Priority of 5% Quince Seed Cream Versus 1% Phenytoin Cream in the Healing of Skin Ulcers: A Randomized Controlled Trial

authors:

avatar Mohamad Omidian 1 , avatar Ali Asghar Hemmati 2 , avatar Hamide Farajzade 1 , * , avatar Gholamreza Houshmand 2 , avatar Alireza Sattari 3 , avatar Maryam Kouchak 4

Department of Dermatology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
Department of Pharmacology and Toxicology, School of Pharmacy, Physiology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
Nanotechnology Research Center, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
Jundishapur Journal of Natural Pharmaceutical Products: Vol.10, issue 2; e24590
published online: May 20, 2015
article type: Research Article
received: October 14, 2014
revised: February 8, 2015
accepted: February 28, 2015
DOI: https://doi.org/10.17795/jjnpp-24590

how to cite: Omidian M, Hemmati A A, Farajzade H, Houshmand G, Sattari A, et al. Priority of 5% Quince Seed Cream Versus 1% Phenytoin Cream in the Healing of Skin Ulcers: A Randomized Controlled Trial. Jundishapur J Nat Pharm Prod. 2015;10(2):e24590. https://doi.org/10.17795/jjnpp-24590.

Abstract

Background:

Previous reports have shown that quince seed might have some healing effects on skin ulcers in rabbits.

Objectives:

To assess the potential healing effect of quince seed cream on human skin ulcers.

Patients and Methods:

The present study was a double-blind, randomized, controlled trial. Fifty patients with skin ulcer caused by disposable biopsy punch 5 mm were allocated in two groups (25 in each) to receive either 5% quince seed cream or 1% phenytoin cream. Skin ulcers were evaluated before and during the study (on the 3rd, 7th, and 14th days), based on the size of ulcers.

Results:

There was no significant difference in ulcer size between the two groups, before the treatment (P = 0.79). The ulcer size was diminished in the quince seed group, in comparison with the phenytoin group, on the 3rd, 7th, and 14th days after the treatment. After two weeks of treatment, complete healing was observed in 19 patients (86.4%) of quince seed group and five patients (21.7%) of phenytoin group that was significant (P < 0.001). The most common complication was burning and local hypersensitivity and both were more frequent in the phenytoin group.

Conclusions:

According to our findings, 5% quince seed cream, compared with 1% phenytoin cream, had several advantages, such as more rapid healing process of skin ulcers, and less complications.

1. Background

Cutaneous wound is indicated by an injury to the skin, following trauma or contusion (1). It has been evidenced that wound healing process consists of four phases: hemostasis, inflammation, proliferation, and remodeling (2). Accordingly, cytokines, such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and interleukin (IL)-1β stimulate re-epithelialization, angiogenesis, granulation tissue formation, fibroblasts proliferation, and collagen synthesis, in the skin wounds (3, 4). The faster recovery and less scarring still represent the most important goals in wound healing. Moreover, shortening of wound repair process is critical, because it reduces the risk of infections and complications, and also is considered cost beneficial (5).

There has been a rapid-growing utilization of herbal medication, which has attracted attention of researchers (6-10). Quince (Cydonia oblonga Miller, Rosaceae family) is known as an important fruit species, with high nutrient value and several advantageous for human health (11, 12). Quince seed mucilage is produced shortly after the exposure of seed coat to water (12). Quince seed mucilage has antioxidants, antibacterial and antifungal effects (13, 14). The investigators have documented that quince seed mucilage could lead to epithelial proliferation, release of VEGF and, subsequently, angiogenesis, deposition of connective tissue, and promotion of wound contraction (15, 16).

Phenytoin is a non-sedative anticonvulsant drug (17). Based on the observation of induced gingival hyperplasia by phenytoin, it might accelerate neovascularization, growth of connective tissue and, consequently, wound healing (18, 19). In addition, phenytoin stimulates fibroblast proliferation, granulation tissue formation, growth of hair follicles, tolerance of tissue elasticity, and inhibits of glucocorticoid production (17, 20, 21).

