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Indian Journal of Pharmacology, Vol. 40, No. 4, July-August, 2008, pp. 170-174 Research Article The effects of topical (gel) astemizole and terfenadine on wound healing Srikanth D, Shenoy Rekha R, Rao C Mallikarjuna Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka Date of Submission: 23-May-2006 Code Number: ph08052 Abstract Objective: To develop topical gel preparations of astemizole and terfenadine and to investigate the actions of the gels on the healing of incision and excision wounds in male albino rats.Materials and Methods: Gels containing 1% astemizole, with varying concentrations of carbopol 934 (polymer), were prepared. Similarly, 1% terfenadine gels were made. The formulations were evaluated for release rate and stability. Incision and excision wounds were inflicted on male albino rats under ketamine anesthesia, taking aseptic precautions. The animals were divided into two groups. They were given a topical application of either astemizole or terfenadine gel, at a dose of 100 mg per wound, once daily, for 10 days in the case of incision wounds and till the time of complete closure in the case of excision wounds. On the 11 th day, breaking strength of the incision wound was measured. In the excision wound model, wound closure rate, epithelization time, scar features and hydroxyproline content of scar tissue were studied from the day of wounding till the day of the scab falling off, with no residual raw area. Results: Gels prepared using 0.8% carbopol 934 and 1% of drug in gel base were found to be stable. The gels of astemizole and terfenadine significantly (P < 0.05) promoted the phases of healing such as collagenation (in incision wounds), wound contraction and epithelization (in excision wounds). Conclusion: The gels of astemizole and terfenadine might play an important role in wound management program. Keywords: Astemizole, breaking-strength, epithelization, terfenadine, wound healing Introduction Wound healing is a complex and complicated process. It runs through a number of phases, which either run concurrently or are intimately interlinked through some chemical, biochemical and cellular pathways. A treatment could influence the healing of wound by intervening in any one or many phases of healing. No treatment, either systemic or local, could be considered inert on healing process, [1] unless it is proved experimentally. Histamine is one of the mediators of acute inflammation. The exact contribution of histamine to repair the process of a wound is difficult to ascertain. However, histamine causes itching in the healing wound and the healed wound (scar). If itching is not contained in the healing wound, it may hamper the healing process or may cause damage to the scar. Doxepin, an antidepressant having anti-histaminic activity, upon topical use, has been shown to reduce the itching in burn wound and scars.[2] However, its influence on healing has not been studied. Thus, it is interesting to study the influence of topical antihistaminics on healing. Astemizole and terfenadine were among the first nonsedating antihistaminic drugs to be introduced for therapeutic use. Subsequently their cardiac toxicity, e.g. ventricular fibrillation and torsades de pointes was discovered when they were given systemically, in high doses and in combination with CYP3A4 inhibitors. The occurrence of many such cases of cardiac toxicity led to a drastic reduction in their use. No attempt has so far been made to discover their topical utility, particularly in wound healing. Thus, the present work was aimed at studying a new use of these drugs in a new dosage form. The study was, therefore, conducted on the healing of incision and excision wounds, using the gel preparations of terfenadine and astemizole. Materials and Methods Preparation of gels [3] Astemizole gel Stability studies Content uniformity In vitro release studies through excised rat skin [4] Wound healing studies Wound models Excision wound: Excision wounds were made as described by Morton and Malone, [7] by excising the full thickness circular skin (approximately 500 mm 2 ) from the nape of neck, under ketamine anesthesia. Wound contraction was assessed by tracing the wound area on polythene paper first and subsequently on a mm sq paper, every alternate day. The wound closure rate was expressed as percentage of the original wound size of 500 mm 2 on selected days. On day 15, an animal from each of the treated groups was sacrificed and the wound was excised and fixed in neutral buffered 10% formalin. Later, paraffin sections of 5 micron were made and stained with H & E stain for histopathological evaluation. The number of days required for the scab to fall off without leaving a raw wound behind was considered the period of epithelization. Healed scar on the day of epithelization was excised and used for determination of hydroxyproline content. [8] The