Wound Healing Effect of a Topical Product from Ajuga chamaecistus ssp. tomentella in Pressure Ulcer: a Randomized Double-Blind Placebo-Controlled Clinical Trial

Document Type : Original paper


1 Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran.

2 Department of Anesthesia and Intensive Care Medicine, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

3 Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

4 Department of Traditional Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran.

5 Department of Pharmacognosy, School of Pharmacy, Alborz University of Medical Sciences, Karaj, Iran.



Background and objectives: Ajuga genus is used as wound healing in traditional Persian medicine. This study aimed to evaluate the effectiveness of Ajuga chamaecistus ssp. tomentella ointment on healing pressure ulcers in patients admitted to the intensive care unit. Methods: In this randomized, double-blind, placebo-controlled clinical trial, 131 patients with grade 1 or 2 pressure ulcers were randomly assigned into one of two groups through simple randomization. The study group received 3% Ajuga ointment, containing 17.26 µg/mL of 20-hydroxyecdysone (ecdysterone) as the main compound, while the control group received placebo twice a day for 14 days in addition to the standard care for pressure ulcers Changes in the degree and size of wounds were considered as the primary outcomes of the study based on the 2-digit Stirling scale. Results: Forty patients in each group completed the research. Mean (95% confidence interval) difference values, for wound degree, between two groups on day 7 vs. day 0 was -0.88 (-1.01 to -0.76, p<0.001), and on day 14 vs. day 0 was -1.57 (-1.78 to -1.36, p<0.001). Mean (95% confidence interval) difference values, for wound area, between two groups on day 7 vs. day 0 was -1.730(-1.979 to -1.48, p<0.001), and on day 14 vs. day 0 was -3.142(-3.563 to -2.72, p<0.001).Conclusion: Topical application of Ajuga ointment significantly improved pressure ulcers  on days 7 and 14 compared to placebo. Evaluation of the effects of this plant on a larger sample size, for a longer period of time and in different medical centers is recommended.