2. Objectives

According to literature review, there was no human study regarding the role of topical quince seed in wound restoration. Therefore, we decided to conduct a clinical trial to compare the efficacy and safety of topical quince seed with phenytoin, in skin wound healing.

3. Patients and Methods

3.1. Study Design

This double blind, randomized controlled trial was conducted at a dermatology clinic in Ahvaz city, southwest Iran, from September 2012 to November 2013.

3.2. Study Population

Fifty patients with skin ulcer, caused by punch biopsy, were enrolled into the study. They were allocated randomly in two groups (25 patients in each group). The patients were excluded from the study if there was a history of hypersensitivity to phenytoin, immune suppression (cancer, HIV), autoimmune disorders requiring immunosuppressive therapy, malignancy, and pregnancy. The ethical committee of Ahvaz Jundishapur University of Medical Sciences approved the study and all patients signed informed consent forms.

3.3. Intervention

We used a disposable biopsy punch of 5 mm for the patients who needed cutaneous biopsy to confirm their dermatological diseases. Treatment group received 5% quince seed cream. It was prepared in the department of pharmacology and toxicology at Ahvaz Jundishapur University of Medical Sciences, as described by Hemmati et al. (22). On the other hand, the control group received 1% phenytoin cream (Abidi pharmaceutical laboratory, Tehran, Iran). All patients were asked to apply the creams to their ulcers, twice per day. Both creams were identical in the appearance, color and texture, and, therefore, both patients and investigator were blinded to the treatment allocation throughout the study.

3.4. Outcome Measure

Demographic data and characteristics of the patients including age, sex, smoking, underlying diseases, and drug history were recorded using a questionnaire. Healing of ulcers was evaluated before and during the study (on the 3rd, 7th, and 14th days), with respect to the size of the ulcer. We used a calibrated transparent paper to record the exact surface area, then scanned for evaluation using computerized planimetry digital image processing software (Florida, USA) to calculate the exact size of ulcers (23). Our criteria for wound healing included reduction of wound surface area to less than 0.03 cm2, based on the aforementioned software. Also, adverse events of two medications were recorded.

3.5. Statistical Analyses

All data were computerized and then analyzed using SPSS 11.5 (SPSS Inc., Chicago, IL, USA). Analytic statistic tests including T test, Chi-square, Man-Whitney, and repeated measure ANOVA were used. A P < 0.05 was considered significant.

4. Results

There was no significant difference between the two groups in baseline demographic data and characteristic (P > 0.05; Table 1). Two patients from the phenytoin group and three from the quince seed group were dropped out the study, because of loss at follow-up. Finally, 23 patients in the phenytoin group and 22 in the other group completed the trial.

Table 1.

Demographic Data and Characteristics of the Treatment Groups a

VariablePhenytoin GroupQuince Seed GroupP Value
Age, y29.8 ± 7.327.9 ± 6.90.37
Gender
Male12 (52.2)10 (45.5)0.65
Female11 (47.8)12 (54.5)
Medication
None14 (60.9)11(50)0.95
Corticoids2 (8.7)3 (13.6)
Aspirin2 (8.7)2 (9.1)
NSAIDs b3 (13)4 (18.2)

a Data are presented as Mean ± SD or No. (%).

b Abbreviation: NSAIDs, non-steroidal anti-inflammatory drug.

There was no significant difference in the mean ulcer size between the phenytoin (0.5258 ± 0.06 cm2) and quince seed (0.5334 ± 0.09 cm2) groups, before the treatments (P = 0.79; Table 2).

Table 2.

