(cid:49)(cid:68)(cid:85)(cid:72)(cid:68)(cid:86)
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`Kirk A James, Craig N Burkhart† & Dean S Morrell
`†UNC School of Medicine - Dermatology, 410 Market Street, Suite 200 Chapel Hill, NC 27516, USA
`
`Acne vulgaris is a common skin disorder that affects most individuals at some
`point in their lives. It may result in significant morbidity, including cutane-
`ous scarring and psychological impairment. Current treatments include topical
`retinoids, benzoyl peroxide, topical and systemic antibiotics, and systemic
`isotretinoin. There are growing concerns of rising antibiotic resistance,
`significant side effects of isotretinoin therapy, and lack of safe and effective
`treatment for pregnant females. Recent advances in the pathogenesis of acne
`have led to a greater understanding of the underlying inflammatory mech-
`anisms and the role the Propionibacterium acnes and biofilms. This has led to
`the development of new therapeutic targets. This article reviews emerging
`treatments of acne, including topical picolinic acid, topical antibiotic dapsone,
`systemic zinc salts, oral antibiotic lymecycline, new formulations of and syner-
`gistic combinations of benzoyl peroxide, photodynamic therapy with topical
`photosensitizers and potential acne vaccines.
`
`Keywords: acne, acne vulgaris, biofilm, dapsone, new treatments, photodynamic therapy,
`picolinic acid, synergy, vaccine, zinc
`
`Expert Opin. Emerging Drugs (2009) 14(4):649-659
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`
`Acne vulgaris is a common skin disorder that is characterized by a spectrum of
`cutaneous lesions. This spectrum ranges from non-inflammatory comedones, such as
`blackheads and whiteheads, to inflammatory lesions that may consist of papules,
`pustules and/or nodules. Adolescence is the most common period in which acne
`begins and is subsequently diagnosed. Furthermore, it is estimated that > 85% of
`teenagers are afflicted with the disorder [1,2]. However, acne may initially present
`during or persist into adulthood. Acne is more common in males than females during
`adolescence; in contrast, acne is more common in females during adulthood [3].
`Acne may result in a distorted body image and visible scarring, which may lead to
`low self-esteem and influence the development of psychological and social impair-
`ment: it has been associated with anxiety, depression and social withdrawal [4]. In
`the US, the direct cost of acne is high, as it is estimated be greater than $ 1 billion
`a year, with $ 100 million being attributed to over-the-counter products [5].
`Pilosebaceous glands, which arise from hair follicles, are the sites from which acne
`lesions arise. These glands, corresponding to the areas of the body most commonly
`afflicted by acne, are found most numerously on the face, back and chest. As the
`level of circulating androgens increase during puberty, the size and activity of
`pilosebaceous glands increase and reaches a peak by 20 – 30 years of age [6].
`The pathophysiology of acne is associated with four etiological factors, including:
`hyperplasia of the pilosebaceous duct, increased sebum (the oily substance produced
`by a pilosebaceous gland) production, colonization with Propionibacterium acnes,
`and inflammatory and immune response of the body. Propionibacterium acnes is
`the principal microorganism found within the pilosebaceous gland. Its role in acne
`pathogenesis may be related to its ability within the pilosebaceous unit to create and
`exist as a biofilm [7], which is a population of microorganisms that live within a
`self-made, extracellular polysaccharide encasement that is adherent to either an
`artificial or living surface.
`
`1. Background
`
`2. Medical need
`
`3. Existing treatment
`
`4. Current research goals
`
`5. Scientific rationale
`
`6. Competitive environment
`
`7. Conclusion
`
`8. Expert opinion
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`Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Allergan ( ACTIVE)
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`For personal use only.
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`Almirall EXHIBIT 2019
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`Amneal v. Almirall
`IPR2019-00207
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`

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`
`Acne vulgaris is estimated to affect (cid:94) 17 million people in the
`US, and 85 – 100% people at some point in their lives [3,8].
`Although the prevalence peaks during the teenage years and
`subsequently decreases during adulthood, 8% of those aged
`25 – 34 years and 3% of those aged 35 – 44 years have
`acne [8]. Acne results in an extremely large number of office
`visits to both dermatologists and primary care physicians alike.
