An integral topical gel for cellulite reduction: results from a double-blind, randomized, placebo-controlled evaluation of efficacy.

BACKGROUND: Cellulite is a serious cosmetic concern for most of the 90% of women affected by it. OBJECTIVE: To assess the clinical efficacy of a complex integral anti-cellulite gel. METHODS: This double-blind, randomized, placebo-controlled study involved 44 healthy women, aged 25-55 years. Subjects had a normal to slightly overweight body mass index and presented slight to moderate cellulite on their thighs, buttocks, and/or hips at baseline. Subjects were randomly assigned to either the treated or placebo group and accordingly applied the active product or placebo on their hips, stomach, buttocks, and thighs, twice daily for 3 months. Skin tonicity, orange-peel aspect, and stubborn cellulite were assessed at day 0, 28, 56, and 84. A self-evaluation questionnaire was completed by all volunteers. RESULTS: At the end of the study, an average of 81% of the subjects applying the active product presented improvement in their cellulite condition versus 32% for the placebo group (all descriptors and sites combined). At day 84, skin tonicity, orange-peel appearance, and stubborn cellulite were improved in a significant manner (P<0.05) over placebo, on all studied areas. Skin tonicity improved on average by +41% for buttocks, +35% for hips, and +31% for thighs. Orange peel appearance was reduced on average by -25% for buttocks, -22% for hips, and -22% for thighs. Stubborn cellulite was reduced on average by -19% for buttocks, -24% for hips, and -22% for thighs. Circumference measurements decreased in a significant manner (P<0.05) over placebo, for the abdomen (average value of -1.1 cm) and thighs (average value of -0.8 cm). The product was well tolerated and perceived by the volunteers themselves as better performing than placebo on all criteria. CONCLUSION: All results validate the efficacy of the present integral formulation to significantly reduce signs of cellulite and reshape the silhouette.

Clinical efficacy of a serum integrating multiple cosmetic ingredients in the management of erythema of the face in aging skin.

BACKGROUND: Skin redness is a common cosmetic concern affecting predominantly fair-skin individuals and often leading to rosacea. On the basis of the current scientific knowledge of the physiological mechanisms underlying the problem, a complex and integral skin care serum (100RXED2025) was developed and tested clinically for efficacy. METHOD: Forty-five healthy men and women volunteers, age 30-65, were recruited. All subjects had fair skin (phototype I, II, or III) and presented some degree of skin redness with telangiectasia on the cheeks, the nose, or the nose sides, at baseline. In the course of this open label study, subjects applied the test product on their face, twice daily for 56 days. For each subject, skin redness was evaluated through colorimetric and visual analysis of photographs taken under cross-polarized light at T = 28 (week 4) and T = 56 (week 8), then compared to baseline measurements obtained at day 0. RESULTS: Forty-four volunteers completed the study. On visual evaluation, skin redness had decreased in average by 32.2% at T = 28 (P < 0.001) and by 48.0% at T = 56 (P < 0.001). Importantly, 91% of the subjects showed improvement of skin redness at T = 28, reaching 100% at T = 56. Colorimetric analysis gave an average reduction in redness of 11.6% at T = 28 (P < 0.001) and 13.7% at T = 56 (P < 0.001). CONCLUSION: The anti-redness efficacy of the test product was demonstrated after 28 days with further increase following 56 days of application.

Prognostic factors of metastatic renal cell carcinoma after failure of immunotherapy: new paradigm from a large phase III trial with shark cartilage extract AE 941.

