Anti-wrinkle agents - A way of regaining beauty

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1 The Pharma Iovatio Joural 2017; 6(6): ISSN (E): ISSN (P): NAAS Ratig 2017: 5.03 TPI 2017; 6(6): TPI Received: Accepted: Deepika Sodh M. pharm, Departmet of Quality Assurace, Delhi Pharmaceutical Scieces Research Uiversity, (DPSRU/DIPSAR) Delhi, Idia Amrita Parle Associate Professor, Departmet of Quality Assurace, Departmet of Quality Assurace, Delhi Pharmaceutical Scieces Research Uiversity, (DPSRU/DIPSAR) Delhi, Idia Ati-wrikle agets - A way of regaiig beauty Deepika Sodh ad Amrita Parle Abstract Recet developmet i the techology has led to the advacemet i ski cosmetology. Ati-wrikle or ati-agig agets are extesively used i the cosmetic products, for acquirig a youthful, firm ski. Ski agig is a atural pheomeo which caot be reversed but with the help of ovel approaches i the cosmetology techiques, scietist ca delay the process of ageig. Ati-wrikle agets are used topically for the treatig wrikles ad sigs of agig. Hyaluroic acid ad botulium euro-toxis are most the extesively used ati-wrikle agets. This review article provides the cocise details about the leadig ati-wrikle agets, their mechaism of actio, uses ad adverse reactios o the body. Hyaluroic acid ad botulium euro-toxis are discussed i detail alog with cost cosideratios. The future treds i the advacemet of dermatological aesthetics ad ati-wrikles agets have also bee icluded. Keywords: Hyaluroic acid, Sodium hyaluroate, Botulium euro-toxis, Aesthetics, ijectio. 1. Itroductio The Ski For better uderstadig of the mechaism of differet dermal fillers ad ati-wrikle agets it is importat to uderstad the differet layers of the ski. The ski is cotiuous membrae alog with the mucous membraes liig the body s surface. The itegumetary system is formed by the ski ad its derivative structures (see Figure 1-1). The ski is composed of three layers: the epidermis, the dermis ad subcutaeous tissue [1]. Fig 1: Represetatio of cross-sectio of the ski Correspodece Deepika Sodh M. pharm, Departmet of Quality Assurace, Delhi Pharmaceutical Scieces Research Uiversity, (DPSRU/DIPSAR) Delhi, Idia Epidermis The peripheral level, the epidermis, comprises of a particular iterstellar groupig of cells kow as keratiocytes, which sythesizes kerati, a log, threadlike protei with a protective role. The thickess of the epidermis fluctuates i various sorts of ski; it is just 0.05 mm thick o the eyelids, ad is 1.5 mm thick o the palms ad the soles of the feet. The epidermis cotais the melaocytes (the cells i which melaoma builds up), the Lagerhas cells (ivolved i the immue system i the ski), Merkel cells ad sesory erves. The epidermis layer itself is comprised of five sublayers that cooperate to cosistetly rebuild the surface of the ski [1]. ~ 7 ~

2 The Pharma Iovatio Joural 1. Basal Cell Layer 2. The Squamous Cell Layer 3. The Stratum Graulosum ad the Stratum Lucidum Dermis The ceter layer, the dermis, is essetially made up of the fibrillary auxiliary protei kow as collage. The dermis is situated udereath the epidermis ad is the thickest of the three layers of the ski (1.5 to 4 mm thick), makig up roughly 90 percet of the thickess of the ski. The mai fuctios of the dermis are to regulate temperature ad to supply the epidermis with utriet-saturated blood. Much of the body's water supply is stored withi the dermis. This layer cotais the vast majority of the skis' specific cells ad structures, icludig veis, lymph vessels, hair follicles, sweat orgas, sebaceous orgas, erve edigs, collage ad elasti. [1]. The dermis layer is comprised of two sub layers: 1. The Papillary Layer- the upper, papillary layer, cotais a thi arragemet of collage fibers. The papillary layer supplies utriets to select layers of the epidermis ad regulates temperature. 