A Few Drops May Go a Long Way: Topical Timolol in Pediatric Dermatology : Indian Journal of Paediatric Dermatology

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A Few Drops May Go a Long Way

Topical Timolol in Pediatric Dermatology

Jain, Naina; Ganjoo, Shikhar

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Indian Journal of Paediatric Dermatology: Jul–Sep 2022 - Volume 23 - Issue 3 - p 260-264
doi: 10.4103/ijpd.ijpd_63_22
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Introduction

Timolol, a nonselective beta-blocker, acts through various mechanisms and has multisystem effects as it antagonizes the beta-adrenoreceptors located on the keratinocytes, melanocytes, and fibroblasts. Since it is a less invasive, cost-effective, and simple treatment its use has garnered interest in multiple indications over the past decade due to the beneficial effects observed in infantile hemangioma. We discuss the emerging role of topical timolol in various pediatric dermatoses.

Mechanism of Action

Timolol is a first-generation, nonselective β adrenergic receptor blocker without an intrinsic sympathomimetic activity, thereby inhibiting the sympathetic responses. It reduces the heart rate, myocardial contraction force, and cardiac output.[1] Timolol also inhibits vasodilatation and increases bronchial resistance.[1] In infantile hemangiomas, timolol acts in multiple ways, i.e., as a vasoconstrictor, inhibiting angiogenesis by decreasing vascular endothelial growth factor (VEGF), basic fibroblast growth factor; promoting apoptosis, and inhibiting tumor proliferation.[2]

In 2009, Sivamani et al. emphasized the possible role of β blockers in managing burn and chronic wounds. Stress-induced epinephrine acts on keratinocytes through β adrenergic receptors to prevent cell proliferation and wound re-epithelialization. The use of β blockers may enhance keratinocyte motility by reducing phosphatase 2A phosphorylation, reducing inflammation, increasing the pro-reparative factors in the wound, and reversing the anti-reparative effects of catecholamine.[3]

Pharmacology

Timolol for ophthalmic use is available in various concentrations such as 0.1%, 0.25%, and 0.5% and formulations such as aqueous solution and gel.[4] Local application of 0.25% or 0.5% timolol solution to the eye has shown to reduce intraocular pressure by 15–20 min, with peak drug levels noted in 2–4 h and the effect lasting over 24 h and more.[56]

Owing to the high systemic bioavailability of topical timolol, the ocular use of 0.1% solution has shown fewer effects on the peak heart rate and lung function in comparison to placebo and 0.5% solution, exhibiting equivalent efficacy. Furthermore, hydrogels increase the ocular absorption of the drug, hence, may be safer with lower systemic adverse effects over aqueous eye solutions.[7] The mean plasma concentration with twice daily application of 0.5% timolol solution was 0.46 ng/ml after the morning dose. This is almost twice the value of 0.28 ng/ml, recorded after the once-daily application of 0.5% timolol gel-forming eye solution.[5] Timolol is majorly metabolized in the liver by cytochrome P450 D26. Children with low activity of this cytochrome may be at risk of dose-related side effects.[8]

Indications in dermatology

The utilization of topical timolol has evolved in dermatology practice to include many off-label indications as reviewed below.

Vascular tumors

Infantile hemangiomas

Infantile hemangiomas (IH) or strawberry hemangiomas are the most common benign tumors of vascular nature, affecting up to 5% of the pediatric population. Most have a predictable course consisting of initial proliferation, maximum by 9 months of age, then a plateau stage followed by complete regression by 4 years of age in 90% of individuals.[9] Seeking early treatment may prevent complications such as ulceration, obstruction, irreversible cosmetic disfigurement, or functional impairment.

The use of topical timolol is by far recommended for small, thin, and superficial lesions over ulcerative hemangiomas in the pediatric age group. It is essential to rule out any history of bronchial asthma, chronic obstructive pulmonary disease, sinus bradycardia, second or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock, and hypersensitivity to timolol or any components of its preparation(s). With a normal electrocardiogram (ECG) at baseline and stable vitals [Table 1], a test dose is administered under direct supervision. If the vitals continue to remain within the normal limit at 2 h and 4 h after, topical timolol can be further safely administered.[10]

Ng et al. in 2016 reviewed the effect of topical timolol on cutaneous facial IH proposing a clinical assessment grading system [Table 2]. A grade of 3 and more was noticed in 47%–88% of cases, with one study postulating a higher rate of involution with earlier (i.e., before 6 months of age than after) introduction of timolol application. A review of 700 IH cases the same year by the hemangioma investigator group pointed out a steady but significant 30% improvement with topical gel-forming timolol solution in superficial, thin IH than with oral β blockers.[11]

