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Age Reversing Drugs and Devices in Dermatology

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					                       “Age Reversing Drugs and Devices in Dermatology”

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Retinol, retinol derivatives, tazarotene and adapalene discussion


       Retinol is also known as vitamin A and is widely available in the U.S. in over the counter

preparations. In an in vivo study of retinol, tretinoin, and vehicle applied to human buttock skin,

retinol 1.6% was found to significantly increase epidermal thickening comparable to tretinoin

0.025% but without the erythema associated with tretinoin [1]. Subsequent studies demonstrated

that retinol inhibits UV induction of collagen degrading enzymes and stimulates collagen

production in photoaged skin [2]. Low dose retinol 0.1% was found to promote keratinocyte

proliferation in vivo and improve clinical photoaging of fine lines and skin tone evenness in the

lateral periorbital regions when applied for a nine month period with minimal irritation [3]. In

addition to the effects on photoaged skin, retinol has been shown to improve naturally aged skin.

This is important because the degree of collagen damage in naturally aged skin tends to be less

pronounced than in photoaged skin, and so the prospect of an irritating regimen becomes even

less desirable when treating subtle changes. Retinol 0.04% applied to sun protected skin of the

upper arms in an elderly population was demonstrated to significantly increase

glycosaminoglycan expression and procollagen I immunostaining compared with vehicle and

only mild irritation was noted in subjects [4].


       Retinol derivatives such as retinyl acetate, retinyl proprionate and retinyl palmitate are

widely used in over the counter anti aging treatments. Retinyl retinoate applied twice daily was

shown to induce significant improvement of lateral periorbital rhytides and improved texture

measured by subject self-assessment, investigator assessment and image analysis when
compared to vehicle or retinol without significant side effects [5]. This novel retinol derivative

has also been associated with upregulation of hyaluronan synthase 2 gene in human

keratinocytes [6]. Hyaluronan is a glycosaminoglycan in the dermal extracellular space which

retains water; an increase in hyaluronan and resulting water retention is associated with

improved appearance and clinical reduction in wrinkling.


       Tazarotene is another retinoid which is metabolized to tazarotenic acid, and it selectively

binds to RARs but does not bind RXRs[7]. In a prospective, multicenter, randomized study of

varying strengths of tazarotene cream (0.01%, 0.025%, 0.05%, and 0.1%) for moderate facial

photodamage, tazarotene was found to significantly improve mottled hyperpigmentation and fine

wrinkles at week 24. The higher concentration demonstrated the best efficacy, and it was found

to be comparable to tretinoin. Tazarotene was fairly well tolerated though mild to moderate local

adverse events were seen at the higher concentrations [8]. It should be noted that tazarotene

carries a Pregnancy category X rating in contrast to tretinoin which is pregnancy category C.


       Only one study has been performed of adapalene, a synthetic retinoid widely used in acne

therapy, for photoaging. Subjects with actinic keratoses and photoaging applied two strengths of

adapalene or vehicle for up to nine months and actinic keratoses were reduced in the adapalene

groups compared to the vehicle. In addition lentigines were lightened in the adapalene groups

and retrospective photographic review revealed significant wrinkle improvement in adapalene

compared to vehicle [9].


Estrogens


       Estrogen exerts its actions on skin through estrogen receptors. The effects of estrogen on

skin are derived from studies of post-menopausal women. Estrogens have been reported to have
effects on both the epidermis and the dermis. In the epidermis, they have been associated with

increased thickness, hydration and an increase in surface lipid content. In the dermis they have

been associated with increased hydration through an increase in glycosaminoglycan content as

well as through increased collagen [10]. Menopause is associated with an increase in skin

dryness, decreased elasticity, and decreased dermal thickness [11, 12]. Estrogen based

treatments are believed to be beneficial for improving the appearance of photoaged skin, but the

scientific evidence is scanty. Women who take estrogen replacement are observed to have better

skin hydration, elasticity and fewer fine lines [13] [14]. Other studies, however, have not

demonstrated beneficial effects of estrogen therapy on photoaged skin [11].


       In a study of menopausal women assigned to receive transdermal estrogen only,

transdermal estrogen and progesterone, or oral estrogen and progesterone for 6 months, mean

levels of epidermal skin moisture, elasticity and skin thickness were significantly improved

compared to a no treatment group [15]. Another study of low-dose hormone therapy

(norethindrone acetate and ethinyl estradiol) in postmenopausal women with mild to moderate

photoaging for 48 weeks demonstrated no significant change in global assessment in wrinkling

and sagging [16].




Antioxidants


NAC is an amino acid derivative that is converted to glutathione, an endogenous antioxidant. In

clinical practice, it is used to treat acetaminophen toxicity, intravenous contrast-induced

nephropathy, and as a mucolytic. In a study of topical NAC 20% applied under occlusion to

human skin, reduced glutathione, the form of glutathione with potent ROS scavenging ability
was increased and the oxidized form was eliminated. Additionally, pre-treatment with NAC

prevented UV induced extracellular signal-regulated protein kinase (ERK) activation and

subsequent upregulation of AP-1 and MMPs which prevent collagen breakdown. NAC did not

function as a sunscreen nor did it reduce UV induced erythema [17]. The unpleasant odor

associated with NAC imparts a major barrier to its use in cosmetic preparations.