2. The Reticular Layer- The lower, reticular layer, is thicker ad made of thick collage fibers that are arraged i parallel to the surface of the ski. The reticular layer is deser tha the papillary dermis, ad it stregthes the ski, providig structure ad elasticity. Hypodermis The sub cutis is the deepest layer of the ski ad comprises of a system of fat ad collage cells. The sub cutis is otherwise called the hypodermis or subcutaeous layer, ad capacities as both a separator, ratioig the body's warmth, ad as a safeguard, securig the iteral orgas. It additioally stores fat as a vitality save for the body. The veis, erves, lymph vessels, ad hair follicles likewise cross through this layer. The thickess of the sub cutis layer varies all through the body ad from idividual to idividual. Ski Agig The hallmark of the agig face is loss of subcutaeous volume over the period of time. Cliically, with this loss, oe commoly fids the sigs, most cliicias see routiely, whe cofroted with a patiet cocered with the agig face idicated by, a icrease i facial vasculature ad pigmet alteratios, as well as a icrease i the lies ad wrikles of the ski. This is associated with a thiig of the epidermis \ad with dermal atrophy ad loss of the elastic tissues preset withi the dermis ad with actiic chages with loss of [2, 3] dermal collage Fig 2: portrayig the distictive locales of the ski havig wrikles Agig is the procedure of aggregatio of molecular damages (NOVOSELTEV et.al 2001) [2, 3] i orgas ad life forms, over a time frame, causig loss of some of the prerogative characteristics of youth. Harms are oly substace alteratios of the cell DNA particles i a livig beig. Gathered molecular damages i cellular DNA are called substatial chages. As idicated by the gee, where these trasformatios happe, the physiology of the cell or of the orga chages astoudigly or drastically. Without a doubt, these harms are the oes straightforwardly coected to the obvious sig of the oset of the maturig procedure. The amassig of harms esuig to the basal metabolism prompts to divisio of agig ito two structures- 1. Natural or Itrisic Agig- This must be see i very seiority ad is described by ublemished, smooth, pale, drier, less flexible ski with fie wrikles. It happes iside the tissue itself, through dimiishmet i dermal pole cells, fibroblasts, collage geeratio ad straighteig of dermal-epidermal itersectio. For better comprehesio of the ski maturig process Paolo U. Giacomoi et.al provoked a model kow as- Micro iflammatory model of ski agig. e of the promiet reaso for ski agig is diapedesis, the passage of blood cells through the itact capillary walls causig micro iflammatio. Diapedesis happes accordigly of aoxia or because of chemotatic sigs like itroductio to perpetual UVA ad UVB, tobacco smoke, electric field ad so o. Diapedesis happes by meas of Itercellular Adhesio Molecule 1 ~ 8 ~

3 The Pharma Iovatio Joural which is a protei that is ecoded by the ICAM1 gee. This gee ecodes a cell surface glycoprotei which is typically expressed o edothelial cells ad cells of the immue system. Upo sythesis of the ICAM1 gee i the edothelium, circulat moocytes ad macrophages roll over ad secrete hydroge peroxide to perform diapedesis across the edothelial liig of the vascular wall. ce i the dermis, the immue cells secrete lythic ezymes ad reactive oxyge species (ROS), to fray a path i the dermis. Macrophages i the dermis ted to release collageases which lead to hydrolysis of collage. Macrophages also release ROS which damage the earby residet cells, such as fibroblasts or keratiocytes. Whe this happes, the damage ca trigger the breakdow of cascade of arachidoic acid ad secrete prostagladis ad leukotriees, which diffuse to the adjacet residet mast cells. Upo bidig these mediators o specific receptors, the residet mast cells release histamie ad TNFα, which i tur stimulate the release of p-selectis ad the eo-sythesis of ICAM-1 i edothelial cells. The cycle is the cotiued ad the micro-iflammatory status is maitaied, leadig to ski agig [2, 3]. Fig.3, (Giacomoi et al., 2000), summarizes the microiflammatory model of ski agig Fig 3: micro iflammatory model of ski agig (I-CAM 1 sythesis) (ref. a mechaistic model for the agig of huma ski by Paolo U.Giacomoi, Gle Rei) 1. Photoagig or Extrisic Agig It is associated with chages i ski structure ad appearace. The greatest source of extrisic agig is accumulatio of chemotactic factor like solar radiatio, gravitatioal attractio, ifectios, electric fields, psychological