Main Subjects

  • Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U. Skin wound healing: an update on the current knowledge and concepts. Eur Surg Res. 2017; 58(1-2): 81-94.
  • Hunter IA, Edwards KJ. Managing pressure sores. Surgery. 2017; 35(9): 505-510.
  • Lechner A, Kottner J, Coleman S, Muir D, Beeckman D, Chaboyer W, Cuddigan J, Moore Z, Rutherford C, Schmitt J, Nixon J, Balzer K. Outcomes for pressure ulcer trials (outputs) project: review and classification of outcomes reported in pressure ulcer prevention research. Br J Dermatol. 2021; 184(4): 617-626.
  • Yücel A, Kan Y, Yesilada E, Akın O. Effect of St. John's wort (Hypericum perforatum) oily extract for the care and treatment of pressure sores; a case report. J Ethnopharmacol. 2017; 196: 236-241.
  • Lyder CH, Ayello EA. Pressure ULCERS: a patient safety issue. In: Hughes RG, editor. Patient safety and quality: an evidence-based handbook for Rockville: Agency for Healthcare Research and Quality, 2008.
  • Westby MJ, Dumville JC, Soares MO, Stubbs N, Norman G. Dressings and topical agents for treating pressure ulcers. Cochrane Database Syst Rev. 2017; 6(6): 1-170.
  • Farzaei H, Abbasabadi Z, Abdollahi M, Rahimi R. A comprehensive review of plants and their active constituents with wound healing activity in traditional Iranian medicine. Wounds. 2014; 26(7): 197-206.
  • Hosseinkhani A, Falahatzadeh M, Raoofi E, Zarshenas MM. An evidence-based review on wound healing herbal remedies from reports of traditional Persian medicine. J Evid Based Complement Altern Med. 2017; 22(2): 334-343.
  • Aghili MH. Makhzan-al-Advieh. Tehran: Tehran University of Medical Sciences Publications, 2009.
  • Sadati N, Jenett-Siems K, Siems K, Ardekania MRS, Hadjiakhoondi A, Akbarzadeh T, Ostad SN, Khanavi M. Major constituents and cytotoxic effects of Ajuga chamaecistus tomentella. Z Naturforsch C J Biosci. 2012; 67(5-6): 275-281.
  • Khanavi M, Najafi B, Sadati SN, Abai MR, Vatandoost H. Chemical constitute and larvicidal activity of fractions of Ajuga chamaecistus tomentella plant against malaria vector Anopheles stephensi. J Arthropod Borne Dis. 2017; 11(1): 116-123.
  • Rahiminiya A, Ghadim HH, Lamardi SNS, Ebrahimabadi MH, Fazljou SM, Ayati MH. Medicinal importance of Ajuga species in Iran: ethnobotanical and traditional applications, phytochemical, and pharmacological studies. Jundishapur J Nat Pharm Prod. 2022; 17(3): 1-13.
  • El-Hilaly J, Lyoussi B, Wibo M, Morel N. Vasorelaxant effect of the aqueous extract of Ajuga iva in rat aorta. J Ethnopharmacol. 2004; 93(1): 69-74.
  • Chenni A, Yahia DA, Boukortt F, Prost J, Lacaille-Dubois M, Bouchenak M. Effect of aqueous extract of Ajuga iva supplementation on plasma lipid profile and tissue antioxidant status in rats fed a high-cholesterol diet. J Ethnopharmacol. 2007; 109(2): 207-213.
  • Taleb-Senouci D, Ghomari H, Krouf D, Bouderbala S, Prost J, Lacaille-Dubois MA, Bouchenak M. Antioxidant effect of Ajuga iva aqueous extract in streptozotocin-induced diabetic rats. Phytomedicine. 2009; 16(6-7): 623-631.
  • Rubnawaz S, Okla MK, Akhtar N, Khan IU, Bhatti MZ, Duong HQ, El-Tayeb MA, Elbadawi YB, Almaary KS, Moussa IM, Abbas ZK, Mirza B. Antibacterial, antihemolytic, cytotoxic, anticancer, and antileishmanial effects of Ajuga bracteosa transgenic plants. Plants. 2021; 10(9): 1-18.
  • Gautam R, Jachak SM, Saklani Anti-inflammatory effect of Ajuga bracteosa Wall Ex Benth. mediated through cyclooxygenase (COX) inhibition. J Ethnopharmacol. 2011; 133(2): 928-930.
  • Khanavi M, Davoodipoor AM, Sadati SN, Ardekani MRS, Sharifzadeh M. Antinociceptive effect of some extracts from Ajuga chamaecistus ssp. tomentella (Boiss.) Rech. f. aerial parts. Daru J Pharm Sci. 2014; 22(1): 1-6.
  • Ramazanov NS. Phytoecdysteroids and other biologically active compounds from plants of the genus Ajuga. Chem Nat Compd. 2005; 41(4): 361-369.
  • Abdukadirov I, Yakubova M, Nuriddinov KR, Mamatkhanov A, Turakhozhaev M. Ecdysterone and turkesterone in Ajuga turkestanica determined by HPLC. Chem Nat Compd. 2005; 4(41): 475-476.
  • Sadati SN, Jahantab S, Ziyarati P, Khanavi M, Shams-Ardekani MR. Quantification of 20-hydroxyecdysone, a major phytoecdysteroid, in Ajuga chamaecistus tomentella using high performance liquid chromatography. Trad Integr Med. 2016; 1(3): 96-100.
  • World Health Organization (WHO). Supplementary information, S.3.7 Microbiological quality of non-sterile products: recommended acceptance criteria for pharmaceutical preparations: Final test for revision of the international pharmacopoeia. [Accessed 2020]. Available from: https://www.who.int/medicines/publications/ pharmacopoeia/2012-04- 3MicrobialPurity_QAS11-41_FINAL.pdf.