`Given that many current treatments have potential for signifi-
`cant side effects, contraindications that preclude use in certain
`groups and experience-reduced responsiveness, there is a need
`to develop safer and effective options to treat this common
`skin disorder.
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`
`The current standard treatment of acne vulgaris is targeted
`towards both the severity and type of lesions involved, and
`consists of a combination of topical and systemic agents.
`Based on the type and number of specific lesions present on
`an individual, acne severity is usually considered comedonal
`(mild), inflammatory (moderate) or nodulocystic (severe) [9].
`Existing treatments target one or more of the four traditional
`pathogenic factors involved in acne.
`
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`Topical retinoids, benzoyl peroxide and antibiotics are used
`to treat comedonal and mild to moderate inflammatory
`acne. These are most commonly used in combination with
`one another.
`The current topical retinoid therapies include tretinoin,
`adapalene and tazarotene. They are thought to inhibit acne
`through several mechanisms, including the induction of come-
`dolysis, inhibition of inflammation and normalization of folli-
`cular hyperproliferation, and hyperkeratinization [10]. Retinoids
`are the foundation of topical acne therapy and are considered
`a first-line treatment of mild to moderate acne. Their side
`effects are generally limited to local skin irritation, such as
`peeling or erythema.
`Benzoyl peroxide is comedolytic [11] and bactericidal [12]
`to P. acnes. It is the oldest and most widely used topical agent
`for the treatment of non-inflammatory and inflammatory
`acne vulgaris. This chemical’s main mechanism of action is
`characterized by the cleavage of oxygen–oxygen bonds, which
`result in the production of benzoyl free radicals [12]. This
`triggers a cascade of events, resulting in the formation of more
`free radicals. These free radicals act as exfoliating agents,
`which clear pores and increase skin turnover: this helps treat
`the non-inflammatory comedones of acne. The free radicals
`also destroy bacteria in both aerobic and anaerobic condi-
`tions, which is an important feature considering the primary
`pathogen responsible for the inflammatory lesions, P. acnes,
`is an aerotolerant anaerobe. Benzoyl peroxide has not been
`associated with antibiotic resistance[13]. It is the most widely
`
`used topical agent for acne as it has proven efficacy, minimal
`side effects, broad availability and affordability.
`Topical antibiotics consist of erythromycin, clindamycin,
`and less commonly, tetracycline. They act as both antibacterial
`and anti-inflammatory agents, and are thus reserved for
`inflammatory acne. Their ability to reduce inflammation is
`thought to be related to the suppression of leukocyte chemot-
`axis, reduction of pro-inflammatory free fatty acids within
`sebum and a decrease in the amount of P. acnes organisms [14].
`There have been growing concerns about antibiotic resistance,
`and it is recommended that topical antibiotics be combined
`with other topical retinoids or benzoyl peroxide to decrease
`the emergence of drug resistance.
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`Oral antibiotics are used for moderate to severe inflammatory
`acne. Like topical antibiotics, they have both antibacterial and
`anti-inflammatory properties. Drugs of the tetracycline class,
`(doxycycline, minocycline and tetracycline), erythromycin
`(a macrolide) and trimethoprim are most often prescribed. The
`lipophilic antibiotics, such as doxycycline and minocycline,
`are generally more effective than others. They have tradition-
`ally been very effective, but according to recommendations of
`the ‘European expert group on oral antibiotics and acne,’ use
`should not exceed 3 months, as the risk of developing anti-
`biotic resistance is known to increase after 3 months of use [15].
`In clinical practice, however, use may be continued longer
`until improvement is noted. In addition to the increased risk
`of resistance, prolonged systemic antibiotic use can alter the
`normal flora of the body, subsequently elevating the risk of
`opportunistic infection. One study found a higher incidence
`of upper respiratory infections in those on oral antibiotics
`for acne, but no increased risk of developing a urinary tract
`infection [16]. Further study is needed to confirm and better
`understand these findings. Side effects of the tetracycline
`class include most commonly gastrointestinal complaints, such
`as nausea or vomiting [17]. Dose-dependent photosensitivity
`may be noted with doxycycline [18], and this class is contrain-
`dicated in pregnancy and children younger than 10, as it may
`cause yellow discoloration of the teeth and hypoplasia of
`tooth enamel [10,19]. Erythromycin is associated with nausea,
`vomiting and abdominal cramps [20].
