone or in combination with timolol, was highly effective in reducing HHT-associated epistaxis. The timolol group had greater improvement in epistaxis and quality of life than the placebo group, but effect estimates were imprecise, and no definitive conclusions on the superiority of timolol can be drawn. Physicians treating patients with HHT-associated epistaxis should consider a thermosensitive gel (with or without timolol) for their patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04139018.

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.