       Genistein is an isoflavone characterized as a phytoestrogen and the major active

constituent in soybeans and has well documented potent antioxidant and chemopreventive

activitie [18] [19]. Topical pre-treatment with genistein 5% prevents UV-induced activation of

the EGF receptor in human skin leading to the prevention of upregulation of AP-1 and MMPs

and subsequent collagen breakdown [17]. In a study of women in their late 30s and early 40s, 40

mg of soy isoflavone aglycone was given to a treatment group and a placebo food to the control

group. The women who received the soy isoflavone aglycone were noted to have a statistically

significant improvement of fine wrinkles at week 12 and of malar skin elasticity at week 8

compared to the control group [20].


       Vitamin C or ascorbic acid is a co-factor for several enzymes and importantly is a

scavenger of free radicals because it allows vitamin E to remain in its active form. In the dermis,

it is required for the formation of stable collagen [21]. Topically applied vitamin C stimulates

the collagen producing activity of the dermis and applied for 6 months led to clinical

improvement in photoaged skin with respect to firmness, smoothness and dryness compared to

vehicle [22] [21].


       Coenzyme Q10 or ubiquinone plays an important role in the mitochondrial respiratory

chain because it distributes electrons between various dehydrogenases. In its fully reduced state
(ubiquinol) it is a potent scavenger of superoxide [23]. Idebenone is a synthetic analog of

Coenzyme Q10 with potent antioxidant activity. It is used in clinical practice for the treatment

of cardiac hypertrophy in Friedreich’s ataxia [24]. Applied topically in 0.5% and 1%

formulations, it was noted to reduce skin roughness, increase hydration, reduce fine lines and

was associated with overall global improvement in photoaged skin [25].




Ablative resurfacing


       The continuous wave carbon dioxide laser was the first ablative resurfacing device and

continues to be the gold standard against which all other resurfacing procedures are compared.

The CO2 laser emits a 10,500nm wavelength whose chromophore is water. CO2 laser light

penetrates 20-30 um into tissue. The CO2 laser generates heat which results in immediate

tightening due to the shrinkage and denaturation of type I collagen [26]. Clinical improvement

and tissue remodeling occurs over a period of several months. Wrinkle improvement has been

reported to be on the order of 50-90% with fine wrinkles around the mouth and eyes being more

improved than the deep, coarse ones seen in the nasolabial creases [27] [28]. The mechanisms of

CO2 laser resurfacing were quantified by Orringer et al. in photodamaged human forearm skin

and were found to proceed through a reproducible wound healing response leading to an

improved dermal structure. Cytokines involved in wound healing responses such as IL-1, TNF-

 and TGF-1 were elevated and accompanied collagen production evidenced by elevated types

I and III procollagen mRNA levels at 21 days after treatment and remained so for at least 6

month. In addition, enzymes associated with breakdown of fragmented collagen known as

matrix metalloproteinases (MMPs) were noted to be elevated when mRNAs levels were
measured. The breakdown of old and damaged collagen coupled with new collagen formation

are known events in wound healing and are also associated with enhanced skin appearance [29].


        The erbium:yttrium-aluminum-garnet (Er:YAG) laser is another ablative skin resurfacing

laser that emits a wavelength of 2940nm and is close to the absorption peak of water. Its

penetration depth is limited to 1-3 um of tissue so is thought to provide more precise skin

ablation than CO2 ablation. In comparative studies, however, of CO2 to Er:YAG, CO2 laser

ablation is considered to be superior likely due to the greater tissue tightening effect of CO2 [30]

[31].




Q-switched lasers, intense pulsed light (IPL) and radiofrequency [32]


Short-pulsed lasers or Q-switched lasers deliver high-energy pulses to selectively target pigment

with minimal thermal damage to surrounding tissue [33]. Examples of these laser sources

include the Q-switched 532nm, Q-switched 755nm alexandrite and the Q-switched 1064nm. The

QS 532nm targets melanin and red/orange and yellow tattoo pigments. The QS 755 alexandrite

targets melanin and green/blue tattoo pigments. The QS 1064nm targets melanin and black

tattoo pigments. Though the QS 1064nm is pigment specific, it has been shown to induce

nonablative dermal remodeling, new collagen formation, and an increase in fibroblasts and

angiogenesis [34]


        Intense pulsed light (IPL) is a light based therapy comprised of several different

wavelengths. It is used to target both pigment and vascularity, and the term “photorejuvenation”

has been used to describe the global improvement seen with this technology [35]. The

improvement seen in rhytides is much more modest with IPL than the improvement seen in
pigment and vascular issues. Pretreatment with the topical photosensitizer 5-ALA results in a

significantly greater improvement in global photodamage, mottled hyperpigmentation and fine

lines than treatment with IPL alone [36].


       Radiofrequency wavelengths [32] produce electrical energy that heats the dermis using

relatively low temperatures. These wavelengths are employed to increase the depth of

penetration in an attempt to achieve skin tightening [37]. RF has the advantage of minimal post

procedure erythema. The theory driving the technology is that uniform volumetric heating of the

reticular dermis occurs due to the tissue’s resistance to the current flow [35].




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