`Isotretinoin, a vitamin A metabolite, is typically reserved
`for severe nodular acne that is unresponsive to other forms of
`treatment. It targets all four pathogenic factors of acne, as it
`decreases sebum production by (cid:94) 70%, reduces the amount
`of P. acnes organisms, inhibits inflammation and normalizes
`follicular proliferation [3]. This is an effective treatment, but is
`severely teratogenic [21] and can be associated with multiple side
`effects. Therefore, its use is restricted by the FDA in the US.
`In women, hormonal agents, such as oral contraceptives
`and spironolactone, can also be considered, especially if
`ovarian or adrenal hyperandrogenism is suspected. Oral con-
`traceptives are thought to increase the amount of serum sex
`hormone-binding globulin, which reduces the amount of
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`circulating free testosterone [22]. This treatment can be rarely
`associated with severe cardiovascular side effects. Spironolac-
`tone decreases androgen production by binding to the
`androgen receptor, preventing its interaction with dihy-
`drotestosterone [23]. Its most significant side effect is hyper-
`kalemia, and it should be avoided during pregnancy to prevent
`feminization of the male fetus.
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`The main limitation of current antibiotic treatment for acne
`is the rise of antibiotic resistance. Although there have been
`studies that have been conducted in vitro that show increased
`resistance of P. acnes colonies to certain antibiotics, it is impor-
`tant to note that this bacteria is thought to exist as a biofilm
`within the pilosebaceous unit in vivo, not as a freely mobile
`microorganism [7]. Unfortunately, P. acnes does not exist as a
`biofilm in vitro. Therefore, studies that have shown increased
`antibiotic resistance of the freely movable bacterial colonies
`in vitro do not really provide an accurate assessment of the
`resistance of the bacteria within the pilosebaceous unit, unless
`there is a subsequent association to a lack of or diminished
`clinical response [24]. Nevertheless, a recent review cited
`studies that have taken P. acnes isolates and tested their resis-
`tance to various drugs in vitro demonstrating that one out
`of every two acne patients in the UK is colonized with strains
`that are resistant to erythromycin and clindamycin [25]. Although
`they found a smaller percentage of patients that had strains
`that were resistant to tetracycline, these P. acnes variants usu-
`ally had resistance to erythromycin and clindamycin as well.
`Another study reported a near doubling of the proportion of
`acne patients with antibiotic-resistant P. acnes from 34.5% in
`1991 to 64% in 1997[26].
`Possible methods to determine antibiotic resistance of
`P. acnes are studies that show either decreased clinically-
`oriented outcomes with the same concentrations over time, or
`increased concentration or duration of antibiotic treatment
`needed to achieve the same clinical results. In order to deter-
`mine a decreased efficacy in reducing the amount of acne
`lesions, it is easiest to follow the clinical results of antibiotic
`treatment over time. For instance, a systemic review revealed
`that 1.5 – 2% topical erythromycin used for 12 weeks had a
`60 – 40% decrease in inflammatory lesion counts from the
`early 1980s to the early 1990s, but by the late 1990s, the
`antibiotic only produced a 20% decrease in lesion count [27].
`Another study showed a correlation between decreased
`in vitro sensitivity or increased resistance to tetracycline and
`erythromycin and a poorer clinical response [28].
`Although isoretinoin therapy is very effective, it is associated
`with many potential side effects. These include dry skin,
`lips, and eyes, headache, decreased night vision, and more
`rarely, benign intracranial hypertension. It may also lead to
`an increase in liver enzymes [29] and hypertriglyceridemia [30];
`the latter may potentially trigger acute pancreatitis. Addi-
`tionally, isotretinoin is a highly teratogenic agent, especially
`if used within the first trimester of pregnancy. It is essential
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`
`that a female have two negative pregnancy tests before begin-
`ning treatment, and must have negative pregnancy tests through-
`out treatment and 6 weeks after cessation; oral contraceptives
`are typically prescribed during this period to prevent preg-
`nancy. Furthermore, treating acne, especially moderate to
`severe inflammatory variants, is especially challenging during
`pregnancy because most of the systemic antibiotics cannot
`be safely used during this time period either.