The Mean of Ulcer Size Before and After the Treatments in Phenytoin and Quince Seed Groups

Ulcer Size, cmPhenytoin GroupQuince Seed GroupP Value
Before trial0.5258 ± 0.06040.5334 ± 0.09060.740
3rd day0.3069 ± 0.04180.1702 ± 0.10950.001
7th day0.1617 ± 0.17200.0436 ± 0.02920.003
14th day0.0336 ± 0.02660.0048 ± 0.00520.001

Repeated measure ANOVA analysis did not demonstrated any significant difference between healing processes with age, sex (P > 0.05). There was no complete healing after 3 days in both groups. On the 7th day of treatment, three patients (13.6%) in the quince seed group and no patient in the phenytoin group showed complete healing that was not significantly different according to Fisher exact test analysis (P = 0.11). At the end of the study (14th days), complete healing was observed in 19 (86.4%) and five (21.7%) patients in the quince seed and phenytoin groups, respectively. This result was statistically significant (P < 0.001; Figure 1).

Frequency of Wound Healing is Shown in the Two Treatment Groups
Frequency of Wound Healing is Shown in the Two Treatment Groups
Figure 1.

Frequency of Wound Healing is Shown in the Two Treatment Groups

The adverse events consisted of itching, pain, burning and local hypersensitivity and the most common complaint was burning. Complications were observed in 23.7% and 61% of patients in the quince seed and phenytoin groups, respectively, that showed significant difference (P = 0.03; Figure 2).

Frequency of Complications is Shown in the Two Treatment Groups
Frequency of Complications is Shown in the Two Treatment Groups
Figure 2.

Frequency of Complications is Shown in the Two Treatment Groups

5. Discussion

Quince seed is an herbal extract with potential healing effects on skin ulcers. To the best our knowledge, there was no clinical study assessing the potential healing effect of topical quince seed on skin ulcer.

When comparing the mean size of the ulcer healing obtained at the 3rd, 7th, and 14th days, there were considerable differences between the two treatments. Accordingly, quince seed group showed superiority in complete healing of skin ulcers. It seems quince seed cream might be more effective than phenytoin cream in the healing of skin ulcers. According to the present study, 60.9% of patients treated with 1% phenytoin cream showed complications, such as burning, itching, and local hypersensitivity, which were higher than in patients treated with quince seed cream (22.7%).

Hemmati and his colleagues studied the efficacy of quince seed 5, 10, and 15% on skin lesions induced by T-2 toxin, in rabbits. They reported that cream containing quince seed 15%, compared with the placebo, had the best therapeutic effect, leading to faster recovery of the lesions (22). Mucilage has no systemic absorption, and therefore is considered to be a safe healing agent, in comparison to other chemical healing medicines, which might have systemic bioavailability and side effects (22). In another in vivo animal study, Tamri et al. evaluated the role of 5%, 10%, and 20% quince seed creams on the full thickness wounds created in rabbits. The researchers showed the superiority of 10 and 20% quince seed creams, compared with eucerine, in wound contraction (24). The possible mechanisms of healing effect of quince seed are proposed, as followed: this herbal medication may play a preservative role by attaching to the surface proteins of wound and facilitating the wound healing (25). On the other hand, quince seed, as a physical barrier, can diminish water evaporation. It may also be a barrier against microorganisms invasion (13). Cydonia oblonga species (including quince seed cream) is an excellent natural source of phenolic acids and flavonoids, which are well known potent antioxidants (25, 26). The phenolic compound in quince has been reported to have free radical-scavenging activities (26, 27). Knowing the fact that antioxidant agents may facilitate wound healing (28, 29), quince seed may exhibit wound healing properties via the aforementioned mechanisms. Other possible theories that can explain the observed wound healing activities of quince seed include: activating the growth factors, induction of the collagen production, and stimulating more blood circulation (16). Therefore, more studies are needed to clarify the underlying mechanisms of the wound healing profile of quince seed.

Acknowledgements

References

  • 1.

    Jouki M, Mortazavi SA, Yazdi FT, Koocheki A. Optimization of extraction, antioxidant activity and functional properties of quince seed mucilage by RSM. Int J Biol Macromol. 2014;66:113-24. [PubMed ID: 24556115]. https://doi.org/10.1016/j.ijbiomac.2014.02.026.

  • 2.

    Pazyar N, Yaghoobi R, Rafiee E, Mehrabian A, Feily A. Skin wound healing and phytomedicine: a review. Skin Pharmacol Physiol. 2014;27(6):303-10. [PubMed ID: 24993834]. https://doi.org/10.1159/000357477.

