the term  macrolide  encompasses a diverse family of unrelated compounds with large macrolactam rings .
macrolide rings are comprised of a large macrocycle lactone ring to which one or more deoxy sugars , usually cladinose and desosamine , may be attached .
in addition to their antibacterial activity , macrolides have diverse biological effects , including modulation of inflammatory and immune responses without affecting homeostatic immunity [ 1 , 2 ] .   macrolides are effective antibiotics that have immunomodulatory effects and inhibit the production of many proinflammatory cytokines such as interleukin 6 ( il-6 ) , il-8 , and tumor necrosis factor alpha ( tnf ) .
many studies have been performed to assess their effectiveness in the treatment of rosacea , psoriasis , pityriasis rosea , alopecia areata , bullous pemphigoid , and pityriasis lichenoides .
however , new strategies for the treatment of cutaneous pathologies are directed towards the development of new nonantibiotic macrolides with anti - inflammatory , antiproliferative , and antiangiogenesis properties .
the most known and used are inhibitors of the phosphatase calcineurin ( pimecrolimus and tacrolimus ) , which under normal circumstances induce the transcription of il-2 . in addition , these drugs inhibit lymphokine production and interleukin release , which lead to a reduced function of effector t - cells .   nowadays ,
novel chemical structures with improved therapeutic anticancer and anti - inflammatory properties by affecting skin disease targets have arose from mammalian rapamycin inhibitors .
these agents inhibit the response to il-2 and thus block the activation of t and b lymphocytes [ 5 , 6 ] . recently ,
new synthetic derivatives of the macrolide azithromycin , namely , csy0073 , ( 8r,9s)-8,9-dihydro-6,9-anhydropseudoerythromycin a ( em900 ) , and ( 8r,9s)-4,13-o - diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin a ( em911 ) having potent anti - inflammatory properties have been developed .
currently , ridaforolimus has been developed but has only been used in vitro thus far .
more studies are required to uncover the possible applications of these promising molecules although one of the first possible applications of these compounds is as an antitumor agent .   in this paper
, we review the clinical use of nonantibiotic macrolides that have become available clinically for chronic inflammatory skin diseases with immune dysfunction .
we searched the cochrane central register of controlled trials ( central ) , med - line ( pubmed ) , and embase ( 2005 to january 2012 ) .
we included case series with 5 or more patients , cohort trials , and randomised controlled trials .
tacrolimus  ,  pimecrolimus  ,  calcineurin inhibitors  ,  new macrolides  ,  rapamycin  , and so forth and  atopic dermatitis  ,  psoriasis  , and other common dermatitises that have been treated using macrolides .
pimecrolimus ( sdz asm 981 , novartis ) is one of the new classes of novel ascomycin immunomodulating macrolactams and was developed for the treatment of inflammatory skin diseases ( figure 1 ) .
ascomycetes , in the early 1960s , was initially researched for its antifungal properties . however ,
more than 20 years later , ascomycin was investigated for its structural and immunomodulatory properties .
interest in pimecrolimus has been intense because it has significant anti - inflammatory and immunomodulatory activity and because it has low potential for systemic immunosuppression .
pimecrolimus binds to fkbp-12 and immunophilin macrophilin-12 , also known as fk506 binding protein . like tacrolimus and
calcineurin is a ca / calmodulin - dependent protein phosphatase that regulates the translocation of the cytosolic components of nfats .
nfats , in turn , regulate the promoter activities of several mediators during mrna transcription . by inhibiting the action of calcineurin , the pimecrolimus - macrophilin complex prevents the dephosphorylation of the cytoplasmic component of nfats .
therefore , pimecrolimus blocks the transcription of these cytokines , especially t - helper th1 ( il-2- , ifn-- ) and th2 ( il-4- , il-10- ) type cytokines ( figure 2 ) .
pimecrolimus decreases the production of other cytokines , including interleukins il-5 , il-10 , and tnf , in a dose - dependent manner .
pimecrolimus also targets mast cells , which play an important role in anti - inflammatory activities .
pimecrolimus inhibits not only the transcription and synthesis of cytokines from mast cells , but also inhibits the release of the preformed mediators serotonin and  -hexosaminidase .
additionally , pimecrolimus inhibits fc epsilon ri - mediated degranulation and secretion ( figure 3 ) .
it is important to note that all of these inhibitory processes occur only when pimecrolimus is bound to macrophilin-12 . in a study of murine mast cell line cpii
, pimecrolimus did not inhibit the transcription of a reporter gene that was under the control of human tnf  promoter in the murine dendritic cell line and had no effect on il-8 release from keratinocytes , fibroblasts , and endothelial cells .
atopic dermatitis ( ad ) is a pruritic disease of unknown origin that usually develops in early infancy ( an adult - onset variant is recognized ) ; it is characterized by pruritus , eczematous lesions , xerosis ( dry skin ) , and lichenification ( thickening of the skin and an increase in skin markings ) .