stress, cigarette smoke, aoxia ad uprotected su exposure (i.e. photo agig). This is largely cofied to the face, eck, hads. Over 80% of facial ski agig is due to low grade chroic UV exposure. Some of characteristics iclude coarse wrikles, rough texture, sallow complexio, mottled pigmetatio ad loss of ski elasticity [1,2]. Ati-Wrikle Agets The treatmets for damaged ski rage from ski care products, to eergy based therapies (lasers, light sources, ad radiofrequecy devices) to fillers ad toxis. Past several years have see growth i umber of ew soft tissue augmetatio products which are used by physicias i the treatmet of agig. Table 1: List of various ati-wrikle agets available i the market No. Name Type 1 2 Phytoceramide [4] Herbal aget Hyaluroic acid [5] Natural chemical Route of admiistratio/ depedig o severity Depedig o type of formulatio Duratio Effects Side-effects 8 days 12 weeks Icreases the depletio of procollage-1 ad fibrilli rich microfibrils i aged ski. It improves tissues hydratio ad their resistace to mechaical damage effects. But may show allergic reactios i few patiets Ski swellig, redess ad itchig. Commercialized product Bella.vei Zyderm, Zyplast Cosmoderm 3 4 Gree tea polypheols [4] Garlic extract (caffei acid, S- Herbal aget Herbal agets Varies accordig to severity 2-3 moths 1 moth Decreases the umber of lagerhas cells ad reduce DNA damage i the ski. ihibits the degradatio of type І procollage ad effects. Cause ski redess i some patiets. Atioxidat Atioxidats ~ 9 ~

4 The Pharma Iovatio Joural allyl cysteie, ad Depedig uracil [6] o severity Retiol [4] Vitami-A Niaciamide [4] Vitami-B3 Tocopherol [4] Vitami-E l-ascorbic acid [4] Nifedipie [4] Alpha-hydroxy acid [4] Vitami-C Sythetic chemical Chemical aget 5% cocetratio 5% cocetratio 5% cocetratio 5% cocetratio patiets ot more tha 8% cocetratio Palmitoyl peptide [5] Polypeptide Botulium toxis [7] Sythetic chemical 13 Chemical peels [8] Sythetic chemicals Laser techiques [9] Adipose derived stem cells. [10] Mixture of paax giseg ad crataegus piatifida [11] Laser emitig light as 532, 595, 755m wavelegth. Huma dermal fibroblast. Huma dermal fibroblast. ijectios the type of eurotoxis used admiistrati o the type chemicals used admiistrati o the wavelegth NOVEL ijectios the patiets. ijectios the severity 2-3 weeks 1 moth 12 weeks 2-3 weeks 30 days 30 days 30 days 12 moths 5-6 moths moths the expressios of MMIPs Iduce biosythesis of collage ad reduce expressio of MMPI (collagease) regulates cell metabolism ad regeeratio Icreases the ability of stratum coreum. helps build collage, reduce iflammatio, promotes elasticity to plump up ski improves the elasticity of the ski, improves the ski pigmetatio exfoliators that getly dissolve the "glue" that holds surface ski cells together, stimulate collage sythesis ad activate dermal metabolism Botulium toxi acts at the level of the euromuscular plate ad of other choliergic syapses icrease i collage fibre cotet water i the dermis has bee reported improvemet i ski elasticity Stimulate fibroblast activity ad iitatio of tissue repair, ehaced collage ad elasti eoformatio TECHNIQUES Reduces UVB iduced apoptosis ad stimulatig collage sythesis of huma dermal fibroblast. ihibitig wrikle formatio ad icreasig moisture i the huma ski ski irritatio is commo effects. effects effects Cotraidicatio with steroidal creams. Hypersesitivity reactios Causes ski redess. Make ski more sesitive i presece of su light. Cause ski irritatio or redess i some patiets. Ski sesitivity reactios may occur i some patiets Dryess ad scalig of the ski May cause redess, burig of the ski effects see till ow. effects see till ow. atioxidats Atioxidat Atioxidat Atioxidat Atioxidat Atioxidat Polypeptides Botox Cosmetic- Vistabel, Vistabex Alpha/beta lipo hydroxy acid, TCE IPL, LASER Activatio of TGF-ß/SMAD ad P38 MAPK sigalig pathway [12] DHEA (Dihydro- Piadrosteroe) [13] multipotet stem cells. Chemical aget fillers the patiets admiistrati o ~ 10 ~ activatig TGF-ß/SMAD ad P38 MAPK sigalig pathway ad the stimulatig fibroblast to secrete ad sythesize collage DHEA is steroid hormoe ivolved i physiological agig. effects see till ow. effects see till ow.