T1-18
Table 1:
Recommended heart rate to age
T2-18
Table 2:
Grading of clinical response to topical timolol in infantile hemangioma
T3-18
Table 3:
Reported side effects*

Only recently in 2021, Fania Z. Muñoz-Garza et al. reported a multicenter, randomized clinical trial on the effects and safety of topical timolol in the early proliferative stage of infantile hemangiomas. At 24 weeks of treatment, 11 of 24 patients using topical timolol and 11 of 26 patients in the placebo group had complete/near-complete resolution of the lesions. In comparison to the placebo group, the volume loss of hemangiomas was superior, thickness reduction was earlier and the color change to the time of evolution was more evident in the study group.[12]

Topical timolol has been used in combination with oral propranolol for deep-seated hemangiomas. Mixed hemangiomas in oral and maxillofacial areas were treated by Li et al. in 2016 with both oral propranolol (1–1.5 mg/kg/day) and topical timolol 0.5% ophthalmic solution (25 mg/5 ml) applied twice daily in the study group and oral propranolol (1.5 mg/kg/day) alone in the control group. The treatment was administered for a maximum of 8 months or until the complete resolution of lesions. It was observed that the mean time duration to resolution was evidently shorter with prominent color fading in the experimental group over the control.[13]

Deep hemangiomas in 5 subjects in a study were treated with topical timolol 0.5% solution alone as three drops three times a day. Complete regression was noticed after about 10 months. Topical timolol has been suggested as a first-line treatment for functionally disabling, deep hemangiomas.[14]

The maximum safe dose of topical timolol 0.5% gel-forming solution (GFS) should be <0.25 mg/kg of body weight/day or one drop/kg of body weight/day. Rork et al. emphasize against starting or escalating the dose to a body weight-based maximum safety limit. Topical use may be restricted to 1–3 drops of 0.5% GFS per day, depending on the wound area.[1516]

Pyogenic granuloma

Also known as lobular capillary hemangioma, the pyogenic granuloma is a benign vascular growth characterized by profound bleeding with trivial manipulation.[17] Surgical removal, especially in children, may be associated with the procedure-and anesthesia-related complications such as anxiety, pain, bleeding, and scarring. The response to topical timolol in treating pyogenic granuloma has been variable, with recurrence being possible.[1819]

A digital pyogenic granuloma in a teenager was successfully treated with 0.5% timolol ophthalmic gel use in a case report by M. Malik and R. Murphy in 2014, with no recurrence at a 7-month follow-up.[18] Similarly, in 2016, Knöpfel et al. illustrated almost complete clearance of two scalp pyogenic granulomas in a 2-year-old child with twice daily application of timolol ophthalmic solution after a month.[19]

Timolol in pyogenic granuloma is hypothesized to act by immediate vasoconstriction and later by blocking angiogenic factors (like hypoxia-inducible factor 1 alpha, VEGF, basic fibroblast growth factor) and promoting apoptosis. A long-standing pyogenic granuloma tends to be less vascular and more fibrous, making timolol more effective in recent-onset lesions (of <6 weeks' duration).[20]

A series of 30 patients were treated for pyogenic granuloma with twice daily application of 0.5% timolol maleate eye solution under occlusion for almost 5 weeks by Ali Al-Turfy et al. in 2020. Eleven candidates showed complete resolution of their lesions with a statistically significant decrease in the mean tumor size of the study group.[21]

Tufted Angioma and kaposiform hemangioepithelioma

In a case report by Behera et al. in 2021, topical timolol 0.5% GFS application in a 4-month-old male infant led to complete clearance of the tufted angioma on his right lower leg. The solution was used thrice a day for 4 months, gradually tapering after resolution over the next 2 months.[22]

Angiofibroma

An angiofibroma is a conglomeration of vascular and interstitial elements, known to express VEGF. Owing to their partly vascular nature, Krakowski and Nguyen treated a case of facial angiofibromas with a single-sided, twice daily application of 0.5% timolol gel for 4 months. This was preceded by full-face ablative fractional resurfacing with a pulsed dye laser. On follow-up, an evident reduction in erythema, number, and the size of lesions was noticed on the treated (left cheek) versus the untreated sites (nose and the right cheek).

