综述：皮肤科中的局部使用噻吗洛尔：应用与进展

《Dermatologic Therapy》：Topical Timolol in Dermatology: Applications and Advances

Timolol, a nonselective β-blocker initially approved for glaucoma, shows promise in topical dermatological applications due to its vasoconstrictive, anti-inflammatory, and促进伤口愈合 effects. It has been effectively used for treating infantile hemangiomas, pyogenic granulomas, Kaposi's sarcoma, acne, rosacea, chronic ulcers, and preventing radiation dermatitis. Clinical studies demonstrate its safety with minimal adverse effects, particularly in children and mucosal areas. However, evidence is primarily from case reports and non-randomized trials, necessitating further rigorous research.

　　
Timolol, a nonselective beta-blocker initially approved by the FDA in 1978 for glaucoma, has gained significant attention in dermatological research due to its versatile therapeutic effects when applied topically. This review explores the growing body of evidence supporting its use in treating diverse skin conditions, ranging from vascular lesions like infantile hemangiomas and pyogenic granulomas to inflammatory skin disorders such as acne and rosacea, while emphasizing its safety profile compared to systemic administration.

The efficacy of topical timolol in superficial infantile hemangiomas (IHs) has been well-documented. A randomized controlled trial demonstrated that applying 0.5% timolol gel twice daily for 24 weeks resulted in complete regression of lesions in 86.1% of patients, with no adverse effects on cardiovascular parameters. For deeper IHs, combination therapies with laser treatments or intralesional corticosteroids have shown enhanced outcomes, reducing recurrence rates and preventing scar formation. These findings highlight timolol's dual role in vasoconstriction and promoting epithelial healing.

In treating pyogenic granulomas (PGs), a randomized double-blind study revealed that twice-daily application of 0.5% timolol solution significantly reduced lesion size and erythema compared to placebo. This effect is attributed to timolol's ability to inhibit hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF), key mediators of angiogenesis and inflammation. However, challenges persist in managing large or deep PGs, where combination therapies with laser or corticosteroids may be necessary. Notably, timolol's noninvasive nature and minimal side effects make it particularly suitable for pediatric patients or cosmetically sensitive areas.

Cutaneous Kaposi’s sarcoma (KS), a virus-induced vascular tumor linked to human herpesvirus-8 (HHV-8), has shown promising responses to topical timolol. Case reports indicate that regular application of 0.5% timolol gel can reduce hyperkeratosis and ulceration, likely through suppressing HHV-8 reactivation via β-adrenergic signaling pathways. While systemic therapies like chemotherapy or radiation remain standard, timolol offers a safer alternative with fewer side effects, particularly for localized KS cases.

The anti-inflammatory properties of timolol have led to its exploration in acne and rosacea management. In acne vulgaris, a multicenter study found that nightly application of 0.5% timolol reduced noninflammatory lesions (comedones) by 50-70%, possibly through vasoconstriction that limits sebum production. Combining timolol with blue light therapy further amplified efficacy in mild-to-moderate cases. For erythematotelangiectatic rosacea, split-face studies showed significant improvement in facial redness and telangiectasia after 28 days of timolol application, with no systemic adverse effects. Its dual action of vasoconstriction and enhancing skin barrier function by modulating epidermal growth factor receptor (EGFR) pathways underscores its versatility.

Postacne scarring and erythema represent another area where timolol demonstrates utility. A case series reported 90% improvement in post-inflammatory erythema after 12 weeks of timolol ophthalmic solution use, with no hyperpigmentation observed. In split-face comparative trials, combining timolol with fractional CO2 lasers accelerated scar remodeling and reduced procedural side effects. These outcomes are likely due to timolol's促表皮修复作用，通过增强ERK信号传导促进角质形成细胞迁移和胶原重塑。

Chronic refractory ulcers, particularly in diabetic patients, have shown remarkable healing potential with topical timolol. Retrospective studies involving 39 patients with refractory ulcers reported 86% wound closure rates after 4 weeks of twice-daily timolol application. The mechanism involves enhanced keratinocyte migration and reduced matrix metalloproteinase (MMP) activity, which accelerates tissue regeneration. When combined with laser therapy for burn wounds, timolol shortened re-epithelialization time by 25%, while reducing pain and inflammation.

Safety profiles of topical timolol are favorable, with most adverse effects being mild and transient, such as localized dryness or erythema. However, caution is advised for patients with cardiopulmonary conditions, as systemic absorption of timolol can lead to bradycardia or bronchospasm. Monitoring heart rate and blood pressure during initial treatment is recommended, especially for patients with preexisting cardiac issues. No severe adverse reactions have been reported in dermatological applications, contrasting sharply with systemic formulations that carry risks of hypoglycemia and bronchospasm.

Clinical challenges include optimizing treatment protocols for different conditions. While randomized controlled trials support timolol's efficacy in superficial IHs and PGs, longer-term studies are needed to evaluate its safety in chronic applications like diabetic ulcers. The lack of standardized dosing guidelines for dermatological uses also presents a barrier. Current evidence suggests that 0.25-0.5% concentrations applied 2-5 times daily are effective, but further research is required to define optimal regimens.

Emerging applications include treating Hailey-Hailey disease, a genetic disorder affecting skin adhesion, where 0.5% timolol gel induced complete lesion resolution over 6 months. In tuberous sclerosis complex, a prospective trial involving 15 children with facial angiofibromas demonstrated 75% reduction in lesion severity after 12 weeks of timolol gel application. These cases suggest timolol's potential in addressing hyperproliferative disorders through its dual action of vasoconstriction and anti-inflammatory effects.

Radiation dermatitis prevention represents another innovative use. A triple-blind trial involving 64 breast cancer patients undergoing radiotherapy found that daily timolol gel application reduced the incidence of severe radiation dermatitis by 60%, with minimal side effects. This is attributed to timolol's antioxidant properties, which protect endothelial cells from oxidative damage, a common mechanism in radiation-induced skin injuries.

Despite its promise, several limitations need addressing. Most studies are retrospective or case reports, lacking robust RCTs to establish causality. Long-term safety data are insufficient, particularly for children and immunocompromised patients. Additionally, the exact mechanisms of timolol's action remain unclear, especially in complex conditions like pyoderma gangrenosum or hypertrophic scars, where multifactorial pathways may be involved.

Future research should prioritize large-scale RCTs to validate efficacy across diverse populations. Mechanistic studies using biopsies or animal models could elucidate how timolol modulates specific pathways like HIF-1α/VEGF, ERK signaling, or anti-inflammatory cytokines. Development of novel formulations, such as sustained-release gels or combinations with other agents (e.g., hydroxychloroquine), may enhance therapeutic outcomes.

In conclusion, topical timolol represents a paradigm shift in dermatological treatment, offering a cost-effective, noninvasive option with broad applicability. From vascular lesions to inflammatory conditions, its efficacy is supported by growing evidence, though standardized protocols and long-term safety data remain priorities. As a repurposed glaucoma drug, timolol exemplifies how expanding the use of existing medications through targeted application can address unmet medical needs in skin diseases.