Synthesis and structure-activity relationship of cyclopentenone oximes as novel inhibitors of the production of tumor necrosis factor-α.

3-Alkyl-2-aryl-2-cyclopenten-1-one oxime derivatives (1) were studied as a novel class of inhibitors of tumor necrosis factor α (TNF-α) with regard to synthesis and in vitro SAR inhibition of TNF-α. The in vitro IC50 values of these compounds in rat and human peripheral blood mononuclear cells were at the sub-micromolar level.

A combination trial of intradermal radiofrequency and hyaluronic acid filler for the treatment of nasolabial fold wrinkles: a pilot study.

BACKGROUND: Within the last few years, hyaluronic acid (HA) fillers and radiofrequency (RF) devices have shown significant promise for skin rejuvenation. But the effects of HA only lasted for a relatively short duration. Therefore, we tried a new combination therapy of intradermal RF and HA filler. OBJECTIVE: To evaluate the clinical efficacy of combination therapy of intradermal RF and HA filler for nasolabial fold (NLF) wrinkle reduction. MATERIALS AND METHODS: Ten Korean female volunteers with mild to severe NLFs were enrolled. In the control group, five subjects were treated with HA filler alone. In the experimental group, the other five subjects were treated with intradermal RF prior to HA filler. Efficacy was evaluated based on the change on the Wrinkle Severity Rating Scale (WSRS) and the Global Aesthetic Improvement Scale (GAIS) from baseline. RESULTS: At 12 and 24 weeks after treatment, the experimental group showed significantly greater improvement in mean WSRS score compared to the control group. And two (40%) of the five patients in the experimental group achieved 'very much improved' and two (40%) showed 'much improved' at 12 weeks after treatment. CONCLUSIONS: Intradermal RF treatment prior to HA filler injection may provide synergistic and long-lasting effects for the reduction of NLF wrinkles.

SNARE-wedging polyphenols as small molecular botox.

Most cosmetic and therapeutic applications of Clostridium botulinum neurotoxin (BoNT) are related to muscle paralysis caused by the blocking of neurotransmitter release at the neuromuscular junction. BoNT specifically cleaves SNARE proteins at the nerve terminal and impairs neuroexocytosis. Recently, we have shown that several polyphenols inhibit neurotransmitter release from neuronal PC12 cells by interfering with SNARE complex formation. Based on our previous result, we report here that myricetin, delphinidin, and cyanidin indeed paralyze muscle by inhibiting acetylcholine release at the neuromuscular junction. While the effect of myricetin on muscle paralysis was modest compared to BoNT/A, myricetin exhibited a shorter response time than BoNT/A. Intraperitoneally-injected myricetin at an extreme dose of 1000 mg/kg did not induce death of mice, alleviating the safety issue. Thus, these polyphenols might be useful in treating various human hypersecretion diseases for which BoNT/A has been the only option of choice.

A botulinum neurotoxin-like function of Potentilla chinensis extract that inhibits neuronal SNARE complex formation, membrane fusion, neuroexocytosis, and muscle contraction.

CONTEXT: Botulinum neurotoxins (BoNTs) are popularly used to treat various diseases and for cosmetic purposes. They act by blocking neurotransmission through specific cleavage of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Recently, several polyphenols were shown to interfere with SNARE complex formation by wedging into the hydrophobic core interface, thereby leading to reduced neuroexocytosis. OBJECTIVE: In order to find industrially-viable plant extract that functions like BoNT, 71 methanol extracts of flowers were screened and BoNT-like activity of selected extract was evaluated. MATERIALS AND METHODS: After evaluating the inhibitory effect of 71 flower methanol extracts on SNARE complex formation, seven candidates were selected and they were subjected to SNARE-driven membrane fusion assay. Neurotransmitter release from neuronal PC12 cells and SNARE complex formation inside the cell was also evaluated. Finally, the effect of one selected extract on muscle contraction and digit abduction score was determined. RESULTS: The extract of Potentilla chinensis Ser. (Rosaceae)(Chinese cinquefoil) flower inhibited neurotransmitter release from neuronal PC12 cells by approximately 90% at a concentration of 10 µg/mL. The extract inhibited neuroexocytosis by interfering with SNARE complex formation inside cells. It reduced muscle contraction of phrenic nerve-hemidiaphragm by approximately 70% in 60 min, which is comparable to the action of the Ca²âº-channel blocker verapamil and BoNT type A. DISCUSSION AND CONCLUSION: While BoNT blocks neuroexocytosis by cleaving SNARE proteins, the Potentilla chinensis extract exhibited the same activity by inhibiting SNARE complex formation. The extract paralyzed muscle as efficiently as BoNT, suggesting the potential versatility in cosmetics and therapeutics.

A double-blind randomized controlled comparison of APDDR-0901, a novel cosmeceutical formulation, and 0.1% adapalene gel in the treatment of mild-to-moderate acne vulgaris.