`It is a concern for the potential rise in antibiotic resistance,
`teratogenicity and unfavorable side effect profile of isotretinoin,
`a lack of safe treatment options during pregnancy and the
`identification of previously unknown microbiological targets
`such as the biofilm hypothesis that necessitate the need to
`explore the potential of evolving alternative treatments for
`acne vulgaris.
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`
`Recent advances have led to new potential therapeutic targets,
`such as the light-absorbing porphyrins produced by P. acnes
`and components of biofilms. Given that the immune system’s
`inflammatory response is a complex interplay between various
`cells and chemical mediators, our understanding of it will
`constantly change. As we delve further into the P. acnes biofilm
`and the reason that makes it so difficult to break down and
`eradicate, we will find new therapeutic targets. There should
`also be a constant focus on finding new antibiotic treatments
`or combination treatments to prevent the development of
`antibiotic resistance, which has been a growing problem. Thus,
`as our understanding of the complex pathogenesis of acne is
`improved, more therapeutic targets will be revealed, and
`these will hopefully lead to more effective treatment options
`for patients with acne vulgaris. Additionally, there have been
`studies that have tested the efficacy of P. acnes vaccines in
`animal models of acne.
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`
`Current drug therapies typically target one of the four tradi-
`tional pathogenic factors of acne mentioned earlier. Advances
`in the understanding of the pathogenesis of acne have led to
`two new potential therapeutic targets. As stated before,
`these include the hypothesis that the P. acnes biofilm may
`be a central event in the acne pathogenesis and the fact that
`P. acnes generates photosensitizing porphyrins within the
`pilosebaceous unit.
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`5.1.1 Pilosebaceous hyperplasia
`Follicles that are affected by acne show increased keratinocyte
`proliferation with subsequent abnormalities in desquamation,
`which leads to marked accumulation of these cells within the
`follicle. The end result is the production of microcomedones
`which eventually become grossly visible comedones. This is
`considered to be the first step in the pathogenesis of acne.
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`
`Follicular hyperkeratosis is thought to result from several
`possible factors including a deficiency in linolic acid or the
`production of certain comedogenic peroxides within sebum [10].
`Inflammatory mediators may also play a role, as one study
`showed that ample concentrations IL-1 within the follicle
`can induce hyperkeratosis [31]. Recently, with the discovery
`that P. acnes can create and exist as a biofilm, it is thought
`that the secreted glycocalyx polymer can actually become
`incorporated into the sebum composition and act as biological
`glue between keratinocytes, and thus, ultimately lead to the
`production of comedones [32]. Therefore, it is highly plausible
`that the initial step may not even be hyperkeratosis of the
`follicle, but rather colonization with P. acnes and subsequent
`biofilm formation.
`
`5.1.2 Increased sebum production
`Excess sebum production can be caused by several different
`factors. Androgens induce the production of sebum, and their
`abrupt increase during puberty explains why acne begins
`during adolescence. It also helps explain why those with
`hyperandrogenism (e.g., polycystic ovarian syndrome, adrenal
`tumors) usually have acne manifestations. However, most acne
`patients have normal circulating levels of androgen within
`their serum [10]. It is hypothesized that these individuals possess
`sebocytes that have an increased sensitivity to androgens.
`Specific neuroendocrine peptides (corticotrophin-releasing
`hormone and (cid:65)-melanocortin) have also been shown to
`stimulate lipid synthesis by sebocytes in vitro, which supports
`an association between stress and acne [33].
`
`5.1.3 Colonization by Propionibacterium acnes
`Propionibacterium acnes is an aerotolerant anaerobe that prefers
`anaerobic areas with increased lipid content. This explains why
`this bacterium thrives and proliferates in a pilosebaceous unit
`that has been plugged from hyperkeratosis (and thus, lacking
`contact with environmental oxygen) and has increased sebum
`production. Additionally, P. acnes possesses the ability to
`form a biofilm within the follicle.