5 The Pharma Iovatio Joural Gee silecig [14] Paracrie cytokie likage [15] Chemical aget PCL betwee keratiocytes ad fibroblasts 21 Querceti [16] Herbal aget 22 Rice-wie [17] huma fibroblast ad Cultured i keratiocytes 23 Pogostoe [18] costituet of patchouli oil Chemical 24 Mesechymal stem cells [19] Medium from huma boe marrow 25 Cyclopia [8] Fermeted ad o-fermeted Coca pod extract [14] Herbal aget Mixture of huma growth factor ad hyaluroic acid serum [20] Semi-sythetic Depeds o patiet ijectios the patiets ijectios Depedig o the severity admiistrati o the patiet No fixed No fixed ijectios No fixed 2-5% cocetratio Not more tha 5% cocetratio the patiets. DNA demethylatio agets ad histoe deacylatio ihibitors gees keratiocytes ad fibroblasts leads to the stimulatio of elastase which helps i maitaiig the elasticity ad firmess of the ski querceti caprylate act as a proteasome activator with atioxidat properties reduces the expressio of UV iduced matrix metalloproteiase-se- Ihibited the wrikle formatio ad ski laxity maily by repairig collage ad elastic fiber. Reduces matrix metalloproteiase-1 expressio ad icreased procollage sythesis ihibitig thickeig of the epidermal layer, i additio to suppressig collage tissue breakdow reactios good atioxidat activity because of pheolic compositio ad tyrosiase ihibitory activities HGF ad HA serum beeficial i reducig peri orbital Wrikles Atioxidats Ati-oxidats Retiyl retioate [15] Autologous platelet rich plasma [11] Micro sphere Whole blood plasma No fixed ijectio No fixed ehaces ski permeatio sythesis of collage ad other matrix compoet by stimulatig the activatio of fibroblast We Will Discuss I Detail the Frequetly Used Ati- foud i the spots where rubbig happes: the joits, Wrikle Agets Namely Hyaluroic Acid ad Botulium ligamets, sheaths, pleura ad the pericardium. Preparatios Neurotoxis cotaiig high molecular mass HA ca be utilized as a part Hylauroic Acid of arragemets for the care of the eyes, face, eck, ad body, Hylauroic acid (HA) has a place with a gatherig of ad also, i agaist cellulite, ad hostile to exted check substaces called mucopolysaccharides havig a place with beauty care products by framig a defesive layer makig the glycosamioglycas (GAGs) family. It is a biopolymer ski seem getler ad feel smoother to the touch. The sodium made out of repeatig uits of disaccharides, which salt of Hylauroic acid is likewise utilized topically to icorporate particles of D-glucuroic acid ad N- dimiishig wrikles [21]. acetylglucosamie atoms coected by ß-(1-4) ad ß-(1-3) Sodium hyaluroate (KH) is curretly the most commoly glycosides. The huma body measurig 70 kg cotais 15 g used cosmetic filler. The fuctio of which is to fill ad of HA. The best measure of the compoud is available i the plump up the extracellular tissue space. I liquid ski (about portio of the aggregate HA). It ca likewise be formulatios, it is utilized to fill little, shallow wrikles, ~ 11 ~

6 The Pharma Iovatio Joural givig the ski versatility ad adaptability, while crosscoected arragemets are utilized for the adjustmet of facial forms, displayig the bosom i ladies. Superb impacts ca be accomplished with the redress of asolabial folds, relievig level brow wrikles, raisig eyebrows, situatig the ose, chagig the shape ad volume of the lips, displayig the cheeks, butto, body moldig (amplificatio ad demostratig of breasts, thighs, rump, ad calves) ad also to improve the state of the labia (labi-aplasty). Little volumes of HA are ifused itradermal or subcutaeously to give aroud 6 moths of fill impact. The medicatio stores likewise offer may creams ad oral plas cotaiig KH however so far o radomized reviews have affirmed a positive, log haul smoothig impact o ski wrikles utilizig these strategies [21]. The cost of differet products cotaiig hyaluroic acid is give i the table o.2. The treatmet