# Skin Depigmenting Agents in Anti-Aging Cosmetics: A Medicinal Perspective on Emerging Ingredients
## 3 Results and Discussion
### Medicinal Chemistry Perspective of New Skin Depignetting Ingredients in Anti-Aging Products
#### 3.2.1. Tranexamic Acid  
Tranexamic acid, _trans_-4-(aminomethyl)cyclohexane carboxylic acid, a synthetic derivative of the amino acid lysine, was developed initially as a plasmin inhibitor for the treatment of heavy bleeding resulting from trauma, surgery, and menstruation [14; 15]. Recently, tranexamic acid emerged as a new standard therapy for the treatment of melasma, a common skin condition in which brown or greyish patches of pigmentation develop [8; 16; 17; 18]. A combination of the demonstrated efficacy coupled with the fact that the use of this agent is rarely associated with secondary effects, contrary to hydroquinone, rendered tranexamic acid as a new gold standard in depigmenting agents [17]. This agent inhibits melanin synthesis in melanocytes by interfering with the interaction of melanocytes and keratinocytes through inhibition of the plasminogen/plasmin system, thereby decreasing free arachidonic acid and the production of prostaglandamins, which are known stimulators of tyrosinase activity [8; 14; 16; 17]. Tranexamic acid has been widely incorporated into cosmetic  
Figure 3: Structures of tranexamic acid, (S)-bakuchiol, and 4-butylresorcinol. Figure 2: Top 12 skin depigmenting ingredients included in the composition of anti-aging products marketed in 2011 and 2018.  
formulations to be used as a skin depigmenting agent in lotions, creams, milky lotions, facial packs, and scalp care cosme [19]. Although studies reported that the topical application of tranexamic acid (2 and 3%) alone was effective in treating melasma [20,21], until recently, a comparison of the effectiveness of these concentrations relative to hydroquinone towards the treatment of other hyperpigmentation disorders, such as senile hyperpigmentation, was missing [17]. Recent studies developed to assess the effectiveness of tranexamic acid as a depigmenting agent proved that it was able to reduce melanin production [8,16,17]. To compare the effectiveness of a tranexamic acid combination serum (with galactomyces ferment filtrate, alpha arbutin, and niacinamide) against hydroquinone as a depigmenting serum in a healthy population, [PERSON] et al. [17] performed a three-arm randomized controlled trial. The skin brightness and pigmentation intensity were evaluated each week for 4 weeks and all groups showed a significant improvement in skin brightness and pigmentation intensity [17], with no significant differences between the treatment groups and hydroquinone; this proved that the tranexamic acid serum (2 and 3%, combined with 4% galactomyces ferment filtrate, niacinamide, and alpha-arbutin) is an effective depigmenting agent [17]. The antiangiogenic and depigmenting effects of a cosmetic formulation containing tranexamic acid and \(\alpha\)-arbutin were screened using an in vitro model of human cells and skin culture [16]. Quantification of melanin, tyrosinase, endothelin-1, PAR-2, vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS) was performed in human fibroblasts, keratinocytes, or melanocytes that were treated with the tested cosmetic formulation and subjected to oxidative stress by UV radiation or inflammatory stress with IL-1\(\alpha\)[16]. Additionally, a histological evaluation of fragments of human skin from elective plastic surgery, treated with the cosmetic formulation containing tranexamic acid and \(\alpha\)-arbutin was performed using the Fontana-Masson technique for melanin view associated with hematoxylin/eosin [16]. The obtained results pointed out a positive result in the reduction of the melanic pigmentation in the skin when using the tested formulation. The reduction of the tyrosinase activity, as well as the production of melanin, reinforces the use of this product in the prevention and treatment of melanoma. The reduction in VEGF and iNOS protein synthesis in cultured dermal fibroblasts indicated a significant antiangiogenic activity and, therefore, a role in the vascular component of melasma [16].