`
`5.1.4 Immune response and inflammation
`Multiple inflammatory mediators are involved in the patho-
`genesis of acne. Propionibacterium acnes binds directly to toll-
`like receptor-2 (TLR2) on monocytes and neutrophils [34].
`TLR2 is a surface-membrane protein receptor involved in
`immune activation through the release of inflammatory
`cytokines [35,36]. Thus, these immune cells then produce pro-
`inflammatory cytokines, including TNF-(cid:65), IL-1 and IL-8,
`which act as chemotactic factors for the migration of more
`neutrophils and lymphocytes. Propionibacterium acnes also
`releases metabolites, such as lipases and proteases, which result
`in an inflammatory response by the host’s immune system [37].
`Propionibacterium acnes may also induce the expression and
`secretion of MMP-9, an inflammatory mediator, by kerati-
`nocytes [34]. In addition to the aforementioned secondary
`immune response, there is mounting evidence that primary
`
`immune response may even be the initiating event in acne.
`Perifollicular leukocytes, such as helper T-cells, could poten-
`tially form initial comedones through the release of IL-1 [38].
`The study by Jeremy et al. demonstrated that there is an
`increase in the numbers of CD3+, CD4+ T cells in the peri-
`follicular and papillary dermis of follicles from uninvolved
`skin of acne patients compared to normal skin of non-acne
`controls. The uninvolved skin follicles of the acne patients
`did not show microcomedonal features or keratinocyte
`hyperproliferation. This evidence supports the possibility
`that inflammation of the follicle precedes the traditional first
`step of acne pathogenesis. There was also increased upregu-
`lation of IL-1 perifollicularly. However, the level of T cells
`was not as great as those found in papules of early inflamed
`lesions of acne patients. As these inflammatory mechanisms
`are further uncovered, they could present new potential
`therapeutic targets for future acne treatment.
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`5.2.1 Biofilm
`The first step in the formation of a biofilm is the adherence
`of bacteria to a surface, in this case, P. acnes attaching to the
`pilosebaceous gland wall. The attached bacteria then begin
`to facilitate the attachment of other bacteria and undergo cell
`division to extend the population. The biofilm is established
`as the bacteria begin to secrete an extracellular polysaccharide
`substance that coats the surface of their colony. This coating
`provides physical protection, as it acts as a barrier between
`the cell populations underlying the biofilm and the relative
`exterior environment.
`The genome sequence of P. acnes has been shown to contain
`clusters of genes involved the biosynthesis of a glycocalyx
`polymer [39,40]. The biofilm concept explains why antibiotics
`must be prescribed for months while treating acne: the bio-
`film limits and retards the penetration of antibiotics into its
`microenvironment of organisms. In addition, the microenvi-
`ronment created by the biofilm also stimulates the produc-
`tion of certain proteins which may enhance antibiotic
`resistance of the colonies. This framework provides new tar-
`gets for potential therapies aimed at halting the progress of
`biofilm formation. These include therapies that prevent the
`initial attachment step of P. acnes to the pilosebaceous wall,
`inhibit or alter the formation of the extracellular glycolax
`polysaccharide, target specific components of the biofilm or
`enhance the penetration of the antibiotic through the
`extracellular matrix [7].
`
`5.2.2 Porphyrin production
`Porphyrins are metabolic products of P. acnes with the innate
`ability to absorb light, which enables them to form free radi-
`cals [41]. These free radicals have direct inflammatory effects, as
`they can help damage and destroy P. acnes and the glycocalyx
`capsule of its biofilm. Additionally, there is evidence that these
`chemicals may induce the expression of IL-8 by keratinocytes [42].
`It is suggested that this cytokine may trigger the production
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`of inflammatory substances, such as squalene peroxide, which
`may lead to perifollicular inflammation [43].