varies accordig the factors like the severity of the wrikles, age of the patiet ad the uits ijected to the patiet ad the outcome may last up to 3-6 moths depedig o the same factors [22]. Table 2: Products Cotaiig Hylauroic Acid Product Compoet Compay Uits Cost(Ir) Hyaluroic Acid Gel Hyaluroate sodium Meso System S.A 30g 2,560 Oz Naturals hyaluroic acid serum Retiol, Hyaluroic acid, vite Oz Naturals 30ml 2,373 Hyaluroic acid serum Hyaluroic acid, vit E Cosmedica 15ml 1,892 Hylauroic acid serum Hylauroic acid, retiol Pyrochem pvt ltd 30ml 700 Hylauroic acid cream Hyaluroic acid, vit E Macaria cosmetic 30g 300 Hylauroic acid (2%) Pure hyaluroic acid Cosderma pvt ltd 15ml 2,500 Syvisc oe ijectio Hyaluroic acid Archit biotech 10ml 1200 Botulium Neuro-Toxis Botulium eurotoxi is the exotoxi produced by Clostridium botulium. Seve distict serotypes of the eurotoxi, desigated as type A to G, have bee idetified. Type A is the most commoly used toxi for cosmetic purposes, although there are some reports about the use of type B toxi i aesthetics. The toxi is a protei molecule cosistig of a 50-kd light chai ad a 100-kd heavy chai liked by a disulfide bod. [24] At preset, there are four ordiarily utilized arragemets of botulium toxis [ 25 ]- a-botulium toxi A (Botox; Botox Cosmetic, Allerga, Irvie, CA), Abo-botulium toxi A (Dysport; Ipse Ltd Berkshire, UK), Ico-botulium toxi A (Xeomi; Merz Pharmaceuticals, Frakfurt, Germay), Rima-botulium toxi B (Myobloc; Solstice Neuroscieces, Sa Fracisco, CA). Despite the fact that the impact of each is comparable, they cotrast i their sythetic structure, related proteis, assemblig ad refiemet forms ad viability. Dosage, Duratio ad Storage -The ormal dosage of the botox ifusio relies o upo the seriousess, mark ame, legth ad i additio recurrece of the treatmet. The measuremets deped o the biologic itesity of the toxi ad is measured i uits. A 100-U vial of the preparatio cotais 5 mg of toxi as lyophilized powder. Sice the arragemet is i powder form, it should be recostituted before the ifusio. The prescribed diluets are 0.9% salie without additives. It is typically prescribed to tederly ifuse the diluets ito the vial, stayig away from the arragemet of froth i the perplexig, which could brig about toxi deaturatio. ce recostituted, the arragemet must store at a temperature of 2 C to 8 C. After recostitutio, the arragemet ought to be utilized withi 4 hours. The cost of the treatmet chages relyig o the seriousess of the wrikles, age of the patiet ad the uits ifused to the patiet, ad the result may last up to 6-8 moths relyig upo the same factors [25], the cost of various items is give i the table o.3 Commo idicatios of botulium eurotoxi are brief chage i the presece of direct to serious glabellar lies, the treatmet of brow lies, crow's feet, buy lies, upper ad lower perioral lip lies, gigival gri, doll lies, dimpled butto, vertical eck lies [23, 24]. Complicatio- Overcorrectio, Uder correctio, Asymmetric result Upper-eyelid ptosis, Dysphagia, eck shortcomig, Perioral hag, Bruisig, Globe aperture, Diplopia (horizotal rectus), Psychosomatic problems [26,27]. Table 3: List of Commercially Available Botox Ijectios Product Compay Uits Cost/Uit(Ir/Usd) Botox cosmetic Allerga, Irvie, Califoria 50ml 1650/120 Dysport Ipse Ltd Berkshire, UK 50ml 1780/290 Xeomi Merz-Pharmaceuticals, Frakfurt, Germay, 50ml 1050/230 Myobloc Solstice-Neuroscieces, Sa Fracisco, CA 50ml 1,050/230 Neurobloc Solstice Neuroscieces Ic, Sa Fracisco, Califoria 50ml 700/125 Botox ijectio P&R Export 50ml 1000 Botox ijectio Plasma life care 100ml 1800 Botox powder Faatic pharma 50ml 5000 Coclusio The above comprehesive study about the types of atiwrikle agets summarizes the curret modalities available i aesthetics for treatig the sigs of agig. Hyaluroic acid may show hypersesitivity reactios i some patiets. The ly accepted ad most frequetly used ati-wrikle agets icludes hyaluroic acid which is used i differet type of topical preparatio for treatig early sig of agig, whereas ~ 12 ~