  • 3.

    Shah JM, Omar E, Pai DR, Sood S. Cellular events and biomarkers of wound healing. Indian J Plast Surg. 2012;45(2):220-8. [PubMed ID: 23162220]. https://doi.org/10.4103/0970-0358.101282.

  • 4.

    Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 2004;9:283-9. [PubMed ID: 14766366].

  • 5.

    Nayak BS, Ramdath DD, Marshall JR, Isitor GN, Eversley M, Xue S, et al. Wound-healing activity of the skin of the common grape (Vitis Vinifera) variant, Cabernet Sauvignon. Phytother Res. 2010;24(8):1151-7. [PubMed ID: 20066659]. https://doi.org/10.1002/ptr.2999.

  • 6.

    Calapai G, Caputi AP. Herbal medicines: can we do without pharmacologist? Evid Based Complement Alternat Med. 2007;4(Suppl 1):41-3. [PubMed ID: 18227932]. https://doi.org/10.1093/ecam/nem095.

  • 7.

    Li GQ, Kam A, Wong KH, Zhou X, Omar EA, Alqahtani A, et al. Herbal medicines for the management of diabetes. Adv Exp Med Biol. 2012;771:396-413. [PubMed ID: 23393692].

  • 8.

    Nassiri-Asl M, Hosseinzadeh H. Review of the pharmacological effects of Vitis vinifera (Grape) and its bioactive compounds. Phytother Res. 2009;23(9):1197-204. [PubMed ID: 19140172]. https://doi.org/10.1002/ptr.2761.

  • 9.

    Shi J, Yu J, Pohorly JE, Kakuda Y. Polyphenolics in grape seeds-biochemistry and functionality. J Med Food. 2003;6(4):291-9. [PubMed ID: 14977436]. https://doi.org/10.1089/109662003772519831.

  • 10.

    Feringa HH, Laskey DA, Dickson JE, Coleman CI. The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. J Am Diet Assoc. 2011;111(8):1173-81. [PubMed ID: 21802563]. https://doi.org/10.1016/j.jada.2011.05.015.

  • 11.

    Silva BM, Andrade PB, Valentao P, Ferreres F, Seabra RM, Ferreira MA. Quince (Cydonia oblonga Miller) fruit (pulp, peel, and seed) and Jam: antioxidant activity. J Agric Food Chem. 2004;52(15):4705-12. [PubMed ID: 15264903]. https://doi.org/10.1021/jf040057v.

  • 12.

    Hamauzu Y, Yasui H, Inno T, Kume C, Omanyuda M. Phenolic profile, antioxidant property, and anti-influenza viral activity of Chinese quince (Pseudocydonia sinensis Schneid.), quince (Cydonia oblonga Mill.), and apple (Malus domestica Mill.) fruits. J Agric Food Chem. 2005;53(4):928-34. [PubMed ID: 15713000]. https://doi.org/10.1021/jf0494635.

  • 13.

    Srinivas Reddy B, Kiran Kumar Reddy R, Naidu VG, Madhusudhana K, Agwane SB, Ramakrishna S, et al. Evaluation of antimicrobial, antioxidant and wound-healing potentials of Holoptelea integrifolia. J Ethnopharmacol. 2008;115(2):249-56. [PubMed ID: 18037253]. https://doi.org/10.1016/j.jep.2007.09.031.

  • 14.

    Silva BM, Andrade PB, Ferreres F, Seabra RM, Oliveira MB, Ferreira MA. Composition of quince (Cydonia oblonga Miller) seeds: phenolics, organic acids and free amino acids. Nat Prod Res. 2005;19(3):275-81. [PubMed ID: 15702641]. https://doi.org/10.1080/14786410410001714678.

  • 15.

    Magalhaes AS, Silva BM, Pereira JA, Andrade PB, Valentao P, Carvalho M. Protective effect of quince (Cydonia oblonga Miller) fruit against oxidative hemolysis of human erythrocytes. Food Chem Toxicol. 2009;47(6):1372-7. [PubMed ID: 19306906]. https://doi.org/10.1016/j.fct.2009.03.017.