experimental protocols were approved by the Institutional Animal Ethics Committee of MAHE, Manipal. Statistical analysis Results Content uniformity Physical stability In vitro release studies of astemizole and terfenadine through rat skin The release of the drugs from the formulations was progressive and steady. At the seventh hour, the rates of release of astemizole and terfenadine from their gel formulations were 71.30% and 67.85% respectively [Table - 2]. Wound Healing Studies Incision wounds Excision wound On day 15, in the control group, a small portion (less than 9%) of the original wound remained to be covered by the epidermis. Thus, these animals took a period of 18 days for complete epithelization. The gel base did not alter this. On the other hand, the gels of astemizole and terfenadine significantly ( P < 0.05) promoted the epithelization process, thus shortening the period by two days [Table - 4]. The collagen content in the healed scar of the control and the base applied wounds was around 45 mg/g of the tissue. The application of the gels of astemizole and terfenadine caused a significant ( P < 0.05) increase in collagen content of the scar tissues [Table - 4]. Histopathological evaluation The histological features of the sections of astemizole and terfenadine treated wounds confirm the pro-healing actions of these two gels. Discussion Wound is a disruption in the continuity of the living tissues. Restoration of the continuity in a damaged area is brought upon by a house keeping mechanism of the body, viz. the repair process. Tissue repair involves regeneration or replacement or, at times both, leading to the healing of a wound. Itching is one of the problems that the patient faces in the healing of a dermal wound. Histamine causes itching. It needs to be contained or it may hamper the healing process or may cause damage to the scar. Doxepin, an antidepressant having antihistaminic activity upon topical use, has been shown to reduce the itching in burn wounds and scars. [2] However, its influence on healing has not been studied. No treatment either systemic or local (including ointment bases, dressing and suture materials etc.) could be considered inert on the healing process. [1] In the light of above, the present study was undertaken to see if topical application of antihistaminic drugs could influence healing. Accordingly, gels of astemizole and terfenadine were prepared and tested for their influence on collagenation, wound contraction and epithelization phases of wound healing, upon topical application to incision and excision wounds. The gels of both astemizole and terfenadine promoted healing in both wound models by influencing collagenation, wound contraction and epithelization phases. While the phase of collagenation gives the required strength to the scars of wounds healed by primary and secondary intentions, wound contraction reduces the gap of the open wound to be filled by extracellular matrix (rich in collagen) and finally covered by epithelium. Two principal components of collagenation phase are collagen synthesis and maturation. Based on the results of the study, it could be assumed that terfenadine and astemizole might have enhanced the strength of the scar by increasing the collagen levels, which could stitch the wound edges together at the repaired site. However, a number of phases of healing, especially coagulation, inflammation, macrophagia, fibroplasia collagenation, wound contraction and epithelization etc. are intimately interlinked. Therefore, a treatment could influence the healing of a wound by intervening in any one or many phases of healing. Thus, based on the present design, it is very difficult to comment on the exact locations and mechanisms of the pro-healing actions of the topical applications. It is quite possible that the drugs could have had a direct influence on the healing, not withstanding their antihistaminic property. For instance, the base of the gel, while it was inert on the collagenation and epithelization phases, promoted contraction during the first ten days. These kinds of differential effects of bases and drug treatments are known to occur. [9] In conclusion, the study reported a new use for drugs such as terfenadine and astemizole. These drugs produce systemic cardiac toxicity following administration in conventional doses. The gels of these drugs could be free from these effects, as the drug concentration reaching systemic circulation from the topical 1% gel applications would be negligible. These gels may, therefore, have the potential to become useful alternatives to systemic antihistaminics, to reduce healing associated itch and to promote healing of wounds in wound care programs. Acknowledgment The authors wish to thank Messers Torrent Pharma, Ahmedabad and Shilpa Organics Pvt Ltd Raichur for the generous gift of terfenadine and astemizole.References
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