7 The Pharma Iovatio Joural botulium eurotoxi is used as Botox ijectios ad admiistrated itra-dermally i the ski for the treatmet of wrikles i the differet parts of the body. The article also throws light o the ogoig trials usig future ovel techiques for the treatmets of wrikles ad other facial deformities. Additio of atioxidats such as iaciamide, tocopherol, gree-tea polypheols etc. to the topical preparatios of hyaluroic acid probably further wriklig of the ski have o side effects o the ski ad body whe applied topically. Refereces 2. Desmod J. Tobi, Itroductio to ski agig, Joural of Tissues viability. 2006; 2: Paolo U. Giacomoi, A mechaistic model for the agig of huma ski, Joural of Dermatology. 2008; 1: Kim H, Kim M, Qua Y, Moo T. Tissuse ad ski egieerig, Ski research techology. 2004; 2: Eleaor J Bradley, Christopher EM, Griffiths Michael J, Sherratt Mike Bell, Rachel EB, Over-the-couter atiageig topical agets ad their ability to protect ad repair photo aged ski, Joural of Dermatological sciece. 2012; 3: Natalia M Sawowska, Domiika A Zadio, Domiika L Weisto. Dziasecka physiochemical properties ad of hyaluroic acid, Joural of cosmetic dermatology. 2000; 2: Staislaw Rburzyski. Hyaluroic acid as dermal fillers, Medical hypothesis. 2011; 60: Michael S Gart, MDa Karol A, Gutowski. Overview of Botulium Toxis for Aesthetic Uses, Joural of cosmetic Asthetics. 2012; 2: Wo-serk, Byugsoo perk, agets for treatmet of agig effect Joural of Dermatological sciece. 2009; 53: Lee Dh, Koo Kt, Suk Jm. Effect of chemical peelig ad laser techiques o ski agig, Joural of cosmetic ad laser therapy, 2014; 34: Miy-Youg seo, So-Youg chug, Wag-keu chai. Adipose defied stem cells for tissues regeeratio, Joural of Bioscieces ad Bioegieerig. 2010; 107(44): Euseo Huwag, Sagyag Park, Chag shik yi. Effect of giseg ad effects o ski, Joural giseg research. 2008; 25: Geji imokawa. Activatio of TGF-stem cells derviatios, Joural of ivestigatio Dermatology symposium proceedigs. 2007; 14: Niki Chodrogiai, Suzae kapeta. Dermatological aspects of DHEA, Experimetal Gerotology. 2012; 45: ARag IM, Jae Hyoug sag. Gee silecig for the treatmet of ski agig, BMC- complemetary ad alterative medicie. 2015; 56: Jiaqiao zhog, Niafag hu, Xia xiog. Characterisatio of Paracrie cytokie likage, Medical hypothesis. 2012; 25: Kwotr Choi EJ, Kim SR. Cliical aspects of Qeurceti, Photodermatology. 2014; 34: Karim AA, Azia A, Ismail A, Hashim P, ABD GANI SS. Effect of rice-wie o the photoaged ski- trial, BMC- complemet alterative medicie. 2015; 56: Stephaie Nouveau, dimiishig effect of photo aged ski usig Pogo stoe, Maturitas. 2013; 59:344-46, 20. Xiu-fe Wag, La wag. Effect of mesechymal stem cells o photo aged ski, Experimetal Gerotology. 2016; 77: Christopher B Highley, Gle D Prestwich, Jaso A Burdick. Recet advaces i hyaluroic acid hydrogels for biomedical s, Joural of Biomedical scieces. 2015; 45: Natalia M Salwowska, Katarzya A Bebeek, Domiika L, Domiika A Zadło, Wcisło-Dziadecka. Physiochemical properties ad of hyaluroic acid: a systematic review, Joural of ski dermatology. 2015; 67: Michael H. Gold, Use of hyaluroic acid fillers for the treatmet of the agig face, Iteratioal joural of ski dermatology. 2012; 34: Maurı cio de Maio. Botulium toxi i associatio with other rejuveatio methods, Idia joural of ski agig. 2007; 57: Timothy Corcora, Fly cary, Botulium Toxi Examiig Duratio of Effect i Facial Aesthetic, Joural of ski dermatology. 2011; 67: Dave WLU, Jaatha Lippitz. Complicatios of botulium eurotoxis Joural of ski Aesthetics. 2010; 34: Steve H Daya, Complicatios from Toxis ad Fillers i the Dermatology, Joural of ski aesthetics. 2010; 55: ~ 13 ~