The First Human Clinical Trial on the Skin Depigmentation Efficacy of Glycinamide Hydrochloride

Abstract

A previous study identified certain low molecular anti-melanogenic peptides that share a common sequence with α-melanocyte stimulating hormone (MSH) and end with a glycinamide moiety. Glycinamide itself also showed anti-melanogenic activity in cell-based assays, but neither glycine nor acetyl glycinamide were active, which indicated a special structure and activity relationship. The aim of this study was to examine the skin depigmentation efficacy of glycinamide hydrochloride in human subjects. The primary skin irritation potential of glycinamide hydrochloride was evaluated by patch testing in 30 human subjects. The skin depigmentation efficacy of glycinamide hydrochloride was evaluated in a double-blinded clinical test in 21 human subjects. The test product and a control product were applied to designated sites on the right or left side of the face twice daily for eight weeks. Skin color parameters, i.e., the melanin index, the L* value (representing skin lightness), a* value (redness), and b* value (yellowness) were measured using instruments. The individual topology angle (ITAo, representing skin color) was calculated from L* and b values. The degree of skin pigmentation was visually assessed by two testers. The primary skin irritation test showed that a solution containing glycinamide hydrochloride up to 10% did not induce any adverse skin responses. In the efficacy test, the test product significantly reduced the melanin index, and increased L* value and ITAo after two weeks of application relative to the baseline value at the start of the test. It also significantly lowered the degree of pigmentation after 6 weeks of application, relative to the baseline value. Differences in the melanin index, L* value, ITAo and the degree of pigmentation between the test and control groups became statistically significant after six weeks or eight weeks of application. No signs of skin irritation were observed during the efficacy test. The present study suggests that glycinamide hydrochloride has great potential to be used in the control of skin hyperpigmentation.

Up- or Downregulation of Melanin Synthesis Using Amino Acids, Peptides, and Their Analogs

“…A variety of peptides and amino acid analogs were described to modulate melanin synthesis in cells, although their therapeutic utility remains to be further verified. In vivo and clinical results have been provided for MC1R targeting molecules, such as [Nle 4 -D -Phe 7 ]-α-MSH [71,72], and glycinamide hydrochloride [126], and an inhibitor of melanin synthetic reaction, such as oxidized glutathione [95]. These studies suggest that certain amino acids, peptides, and their analogs may be a promising drug candidate for up-and downregulating skin pigmentation.…”

“…Melanin increasing molecules can be used to alleviate photosensitive skin, to prevent photocarcinogenesis, and to treat vitiligo vulgaris [15,71,72]. Conversely, melanin decreasing molecules can be used to treat various types of hyperpigmentation for medical and aesthetic purposes [58,59,95,126].…”

“…Glycinamide hydrochloride (Gly-NH 2 •HCl) suppressed the activation of CREB and the mRNA expression of MITF and TYR in response to α-MSH, resulting in lower melanin synthesis [125]. In a subsequent clinical study, performed in a double-blinded format for eight weeks in 21 human subjects, a preparation containing 10% glycinamide hydrochloride showed a significant depigmentation effect without any noted adverse effects on the skin, compared with the control preparation without glycinamide hydrochloride [126]. This very small molecule has great potential to be used as a skin depigmentation agent.…”

Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist

“…50 Follow-up work in a human clinical trial reported that application of glycinamide to facial skin decreased melanin index and skin pigmentation while increasing skin lightness, as compared to a control formulation lacking glycinamide. 51 These data suggest that an in vitro functional antagonist mixture-based positional scan can successfully identify clinically relevant compounds.…”

“…Further truncation studies led to the observation that the C-terminal amino acid in these tetrapeptides, glycinamide (H-G-NH 2 ), possessed anti-melanogenic activity at 30 and 100 μM concentrations . Follow-up work in a human clinical trial reported that application of glycinamide to facial skin decreased melanin index and skin pigmentation while increasing skin lightness, as compared to a control formulation lacking glycinamide . These data suggest that an in vitro functional antagonist mixture-based positional scan can successfully identify clinically relevant compounds.…”