Local Application of Timolol 0.5% Solution in Treating Chronic Non-Healing Ulcers – A Prospective Study

Chronic non-healing ulcers are a variety of ulcers that occur mainly over the lower limb and are resistant to conventional therapy. There are modern treatments like various types of dressings and topical preparations available in the market. However, they are costly and may not be freely available to the general population. Topical usage of β 2-AR antagonists like timolol may promote wound healing by enabling keratinocyte migration into the wound to initiate the re-epithelisation. The objective of this study is to assess the effectiveness of topical timolol 0.5% in accelerating the wound healing process by observing the signs of healing. It is a prospective observational study conducted in Government General Hospital, Rangaya Medical Medical College, Kakinada, after getting Institutional Ethical Committee approval from March 2021 to March 2023. One hundred patients with Chronic non-healing foot ulcers were taken for this study. Mean age was 47.64.60% of the study population was in the 20-55 years age group. Reduction in mean ulcer area was on day 15 and day 30 with topical application of timolol.


INTRODUCTION
Chronic non-healing ulcers are those that do not respond to a regular way of conventional management, and they are resistant to healing even after 6 weeks. 1 They have multifactorial etiology and cause severe complications if not treated wisely.The prevalence is estimated to be about 1.51 per 1000 population. 1 It is seen in 1% of the adult population.3.6% is noticed in those above 65 years. 2It causes deterioration in quality of life, becomes a financial burden to the person's family, and even damages the healthcare system.ocular conditions like glaucoma and migraine. 3Beta2 adrenergic receptors are present in keratinocytes.A topical application of Timolol acts by mobilizing the keratinocytes into the wound area and further by re-epithelisation. 4,5e objective of this study is to assess the safety of the patient after this local application, any adverse effects or drug interactions.The efficacy of topical application of 0.5% timolol solution is assessed by regular examination of the wound and by measuring the wound size at 15 and 30 days.Any decrease in size is to be recorded.

METHOD
This study was conducted in Government General Hospital, Rangaraya Medical Medical College, Kakinada, after getting Institutional Ethical Committee approval from March 2021 to March 2023.One hundred patients were taken for this study.

Inclusion Criteria
More than 18 years age group, nonhealing ulcers for more than 6 weeks with no progress were noticed even after 4eeks of continuous treatment, size of 5 to 50 cm ² and with granulation tissue.If more number of ulcers are present, the greatest is to be chosen.Bacteriologically sterile wound, the ulcer area must contain granulation tissue of nearly 50 percent.

Exclusion Criteria
The exclusion criteria in this study are ischaemic limb ulcers, slough and debris wounds, wounds with dead bone and tendon, glaucoma patients, patients sensitive to beta blockers, chronic lung diseases, ischaemic heart diseases, and thyroid disorders.
After taking informed consent, some important details were noted in the record.They are age, sex, occupation, address, and socio-economic status, including chief complaints and duration, history of present illness, family history, personal history, and treatment history.Local examination findings like ulcer site, size, number, shape, margin, edge, floor, base, discharge, and surrounding area were noted.Discharge was to be sent for bacteriological examination.Specific drug treatment had to be given.Ulcer size was to be measured and plotted on graph paper.The size of the ulcer was recorded on the 1st day, 15th day and 30th day.Detailed clinical examinations for all peripheral pulses, cardiovascular system, and nervous system were conducted.Routine blood investigations and x-rays of the affected part were taken.
Drug administration method: The First ulcer was to be treated with various types of available treatments like debridement and dressings.Once bacteriological examination came as a sterile report and the ulcer area was filled with granulation tissue for more than 50%, the size of the ulcer had to be noted.Now, we had to apply timolol 0.5% solution locally and cover the area with dry dressings with a dosage of 3 drops/cm2/day = 0.25mg/cm2/day.These drops were to be applied on the 1st, 3rd and 7th days.The healing and size of the ulcer were assessed on the 15th and 30th day.All the data was to be recorded.

RESULTS AND DISCUSSION
This study showed that the majority of ulcers are located over the plantar aspects of the foot in the pressure-bearing areas.Timolol efficiency assessment: The ulcer area of day 1 was reduced to minimum size on day 15 and day 30.Giving topical timolol for treating chronic non-healing ulcers is well understood.Kaur et al. demonstrated that timolol was useful in chronic diabetic foot ulcers. 6raun et al. and Vestita et al. showed the efficacy of timolol in treating chronic resistant wounds. 7Similarly, there are cases reported where chronic ulcers were successfully treated with topical timolol. 8n this study, we used timolol eye drops, commercially available as a 5 ml solution of 0.5% w/v timolol maleate.Oliver et al. said that the etiology in the case of diabetic ulcers are lack of blood sugar control, deformities, ill-fitting footwear, peripheral neuropathy, hypoperfusion, and dry skin. 9Vestita et al also demonstrated the advantage of using topical in managing chronic non-healing ulcers. 10Manhan et al. reported that they successfully treated chronic non-healing ulcers with topical timolol. 113][14] Larsen L et al also discovered a significant reduction in the size of ulcers after topical timolol administration. 15Dabiri G. et al also determined that there is improved cosmosis in surgical wounds with Timolol. 16 Mokadem SM et al. found significant improvement in the prognosis of acne with topical timolol application. 17Alcántara-Reifs CM et al also published an advantage of topical timolol in managing Kaposi sarcoma. 18Chiaverini C et al found a good response in chronic wounds of junctional epidermolysis bullosa with topical timolol. 19Yoon DJ et al expressed that topical timolol may be safe and effective in various dermatological conditions. 20Chen L et al. demonstrated topical timolol in infantile haemangioma and other skin conditions. 21Baltazard T et al evaluated and supported the safety and benefits of using timolol locally in chronic non-healing venous ulcers. 22Cahn BA et al. found that topical timolol is safe and effective in healing recalcitrant wounds of various etiologies. 23However, there is no need for any special training, and it could be done even in rural areas.There were no adverse drug reactions or drug interactions seen in our study.

CONCLUSION
Managing chronic non-healing ulcers is complicated.Each method of treatment had its drawbacks and limitations.In this study, topical application of timolol was effective in treating Chronic non-healing ulcers.Other studies also supported the findings.In India, with a large population residing in rural areas, timolol is available at cheaper rates.It also does not require any special expertise in its application, making it a good solution at the primary healthcare level.
Most of the patients are agricultural laborers and manual workers.

Table 1 . Age and Frequency
Table 1 and 2 shows a significant reduction in ulcer area.A decrease in ulcer area on day 15 and day 30 was noted.The effect of timolol on the 20-50 years age group and the age group is similar.The youngest was 20 years old, and the oldest was 85 years old.The mean age was 47. 64.60% of them were in 20-55 years of age.The male dominated by 60% while the female was 40%.