  • Farsaei S, Khalili H, Farboud Potential role of statins on wound healing: review of the literature. Int Wound J. 2012; 9(3): 238-247.
  • Reddy M, Gill SS, Kalkar SR, Wu W, Anderson PJ, Rochon PA. Treatment of pressure ulcers: a systematic review. Jama. 2008; 300(22): 2647-2662.
  • Long C, Finlay A. The fingertip unit-a new practical measure. Clin Exp Dermatol. 1991; 16(6): 444-447.
  • Bhattacharya S, Mishra Pressure ulcers: current understanding and newer modalities of treatment. Indian J Plast Surg. 2015; 48(1): 4-16.
  • Reid J, Morison Towards a consensus: classification of pressure sores. J Wound Care. 1994; 3(3): 157-160.
  • Kottner J, Raeder K, Halfens R, Dassen T. A systematic review of interrater reliability of pressure ulcer classification systems. J Clin Nurs. 2009; 18(3): 315-336.
  • Thomas DR. Prevention and treatment of pressure ulcers: what works? What doesn't? Cleve Clin J Med. 2001; 68(8): 704-707.
  • Pedley GE. Comparison of pressure ulcer grading scales: a study of clinical utility and inter-rater reliability. Int J Nurs Stud. 2004; 41(2): 129-140.
  • Lee MA, Choi KK, Yu B, Park JJ, Park Y, Gwak J, Lee J, Jeon YB, Ma DS, Lee GJ. Acute physiology and chronic health evaluation II score and sequential organ failure assessment score as predictors for severe trauma patients in the intensive care unit. Korean J Crit Care Med. 2017; 32(4): 340-346.
  • Kashefi P, Saghaei M, Dehghani-Meibodi D. Comparison of sequential organ failure assessment and acute physiology and chronic health evaluation II scoring systems on detection prognosis of mortality in patients with trauma admitted to the intensive care unit. J Isfahan Med Sch. 1397; 36(478): 460-465.
  • Rahiminiya A, Ayati MH, Shirbeigi L, Salehi SH, Bagher Fazljou SM, Sadati Lamardi SN. Evaluating the healing effects of Ajuga chamaecistus tomentella, on second grade burn wounds, a double-blind randomized controlled clinical trial. Res J Pharmacogn. 2022; 9(2): 9-17.
  • Ghiasian M, Niroomandi Z, Dastan D, Poorolajal J, Zare F, Ataei S. Clinical and phytochemical studies of Plantago major in pressure ulcer treatment: a randomized controlled trial. Complement Ther Clin Pract. 2021; Article ID 101325.
  • Parizi FK, Sadeghi T, Heidari S. The effect of rosemary ointment on the pressure ulcer healing in patients admitted to the intensive care unit: a randomized clinical trial. Nurs Pract Today. 2021; 9(1): 15-23.
  • Dinan L. The Karlson lecture. phytoecdysteroids: what use are they? Arch Insect Biochem Physiol. 2009; 72(3): 126-141.
  • Majidi Z, Alipour C, Farajzadeh S, Gohari A, Shafaroodi H, Vazirian M, Ostad SN. Antioxidant potential, hypoglycemic effect and safety of Ajuga chamaecistus ssp. tomentella (Boiss.) Rech. f. aerial parts. Res J Pharmacogn. 2018; 5(4): 53-63.
  • Israili ZH, Lyoussi B. Ethnopharmacology of the plants of genus Ajuga. Pak J Pharm Sci. 2009; 22(4): 425-462.
  • Khalil EA, Afifi FU, Al-Hussaini Evaluation of the wound healing effect of some Jordanian traditional medicinal plants formulated in Pluronic F127 using mice (Mus musculus). J Ethnopharmacol. 2007; 109(1): 104-112.
  • Korkina LG, Mikhal’Chik E, Suprun M, Pastore S, Dal Toso R. Molecular mechanisms underlying wound healing and anti-inflammatory properties of naturally occurring biotechnologically produced phenylpropanoid glycosides. Cell Mol Biol. 2007; 53(5): 84-91.
  • Stojadinovic O, Lebrun E, Pastar I, Kirsner R, Davis SC, Tomic-Canic M. Statins as potential therapeutic agents for healing disorders. Expert Rev Dermatol. 2010; 5(6): 689-698.
  • Shaw J, Hughes C, Lagan K, Bell P. The clinical effect of topical phenytoin on wound healing: a systematic review. Br J Dermatol. 2007; 157(5): 997-1004.
  • Hrynyk M, Neufeld RJ. Insulin and wound healing. Burns. 2014; 40(8): 1433–1446.
  • Oryan A, Alemzadeh E. Effects of insulin on wound healing: a review of animal and human evidences. Life Sci. 2017; 174: 59-67.
  • Tsai ML, Huang HP, Hsu JD, Lai YR, Hsiao YP, Lu FJ, Chang HR. Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC/Stat3 pathway. Int J Mol Sci. 2014; 15(5): 7563-7578.
  • Lipsky BA, Hoey Topical antimicrobial therapy for treating chronic wounds. Clin Infect Dis. 2009; 49(10): 1541-1549.
  • Tarvady S, Anguli V, Pichappa Effect of heparin on wound healing. J Biosci. 1987; 12(1): 33-40.