Considering similar findings on histology to angiofibromas, it may be worth exploring the therapeutic response of Koenen's tumors, pearly penile papules, and fibrous papules of the nose to topical timolol.[23]

-Cutaneous wounds (including in epidermolysis bullosa)

In 2016, Chiaverini et al. reported two 1-year-old cases of junctional epidermolysis bullosa with chronic wounds of the nail bed and neck fold, irresponsive to topical steroids and silicone dressings. Twice daily use of timolol 0.5% eye drops under occlusion; however, for 3 and 8 weeks resulted in 100% and 80% improvement, respectively, without noting any side effects.[24]

A case series of 5 patients with chronic, nonhealing wounds of varied etiology (venous insufficiency, trauma, decubitus ulcer) were treated with topical timolol failing other modalities by Braun et al. in 2013. A drop of 0.5% topical timolol was applied every 2 cm along the wound margin on a daily or weekly basis over 4–8 weeks. All of the patients improved with three demonstrating complete resolution.[25]

Paronychia

It is a frequent and debilitating side effect of chemotherapy, as with taxanes, mitogen-activated protein kinase inhibitors, and epidermal growth factor receptor inhibitors. In a report by Martínez-de-Espronceda et al. in 2019, a 4-year-old child suffered from trametinib induced paronychia. He responded favorably to twice daily application of timolol 0.5% gel over 2 months to the affected nails with ongoing treatment with trametinib for optic chiasm glioma.[26]

Acne vulgaris, rosacea, postacne erythema, and hyperpigmentation

Recently, Al Mokadem et al. assessed the effect and safety of topical timolol 0.5% in acne vulgaris and rosacea cases based on its anti-inflammatory action on matrix metalloproteinase (MMP)-2, MMP-9, and interleukin-6 in acne and vasoconstriction in rosacea. Single daily application of a few drops over 8 weeks resulted in a reduced number of comedones, pustules, and papules in acne patients. Improvement in erythematotelangiectatic rosacea was more pronounced than papulopustular lesions of rosacea in this study.[27]

Post-inflammatory erythema and hyperpigmentation are a result of underlying vasodilatation and melanogenesis. Timolol, being a vasoconstrictor, and anti-angiogenic, was used in a patient with prominent postacne erythema by Afra et al. in 2020. Once-daily bedtime application of 0.5% solution after 12 weeks led to significant improvement with no side effects noted.[28]

Hidradenitis suppurativa

Topical timolol may salvage the acute recurrences often associated with the condition. In 2019, severe hidradenitis suppurativa in a patient was managed with a combination of minocycline 100 mg, infliximab 5 mg/kg every 8 weeks, and clindamycin 1% lotion by Xizhao Chen et al. Significant improvement was noted with multiple areas of persisting granulation tissue. Failing resolution with triamcinolone 40 mg/ml injections and curettage-assisted extirpation, these granulation tissues regressed with a once-daily application of 0.5% timolol ophthalmic GFS over 3 months.[29]

Scars

In 2017, Dabiri et al. reported the use of topical timolol for acute scars post excision or Mohs Micrographic Surgery for nonmelanoma skin cancer. According to the visual analog scale, candidates applying topical timolol versus in the saline group as control had superior scar cosmesis.[30]

Adverse effects and monitoring

Screening for risk factors to the use of timolol is of prime essence to minimize side effects. Contraindications include preexisting asthma, heart block, syncope, or bradycardia. Owing to its nonselective antagonism on beta-adrenergic receptors, cardiopulmonary adverse events have been reported with the ocular use of topical timolol. It may be worth noting that side effects of local cutaneous use have been mild and transient so far [Table 3].[31] Systemic adverse effects are more like to occur in patients with ulcerated lesions, in preterm babies, and lesions involving mucosal and occluded surfaces (for instance, the diaper area).[22]

The use of topical timolol in ocular hypertension/open-angle glaucoma has been associated with systemic side effects. These include arrhythmia, tachycardia, palpitations, heart failure, angina, respiratory arrest, respiratory failure, respiratory distress, dyspnea, apnea, asthma, bronchitis, contracted lung function, apneic spell, syncope, headache, cerebrovascular accident, depression, gastrointestinal distress, and sexual impotence, apart from those encountered with dermatological use.[31]

Yoon et al. recommend monitoring the heart rate, blood pressure, and lung auscultation at baseline and 20 min postapplication. An ambulatory ECG may only be crucial in a high-risk candidate.[31]

Conclusion

Most indications are off-label, but topical timolol is increasingly being used due to its multisystem effects. Prolonged use is safe and effective. Application site adverse effects are common but not a limitation to the treatment. Larger RCTs and meta-analyses are required to determine the concentration, frequency of usage, and the side effect profile of topical timolol in various pediatric dermatoses. We believe this molecule has just started its journey into the broad realm of pediatric cutaneous dermatoses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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