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`6.1.1 Picolinic acid
`Picolinic acid is thought to act as a chelating agent of various
`transitional metal ions in the human body, such as zinc, iron,
`chromium and copper. By binding to ions such as zinc, it
`increases their uptake into the circulatory system and through
`the gastrointestinal membrane [44]. Furthermore, picolinic acid
`has been shown to have antiviral, antibacterial and immune-
`modulating properties [45]. It disturbs zinc binding within
`zinc finger proteins, which are DNA-binding proteins that
`usually exist as part of transcription factors [46]. By altering
`this interaction, picolinic acid leads to the alteration of
`chemokine expression. Specifically, Bosco et al. found that
`picolinic acid is potent activator of the inflammatory chemok-
`ines macrophage inflammatory protein-1 (cid:65) and (cid:66) in murine
`macrophages [47]. Although its action against P. acnes has not
`been formally studied, picolinic acid has been shown to be
`particularly effective in inhibiting mycobacterial growth both
`extracellularly and intracellularly [48].
`In a recent study, the application of a 10% picolinic acid
`gel twice a day to the face for 12 weeks reduced the amount of
`total acne lesions by 58.2%, inflammatory lesions by 55.2%
`and non-inflammatory lesions by 59.7% in 20 patients with
`mild to moderate acne vulgaris by the end of the study [49].
`The side effects were considered mild, and the most common
`was burning at the application site. Although the results of the
`study are encouraging, it is still necessary to confirm these
`with a randomized control study.
`
`6.1.2 Anti-inflammatory/antibiotic therapy
`(cid:22)(cid:14)(cid:17)(cid:14)(cid:18)(cid:14)(cid:17)(cid:0) (cid:36)(cid:65)(cid:80)(cid:83)(cid:79)(cid:78)(cid:69)
`Dapsone is an antibacterial medication traditionally used to
`treat Mycobacterium leprae infections; however, two recent
`studies have shown that a 5% dapsone topical gel solution is
`effective in reducing the amount of both non-inflammatory
`and inflammatory acne lesions when used as a monotherapy
`and applied twice a day for 12 weeks [50]. The most pronounced
`effect was in treating the inflammatory lesions, which decreased
`by 47.5% after 12 weeks of treatment.
`It is thought that dapsone possesses anti-inflammatory
`properties that are especially beneficial in treating inflammatory
`acne. Proposed mechanisms of action include the inhibition of
`leukocyte migration and subsequent release of cytokines, and
`altering of the action of P. acnes in the pilosebaceous unit [50].
`The side effect profile is considered safe, with the most
`abnormal events being local site reactions such as dryness and
`erythema. Unlike dapsone delivered by the oral route which
`may cause dose-dependent hemolysis and should be used
`cautiously in those with glucose-6-phosphatase deficiency
`(G6PD), [51] the topical preparation resulted in no changes
`
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`
`from baseline hematologic status in those with or without
`G6PD deficiency, most likely attributable to limited systemic
`absorption [52].
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`6.2.1 Systemic minerals
`(cid:22)(cid:14)(cid:18)(cid:14)(cid:17)(cid:14)(cid:17)(cid:0) (cid:58)(cid:73)(cid:78)(cid:67)(cid:0)(cid:83)(cid:65)(cid:76)(cid:84)(cid:83)
`Zinc salts have been proposed to be helpful in reducing the
`severity of inflammatory acne by a variety of mechanisms. First,
`zinc has been shown to inhibit the migration of neutrophils
`to sites of inflammation, and thus prevent or reduce acute
`inflammatory processes [53]. The growth of the acne-causative
`bacterium P. acnes has been shown to be hindered by zinc [53].
`Additionally, recent studies have shown that zinc reduces the
`expression of TLR2 on the surface of keratinocytes [54].
`Limiting its expression subsequently inhibits the activation of
`the immune response. Other anti-inflammatory mechanisms
`of action include decreasing the release of both TNF-(cid:65) and
`IL-6, which are cytokines involved in inflammation [55].
`Oral zinc salt preparations have historically been shown
`to be effective in reducing the severity of mild and moderate
`inflammatory acne vulgaris when either used alone or in
`combination with another acne treatment [56,57]. A recent
`study compared the effectiveness of oral zinc gluconate to the
`antibiotic minocycline, and although the latter decreased the
`amount of inflammatory acne lesions by a larger percentage,
`zinc was still viewed as a viable alternative [58]. The major side
`effects of systemic zinc treatment include nausea and vomiting,
`but these are dose