PURPOSE: We analyzed prognostic factors, described survival and generated a prognostic model in patients with metastatic renal cell carcinoma in whom immunotherapy failed and who were potentially eligible for novel agents. MATERIALS AND METHODS: An analysis of the relationship between clinical features and survival was performed in 300 patients with advanced renal cell carcinoma in whom immunotherapy had failed and who were subsequently treated as part of a single, phase III clinical trial with the anti-angiogenic agent Neovastat (shark cartilage extract AE 941). Clinical features were first examined univariately and a stepwise modeling approach based on Cox proportional hazard regression was then performed to generate a multivariate model. RESULTS: Median and progression-free survival (prognostic factors) for the whole cohort was 12.6 and 2 months, respectively. Prognostic features associated with shorter survival on multivariate analysis were the number of metastatic sites (greater than 1), time from nephrectomy to metastatic disease (less than 2 years), high alkaline phosphatase, abnormal corrected serum Ca and high lactate dehydrogenase (greater than 1.5 x the upper limit of normal). Four prognostic subgroups were identified by counting the number of adverse prognostic factors. Median survival in patients with zero adverse prognostic factors was 15.6 months compared to 11.7 months in patients with 1, 8.5 months in patients with 2 and 3.5 months in patients with 3 or more. CONCLUSIONS: We identified 4 risk groups to predict survival in previously treated patients with renal cell carcinoma. This model was based on data from what is to our knowledge the largest experience in this population. It should be used in clinical trial design, risk stratification and patient counseling.

Phase I/II trial of the safety and efficacy of AE-941 (Neovastat) in the treatment of non-small-cell lung cancer.

AE-941 (Neovastat), an antiangiogenic component extracted from cartilage, selectively competes for the binding of vascular endothelial growth factor to its receptor, inhibits matrix metalloproteinases, stimulates tissue plasminogen activator enzymatic activities, and induces apoptotic activities in endothelial cells. A phase I/II study was conducted to obtain information on its safety and efficacy in patients with advanced cancer refractory to treatment or for which no standard treatments were available. Eighty patients with histologically confirmed lung cancer were enrolled in a multicenter, open-label, dose-escalation study of AE-941 (30, 60, 120, or 240 mL/day) administered orally b.i.d. as monotherapy. No dose-limiting toxicity was reported. The most frequent adverse events were nausea (9%), pruritus (5%), anorexia (4%), and vomiting (4%). All adverse events were grade 1/2 except grade 3 constipation (n = 1). A survival analysis was conducted in the 48 patients with unresectable stage IIIA, IIIB, or IV non-small-cell lung cancer. A significant survival advantage was observed for patients receiving doses > 2.6 mL/kg/day (which correspond to approximately 180 mL/day in a 70-kg patient) compared to patients receiving lower doses (median, 6.1 months vs. 4.6 months; P = 0.026). No tumor responses were observed. On the other hand, 26% of the patients in the high-dose group had stable disease compared to 14% in the low-dose group. AE-941 is well tolerated in patients with advanced lung cancer. The higher dose of AE-941 explored in this phase I/II trial may confer a survival benefit.

Neovastat (AE-941), an inhibitor of angiogenesis: Randomized phase I/II clinical trial results in patients with plaque psoriasis.

There is considerable evidence to support an immunopathogenic basis of psoriasis. However, changes such as altered angiogenesis have also been implicated in the pathogenesis of psoriasis. AE-941 (Neovastat; Aeterna Laboratories, Quebec City Quebec, Canada) is a naturally occurring product currently in clinical investigation that blocks two main mechanisms of angiogenesis activation, namely, vascular endothelial growth factor and matrix metalloproteinase. We hypothesized that psoriasis could be modulated by inhibiting the neovascularization of psoriatic plaques. We conducted a randomized dose-comparison trial to evaluate the safety and potential therapeutic benefit of AE-941, administered orally to patients with psoriasis. Forty-nine patients with psoriasis were enrolled and assigned to receive AE-941 at 30, 60, 120, or 240 mL/d for 12 weeks. Patients were followed up for another 12-week period. Improvement in the Psoriasis Area and Severity Index (PASI) score was observed in 50%, 41.7%, and 30.8% of the patients receiving 240, 120, and 60 mL/d, respectively. No patients receiving a dosage 30 mL/d showed a PASI score improvement. A statistically significant improvement with increasing dose was observed for the PASI score, severity of itch, and the physician's global assessment. The most commonly reported nonserious drug-related adverse events affected the gastrointestinal system in 12 of 49 patients (primarily nausea, diarrhea, vomiting, flatulence, and constipation) and the skin and appendages in 4 of 49 patients (primarily acne and rash). This randomized phase I/II study provides evidence that the antiangiogenic agent AE-941 offers a new therapeutic approach to the management of psoriasis.