  • 16.

    Saito M, Hosoyama H, Ariga T, Kataoka S, Yamaji N. Antiulcer activity of grape seed extract and procyanidins. J Agric Food Chem. 1998;46(4):1460-4.

  • 17.

    Shaw J, Hughes CM, Lagan KM, Bell PM. The clinical effect of topical phenytoin on wound healing: a systematic review. Br J Dermatol. 2007;157(5):997-1004. [PubMed ID: 17854378]. https://doi.org/10.1111/j.1365-2133.2007.08160.x.

  • 18.

    Scheinfeld N. Phenytoin in cutaneous medicine: its uses, mechanisms and side effects. Dermatol Online J. 2003;9(3):6. [PubMed ID: 12952753].

  • 19.

    Baharvand M, Mortazavi A, Mortazavi H, Yaseri M. Re-evaluation of the first phenytoin paste healing effects on oral biopsy ulcers. Ann Med Health Sci Res. 2014;4(6):858-62. [PubMed ID: 25506476]. https://doi.org/10.4103/2141-9248.144877.

  • 20.

    Rhodes RS, Heyneman CA, Culbertson VL, Wilson SE, Phatak HM. Topical phenytoin treatment of stage II decubitus ulcers in the elderly. Ann Pharmacother. 2001;35(6):675-81. [PubMed ID: 11408983].

  • 21.

    Oluwatosin OM, Olabanji JK, Oluwatosin OA, Tijani LA, Onyechi HU. A comparison of topical honey and phenytoin in the treatment of chronic leg ulcers. Afr J Med Med Sci. 2000;29(1):31-4. [PubMed ID: 11379464].

  • 22.

    Hemmati AA, Kalantari H, Jalali A, Rezai S, Zadeh HH. Healing effect of quince seed mucilage on T-2 toxin-induced dermal toxicity in rabbit. Exp Toxicol Pathol. 2012;64(3):181-6. [PubMed ID: 20832267]. https://doi.org/10.1016/j.etp.2010.08.004.

  • 23.

    Mayrovitz HN, Soontupe LB. Wound areas by computerized planimetry of digital images: accuracy and reliability. Adv Skin Wound Care. 2009;22(5):222-9. [PubMed ID: 19521289]. https://doi.org/10.1097/01.ASW.0000350839.19477.ce.

  • 24.

    Tamri P, Hemmati A, Boroujerdnia MG. Wound healing properties of quince seed mucilage: in vivo evaluation in rabbit full-thickness wound model. Int J Surg. 2014;12(8):843-7. [PubMed ID: 25017948]. https://doi.org/10.1016/j.ijsu.2014.06.016.

  • 25.

    Hemmati AA, Arzi A, Amin M. Effect of Achillea millefolium extract in wound healing of rabbit. J Nat Remed. 2002;2(2):164-7.

  • 26.

    Hamauzu Y, Inno T, Kume C, Irie M, Hiramatsu K. Antioxidant and antiulcerative properties of phenolics from Chinese quince, quince, and apple fruits. J Agric Food Chem. 2006;54(3):765-72. [PubMed ID: 16448180]. https://doi.org/10.1021/jf052236y.

  • 27.

    Patel NC, Rathod BG, Shah VN, Mahajan AN. Cydonia vulgaris Pers.: A review on diversity, cultivation, chemistry and utilization. Pharmacia Lett. 2011;3(3):51-61.

  • 28.

    Riahy S, Imany H, Torkaman G, Mofid M, Goshoony H, Khoshbaten A. Effect of topical application of honey on skin wound healing with full thickness in male rats. Trauma Mon. 2008;2008(3):169-78.

  • 29.

    Hemmati AA, Forushani HM, Asgari HM. Wound healing potential of topical amlodipine in full thickness wound of rabbit. Jundishapur J Nat Pharm Prod. 2014;9(3).