EFFICACY AND SAFETY OF CENTELLA ASIATICA 453 whether rashes were local or systemic. The C. asiatica versus tretinion trial (20) reported many AEs, but it is not clear whether multiple AEs coincided in the same participant at the same time and what constituted an AE (whether one AE continued through more than one 4-w period). Withdrawal criteria were unclear. Participant satisfaction questionnaires were not quantitated. Details about C. asiatica and P. M. extracts (plant source, processing meth- ods, and how standardized), and, most importantly, the absence of ingredient reporting compromise study replication. These results are clinically non-translatable and not general- izable to C. asiatica. Nevertheless, other dermatological studies provide some clues about which active ingredients might be effective (12). Our review also had some l imitations. Of all studies discovered, only three were placebo- controlled RCTs testing a single ingredient. Two studies were found in Thai national archives, but databases and obscure repositories may exist elsewhere. The anti-wrinkle study cohorts were predominantly younger premenopausal women where the well-estab- lished role of estrogens contributes to cutaneous structure, function, immunity, and tis- sue repair. Thus, wrinkly, thin-skinned older women may respond differently exemplifi ed by long-term use of tretinoin that remarkably improves skin structure (26). All the stud- ies were short (8–12 w) and effects more noticeable at the longer times. Longer tretinoin exposures ( 6 mo) show greater effect sizes (27) which may also apply to C. asiatica. Future cosmetic studies shou ld fully comply with CONsolidated Standards of Reporting Trials 2010 and its extension herbal medicinal interventions. Reporting must provide chromatographs quantitating the intervention contents, a complete participant fl ow- chart, full clinical oversight, full compliance with the latest Declaration of Helsinki, ad- equate powering (minimum 20 per group), provide participants with a diary to note AEs, and verify adherence to the intervention, and placing the raw data in the public domain as required by many journals. CONCLUSION The topical app lication of C. asiatica extracts or of one of its components, asiaticoside, can improve several cosmetic outcomes, especially facial wrinkles. It may be an option for reducing periocular wrinkles and may avoid some AEs of tretinoin. Because the C. asiat- ica extract was not standardized, longer term studies are needed to rectify the defi ciencies in the discovered studies and to establish acceptable long-term and generizable effective- ness and safety. REFERENCES (1) B. P. Pimp l e and S. L . Badole, “Polyphenols: a remedy for skin wrinkles,” in Polyphenols in Human Health and Disease, R. R. Watson, V. R. Preedy, and S. Zibadi. Eds. (Academic Press, San Diego, CA, 2014), pp. 861–869. (2) R. R. Riahi, A. E. Bu s h, and P. R. Cohen, Topical retinoids: therapeutic mechanisms in the treatment of photodamaged skin, Am. J. Clin. Dermatol., 17, 265–276 (2016). (3) K. J. Gohil, J. A. Pa t el, and A. K. Gajjar, Pharmacological review on Centella asiatica: a potential herbal cure-all, Indian J. Pharm. Sci., 72, 546–556 (2010). (4) M. A. Abdulla, F. H. A l-Bayaty, M. I. Abu Hassan, and L. T. Younis, Anti-ulcer activity of Centella asiatica leaf extract against ethanol-induced gastric mucosal injury in rats, J. Med. Plants Res., 4, 1253– 1259 (2010). (5) K. Zahara, Clinical a n d therapeutic benefi ts of Centella asiatica, Pure Appl. Biol., 3, 152–159 (2014).

JOURNAL OF COSMETIC SCIENCE 454 (6) G. Visweswari, K. S. Prasad, P. S. Chetan, V. Lokanatha, and W. Rajendra, Evaluation of the anticonvul- sant effect of Centella asiatica (gotu kola) in pentylenetetrazol-induced seizures with respect to choliner- gic neurotransmission, Epilepsy Behav., 17, 332–335 (2010). (7) M. H. Veerendra Kumar and Y. K. Gupta, Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer’s disease in rats, Clin. Exp. Pharmacol. Physiol., 30, 336–342 (2003). (8) M. S. Ahshawat, S. Saraf, and S. Saraf, Preparation and characterization of herbal creams for improve- ment of skin viscoelastic properties, Int. J. Cosmet. Sci., 30, 183–193 (2008). (9) L. Martelli, E. Berardesca, and M. Martelli, Topical formulation of a new plant extract complex