208 JOURNAL OF COSMETIC SCIENCE Table IV Results Obtained by Laser Doppler Flowmetry (mean and standard deviation) Microcirculation TO T28 days T56 days T84 days Mean value Placebo 0.094 (0.009) 0.117 (0.013) 0.112 (0.011) 0.095 (0.008) Product 0.096 (0.008) 0.132 (0.021) 0.133 (0.017) 0.121 (0.026) Homogeneity Placebo 0.160 (0.019) 0.244 (0.038) 0.166 (0.015) 0.157 (0.014) Product 0.156 (0.014) 0.237 (0.035) 0.222 (0.045) 0.223 (0.054) Bold type: significantly different from TO (p •0.05). DISCUSSION The effect of the association of retinol, caffeine, and ruscogenine in an alcoholic vehicle was tested by a unique combination of objective non-invasive methods. It allowed visual and measurable results on several parameters. The results clearly show a significant benefit of the product versus placebo for the microrelief and the microcirculation parameters. The echogenicity and the texture of the dermis as well as the mechanical properties of the skin were improved with the two products versus baseline. The placebo effect might be explained by two factors. First, massage by itself can have a beneficial action on cellulite since massage has been shown to accelerate blood flow and prevent fibrosclerosis (1). Second, the ethanol that was used with the placebo in order to obtain the same cosmetic feeling on application can also be an adipo-kinetic substance like noradrenaline and induce qualitative changes in plasma non-esterified fatty acids (9,10). Further studies where the placebo is devoid of ethanol should be performed in order to evaluate the actual role of ethanol in cellulite. The macrorelief assessed by profilometric measurement was significantly improved by the active product compared to the placebo. This activity is likely to be linked to the improvement of the other measured parameters: dermal and hypodermal structures, skin firmness, and indirectly, skin microcirculation. This efficacy can be explained by the chosen active ingredients that have been described by several authors. The lipolytic activity of caffeine has been known for a long time (11). It is related to an inhibition of phosphodiesterase, which transforms the active cAMP into inactive 5'AMP. The resulting increase in cAMP stimulates the degradation of triglycerides into fatty free acids by the triglyceride lipase, therefore inhibiting fat accumulation. How- ever, different studies (12) have demonstrated that the lipolytic action of caffeine also results from a synergy with the catecholamines present in the adipose tissue that stimu- late peripheral lipolysis by acting on the adrenalino-sensitive lipase (Figure 3). Ruscogenine extract has demonstrated a remarkable inhibition of elastase (13). This inhibition can promote the recovery of extracellular matrix integrity, resulting in an improvement in nutriment exchange between the microcirculatory system and the ground substance. Indeed, according to some authors, the lack of communication be- tween the cells and the ground substance is responsible for the process of cellulite (12). Ruscogenine extract presents a tonic effect on blood vessel tone by an adrenergic-type action. This effect can be direct (agonist of the adrenergic receptors of the smooth cells) or indirect (noradrenaline liberation) (12). This activity has been associated with a

ANTI-CELLULITE ACTIVITY 209 ATP •UPRARENAL GL.•.• • AMPc •' 5' AMP Membranear Adenylcyclase • Phophodiesterase receptor Inactive Active Tr•ase Trigiceride lipase glycerides '• • Free fatty acids + Glycero Sho Noradrenaline• l inergic Catechølamines:AdrenaX•drenergic •g-YMPATHETIC NERVOUS SYSTE•"• BLOOD Figure 3. Mechanisms acting on lipolysis (enzymatic, nervous, and suprarenal). significant increase in lymphatic and venous flow, with a reduction in capillary perme- ability (12). More recently, retinol has been shown to have a beneficial effect on cellulite (4,14). This effect might result from the action of retinol on dermal collagen deposition, improving both thickness and firmness of the dermis (14-16). A direct effect of retinol on prea- dipocytes has also been demonstrated recently, since the exposure of cultured human preadipocytes to retinol results in a marked reduction in the differentiation of the fat cells and a decrease in the number of mature adipocytes (17). The different methods used allowed us to detail the activity of the product compared to baseline and placebo. The assessment of the dermal-hypodermal structure conducted by a novel method allowed us to characterize skin texture during the use of the two products (active product and placebo) and, therefore, to assess a possible result of the product activities on the dermis and hypodermis. The skin firmness improvement observed with the two products, measured conventionally, is probably due, in great part, to the massage, because the placebo increases it at the same level as the product. The flowmerry of skin perfusion was more improved with the product than with the placebo. This activity may be explained by the presence of ruscogenine extract (12,13). CONCLUSION The association of the three tested active ingredients was significantly active on the "orange peel" appearance of the skin, which is the most apparent manifestation of cellulite (53.1% at T84 versus 14.1% for the placebo). The skin microcirculation, whose dysfunction is involved in the pathophysiology of cellulite, was also significantly and durably improved by the product, compared to the placebo. The combination of these different methods allowed measurement of different skin parameters, which change