[Early and lasting remission of protein-losing enteropathy with corticosteroids]. / Rémission précoce et durable d'une entéropathie exsudative par corticothérapie.

OBJECTIVE: To emphasize the possibility of obtaining good quality and lasting remission of a severe idiopathic protein-loosing enteropathy with corticosteroid therapy. OBSERVATION: A 30 year-old woman was hospitalized for edema of the lower limbs related to hypoalbuminemia due to a protein-loosing enteropathy, demonstrated by measurement of alpha-1 antitrypsin clearance. Diagnosis of lupus was evoked but not confirmed. Nutritional treatment failed. Corticosteroids administered in a bolus, and subsequently per os, rapidly led to complete, lasting (22 months later) remission. DISCUSSION: Corticosteroid therapy is the classical treatment of a protein-loosing enteropathy concomitant to disseminated lupus erythematosus, a rare combination. In the absence of lupus, a few cases of remission from a protein-loosing enteropathy have been reported. However, the delay before remission was longer than in our case report, and the remission-free period generally shorter. CONCLUSION: Corticosteroid therapy is an effective treatment of an idiopathic protein-loosing enteropathy.

Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue.

A novel naturally occurring antiangiogenic agent isolated from cartilage, referred to as Neovastat (AE-941), was examined for its efficacy against tumor neovascularization and progression. Exposure to Neovastat results in ex ovo antiangiogenic properties in the chorioallantoid membrane of chicken embryo (71% decrease in the angiogenic index as compared to the basic fibroblast growth factor (bFGF) treated control embryos, P < 0.0001). Oral administration of Neovastat inhibits bFGF-induced angiogenesis in the Matrigel mouse model (87.5% decrease in hemoglobin as compared to the bFGF-treated control implants, P < 0.0001). Neovastat also induces a dose response decrease of lung metastases in the Lewis lung carcinoma model (oral administration; 69.1% of inhibition obtained at the maximal dose of 0.5 ml/day, P < 0.0001). Combined with a sub-optimal dose of cisplatinum (2 mg/kg, i.p.), Neovastat (0.5 ml/day) improved the therapeutic index by increasing the antimetastatic efficacy and by exerting a protective activity against cisplatinum-induced body weight loss and myelosuppression. In summary, our experimental data provide evidence of antiangiogenic and antimetastatic properties of Neovastat, following oral administration.

The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, which exerts direct effects on vascular endothelial cells, including endothelial cell proliferation and survival, tubulogenesis, and vascular permeability. In this study, we examined whether Neovastat, a naturally occurring multifunctional antiangiogenic drug, could inhibit the endothelial cell response to VEGF stimulation. RESULTS: We demonstrated that Neovastat was able to block the VEGF-dependent microvessel sprouting from Matrigel-embedded rat aortic rings, and it also blocked the VEGF-induced endothelial cell tubulogenesis in vitro. In vivo studies showed that Neovastat was able to specifically inhibit VEGF-induced plasma extravasation in numerous tissues, including pancreas and skin. The mechanism of action of Neovastat on VEGF-mediated effects was also evaluated at the molecular level. Neovastat was shown to compete against the binding of VEGF to its receptor in endothelial cells and significantly inhibited the VEGF-dependent tyrosine phosphorylation of VEGF receptor-2, whereas it had no significant effect on VEGF receptor-1 activity. Moreover, the inhibition of receptor phosphorylation was correlated with a marked decrease in the ability of VEGF to induce pERK activation. Neovastat does not compete against the binding of basic fibroblast growth factor, indicating a preferential inhibitory effect on the VEGF receptor. CONCLUSIONS: Because Neovastat was shown previously to inhibit metalloproteinase activities, these results suggest that Neovastat is able to target multiple steps in tumor neovascularization, further emphasizing its use as a pleiotropic, multifunctional antiangiogenic drug.