with refi rming properties. Clinical and non-invasive evaluation in a double-blind trial, Int. J. Cosmet. Sci., 22, 201–206 (2000). (10) J. A. Garcia Hernandez, D. Madera Gonzalez, M. Padilla Castillo, and T. Figueras Falcon, Use of a spe- cifi c anti-stretch mark cream for preventing or reducing the severity of striae gravidarum. Randomized, double-blind, controlled trial, Int. J. Cosmet. Sci., 35, 233–237 (2013). (11) M. Haftek, S. Mac-Mary, M. A. Le Bitoux, P. Creidi, S. Seite, A. Rougier, and P. Humbert, Clinical, biometric and structural evaluation of the long-term effects of a topical treatment with ascorbic acid and madecassoside in photoaged human skin, Exp. Dermatol., 17, 946–952 (2008). (12) W. Bylka, P. Znajdek-Awizen, E. Studzinska-Sroka, A. Danczak-Pazdrowska, and M. Brzezinska, Cen- tella asiatica in dermatology: an overview, Phytother. Res., 28, 1117–1124 (2014). (13) J. James and I. Dubery, Identifi cation and quantifi cation of triterpenoid centelloids in Centella asiatica (L.) Urban by densitometric TLC, J. Planar Chromatogr., 24, 82–87 (2011). (14) J. Lv, A. Sharma, T. Zhang, Y. Wu, and X. Ding, Pharmacological review on asiatic acid and its deriva- tives: a potential compound, SLAS Technol., 23, 111–127 (2018). (15) J. A. C. Sterne, J. Savović, M. J. Page, R. G. Elbers, N. S. Blencowe, I. Boutron, C. J. Cates, H.-Y. Cheng, M. S. Corbett, S. M. Eldridge, J. R. Emberson, M. A. Hernán, S. Hopewell, A. Hróbjartsson, D. R. Junqueira, P. Jüni, J. J. Kirkham, T. Lasserson, T. Li, A. McAleenan, B. C. Reeves, S. Shepperd, I. Shrier, L. A. Stewart, K. Tilling, I. R. White, P. F. Whiting, and J. P. T. Higgins, RoB 2: a revised tool for assessing risk of bias in randomised trials, BMJ, 366, l4898 (2019). (16) R. DerSimonian a n d N. Laird, Meta-analysis in clinical trials, Control Clin. Trials, 7, 177–188 (1986). (17) J. P. Higgins, S . G. Thompson, J. J. Deeks, and D. G. Altman, Measuring inconsistency in meta-analyses, BMJ, 327, 557–560 (2003). (18) J. Lee, E. Jung, H. Lee, Y. Seo, J. Koh, and D. Park, Evaluation of the effects of a preparation containing asiaticoside on periocular wrinkles of human volunteers, Int. J. Cosmet. Sci., 30, 167–173 (2008). (19) J. S. Ryu, S. G. Park, T. J. Kwak, M. Y. Chang, M. E. Park, K. H. Choi, K.-H. Sung, H.-J. Shin, C.-K. Lee, Y.-S. Kang, M.-S. Yoon, M.-J. Rang, and S.-J. Kim, Improving lip wrinkles: lipstick-related image analysis, Skin Res. Technol., 11, 157–164 (2005). (20) P. Tangsumroengw o ng, A randomized split-face double-blind control trial of the effi cacy of 5% Centella asiatica gel versus 0.02% tretinoin gel on the treatment of periorbital wrinkle in Thai woman, Master of Science thesis, Mae Fah Luang University, Thailand. (2013). (21) C. Tongsrikeaw, A randomized split-face double-blind control trial of the effi cacy of 5% Centella asiatica gel versus 5% Puerarua gel for the treatment of periorbital wrinkle, Master of Science thesis, Mae Fah Luang University, Thailand. (2016). (22) J. Zhang, W. Hou , S. Feng, X. Chen, and H. Wang, Classifi cation of facial wrinkles among Chinese women, J. Biomed. Res., 31, 108–115 (2017). (23) K. Tsukahara, K. Sugata, O. Osanai, A. Ohuchi, Y. Miyauchi, M. Takizawa, and M. Hotta, T. Kitahara, Comparison of age-related changes in facial wrinkles and sagging in the skin of Japanese, Chinese and Thai women, J. Dermatol. Sci., 47, 19–28 (2007). (24) M. F. Nagoor Mee r an, S. N. Goyal, K. Suchal, C. Sharma, C. R. Patil, and S. K. Ojha, Pharmacological properties, molecular mechanisms, and pharmaceutical development of asiatic acid: a pentacyclic triter- penoid of therapeutic promise, Front. Pharmacol., 9, 892 (2018). (25) J. Lee, E. Jung, Y. Kim, J. Park, J. Park, S. Hong, J. Kim, C. Hyun, Y. Shik Kim, D. Park, Asiaticoside induces human collagen I synthesis through TGFbeta receptor I kinase (TbetaRI kinase)-independent Smad signaling, Planta Med., 72, 324–328 (2006). (26) Y. Shao, T. He, G . J. Fisher, J. J. Voorhees, and T. Quan, Molecular basis of retinol anti-ageing proper- ties in naturally aged human skin in vivo, Int. J. Cosmet. Sci., 39, 56–65 (2017). (27) S. Mukherjee, A. Date, V. Patravale, H. C. Korting, A. Roeder, and G. Weindl, Retinoids in the treat- ment of skin aging: an overview of clinical effi cacy and safety. Clin. Interv. Aging, 1, 327–348 (2006).