Topical retinoids have been widely used in the treatment of acne. They comprise several products used as prescription drugs as well as cosmeceuticals. Of these products, retinol has better tolerability compared with prescription retinoids such as tretinoin, but it is only used in cosmeceuticals due to its low biologic activity. A combination formulation could be an effective alternative to address the problem of decreased therapeutic activity. Recently, hexamidine diisethionate is known to have antibacterial activity, and rose extract has been shown to possess anti-inflammatory activity. In this study, we compared the efficacy and safety of the combination product APDDR-0901 (0.03% retinol, 0.7% rose extract, and 0.05% hexamidine diisethionate) vs 0.1% adapalene gel for the treatment of mild-to-moderate acne. This 12-week, multicenter, double-blinded study included 97 patients with mild-to-moderate acne. Efficacy was evaluated using 4 discrete variables: lesion count, acne grade, physician-assessed global improvement, and patient self-assessment. We also assessed safety profiles, including cutaneous irritation. Both APDDR-0901 and adapalene showed significant improvements without significant differences. Otherwise, the APDDR-0901 group showed better safety profiles, particularly in the first 2 weeks. In conclusion, APDDR-0901 could be an effective and safe alternative in the treatment of mild-to-moderate acne.

Novel treatment of neck wrinkles with an intradermal radiofrequency device.

Neck wrinkles commonly develop owing to the aging process. However, recently, the number of patients with neck wrinkles has been increasing. Also, an increasing number of young patients have presented with this condition, possibly because of the effect of the head-down posture that they adopt when using their computer or smartphone. We report two cases of young adults with a prominent neck wrinkle. In case 1, a 29-year-old woman with a neck wrinkle was treated with six intradermal radiofrequency (RF) procedures. Her neck wrinkle was significantly improved with the RF treatment. In case 2, a 32-year-old woman with a wrinkle and generalized light brownish tiny papules on the neck was treated with three intradermal RF procedures simultaneously with 30% glycolic acid peeling. Her wrinkle and skin tone were improved dramatically. We conclude that intradermal RF has a considerable efficacy for reducing neck wrinkles.

In vitro structure-activity relationship and in vivo studies for a novel class of cyclooxygenase-2 inhibitors: 5-aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives.

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.

Investigation of the degradation-retarding effect caused by the low swelling capacity of a novel hyaluronic Acid filler developed by solid-phase crosslinking technology.

BACKGROUND: A variety of hyaluronic acid (HA) fillers demonstrate unique physical characteristics, which affect the quality of the HA filler products. The critical factors that affect the degradation of HA gels have not yet been determined. OBJECTIVE: Our objective was to determine the characteristics of HA gels that affect their resistance to the degradation caused by radicals and enzymes. METHODS: Three types of HA fillers for repairing deep wrinkles, Juvederm Ultra Plus (J-U), Restylane Perlane (Perlane), and Cleviel, were tested in this study. The resistance of these HA fillers to enzymatic degradation was measured by carbazole and displacement assays using hyaluronidase as the enzyme. The resistance of these fillers to radical degradation was measured by the displacement assay using H2O2. RESULTS: Different tests for evaluating the degradation resistance of HA gels can yield different results. The filler most susceptible to enzymatic degradation was J-U, followed by Perlane and Cleviel. The HA filler showing the highest degree of degradation caused by H2O2 treatment was Perlane, followed by J-U, and then Cleviel. Cleviel showed higher enzymatic and radical resistances than J-U and Perlane did. Furthermore, it exhibited the highest resistance to heat and the lowest swelling ratio among all the fillers that were examined. CONCLUSION: The main factor determining the degradation of HA particles is the gel swelling ratio, which is related to the particle structure of the gel. Our in vitro assays suggest that the decrease in the swelling ratio will lead to a retarding effect on the degradation of HA fillers.

The efficacy, longevity, and safety of combined radiofrequency treatment and hyaluronic Acid filler for skin rejuvenation.

BACKGROUND: Recent advances in hyaluronic acid (HA) fillers and radiofrequency (RF) devices have been made in the context of skin rejuvenation and cosmetic surgery. Moreover, combination regimens with both techniques are currently being developed. OBJECTIVE: The present study was designed to examine the clinical and histologic effects of a new needle that incorporates an RF device for HA injections. METHODS: A new intradermal needle RF device (INNOfill; Pacific Pharma, Korea) was assessed in the present study. In the animal arm, procollagen production was measured by using enzyme-linked immunosorbent assay, the filler volume was quantified by incorporating a dye with filler, and the filler distribution was assessed through the changes in tissue structure. In the human arm, the efficacy of the combination regimen was assessed by using the wrinkle severity rating scale (WSRS). RESULTS: In the animal study, RF treatment increased procollagen production in a time-dependent fashion. The total volume was significantly increased with the RF treatment when compared with the filler injections alone, and lasted for up to 7 weeks after treatment. Additionally, the filler distribution was reduced in animals treated with RF when compared with the untreated group. In the human study, the nasolabial folds of subjects treated with RF before filler injections exhibited a significantly greater change in the WSRS score from baseline when compared with the nasolabial folds treated with filler injections alone. CONCLUSION: A new device incorporating RF treatment before HA filler injection may represent a biocompatible and long-lasting advance in skin rejuvenation.

Biarylcarboxybenzamide derivatives as potent vanilloid receptor (VR1) antagonistic ligands.

Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC(50)=31 nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl)benzamide (3g, IC(50)=31 nM), showed 5-fold higher antagonistic activity than 1 in (45)Ca(2+)-influx assay.

Synthesis of N,N',N"-trisubstituted thiourea derivatives and their antagonist effect on the vanilloid receptor.

Twenty-seven N,N',N"-trisubstituted thiourea derivatives were prepared. Among them, 1-[3-(4'-hydroxy-3'-methoxy-phenyl)-propyl]-1,3-diphenethyl-thiourea (8l, IC(50)=0.32 microM), showed 2-fold higher antagonistic activity than that of capsazepine (3, IC(50)=0.65 microM) against the vanilloid receptor in a (45)Ca(2+)-influx assay.