ad may be associated with other atopic ( immunoglobulin - e-(ige- ) associated ) diseases ( e.g. , acute allergic reaction to foods , asthma , urticaria , and allergic rhinitis ) .
pimecrolimus inhibited cytokines , il-2 and interferon gamma ifn , and th2-type cytokines , il-4 and il-10 .
in addition , pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen / ige .
pimecrolimus cream 1% is a good option for treatment of mild to moderate ad in adults and children aged 2 years [ 4 , 10 ] .
no novel systemic applications have appeared since 2005 . in 2005 , however , there was a study of oral pimecrolimus for use in the treatment of moderate to severe ad .
this study demonstrated the efficacy and short - term safety of oral pimecrolimus in adults in a double - blind study with a 12-week treatment and 12-week post - treatment phase .
psoriasis may develop because of a combination of factors , including genetic predisposition and environmental factors .
the immune system is thought to play a major role in the development of this condition .
the dry flakes and skin scales are thought to result from the rapid proliferation of skin cells that is triggered by abnormal lymphocytes in the blood .
another important application for pimecrolimus is psoriasis treatment , where it acts through blockage of t - cell activation and signal transduction pathways in t cells and through inhibition of the synthesis of inflammatory cytokines , which play a key role in the pathogenesis of psoriasis .
oral pimecrolimus was tested in healthy adult outpatients with moderate to severe chronic plaque - type psoriasis ( n = 143 ) who received either an oral placebo or pimecrolimus for 12 weeks .
oral pimecrolimus was well tolerated and produced a dose - dependent reduction in psoriasis severity .
doses of 20  mg and 30  mg b.d . were the most effective [ 14 , 15 ] .
oral lichen planus ( olp ) is an inflammatory condition that affects the mucous membranes of the mouth .
olp may appear as white lacy patches , red swollen tissues , or open sores .
olp is a t - cell - mediated chronic inflammatory oral mucosal disease of unknown cause , and lesions contain few b cells or plasma cells and minimal deposits of immunoglobulin or complement .
therefore , olp is ideal for studying human t - cell - mediated inflammation and autoimmunity .
antigen - specific mechanisms in olp include antigen presentation by basal keratinocytes and antigen - specific lysis of keratinocytes by cd8 + cytotoxic t cells .
a combination of these mechanisms may cause t cell accumulation in the superficial lamina propria , basement membrane disruption , intraepithelial t cell migration , and apoptosis of keratinocytes in olp ( figure 4 ) [ 9 , 16 ] .
pimecrolimus , as described above , inhibits dephosphorylation of nuclear factor of activated t cells by calcineurin , thus , reducing t - cell cytokine production and inhibiting t - cell activation .
the most compelling of these suggests a combination of genetic and immunologic factors that results in autoimmune melanocyte destruction .
it was effective in their treatment better than topic corticoids [ 19 , 20 ] .
patients in whom the cause of urticaria is unknown are said to have chronic idiopathic urticaria ; however , findings suggest that in 2545% of patients , chronic idiopathic urticaria is not idiopathic but is an autoimmune disease termed as chronic autoimmune urticaria .
chronic autoimmune urticaria is dependent not only on the cross - linking of ige receptors ( by anti - fc epsilon ria or anti - ige ) , but also on the activation of complement .
cross - linking of ige receptors leads to histamine release via a calcineurin - dependent signal transduction pathway , whereas complement c5a receptors act through g - proteins .
histamine release by patient sera or isolated igg can be inhibited by ascomycin but not the c5a .
the failure of pimecrolimus to satisfactorily treat chronic autoimmune urticaria may at least in partly result from this .  
rosacea is a common cutaneous disorder , which occurs most frequently in light - skinned middle - aged individuals .
an important reference we found to the use of pimecrolimus for the treatment of rosacea was a study  by kim  in 26 patients with mild to moderate inflammatory rosacea .
alopecia areata ( aa ) is an autoimmune disease of the hair follicle caused by a t - lymphocytic infiltrate , although its pathogenesis is not yet completely clear . aa results in hair loss and baldness , and may frequently remit and relapse .
histologically , the peribulbar infiltration consists mainly of activated cd4 + and cd8 + t - cells .
type 1 cytokines , including il-2 , ifn - c , and tnf , mediate initiation of the immune response in aa .
pimecrolimus prevents calcineurin - mediated dephosphorylation of the nfats , which inhibits the synthesis of th1 and th2 cytokines in t lymphocytes .
topical pimecrolimus treatment is as effective as topical corticosteroids for the treatment of aa and frontal fibrosing alopecia , and has fewer side effects than topical corticosteroids [ 24 , 25 ] .
this condition is diagnosed by excluding other causes of similar - appearing cutaneous ulcerations , including infection , malignancy , vasculitis , collagen vascular diseases , diabetes , and trauma .
pathergy involves development of new ulcerations after trauma or injury to the skin in 30% of patients with existing pg .
the pathogenesis of pg is not entirely understood , but defects in cell - mediated immunity , humeral immunity , neutrophil chemotaxis , and monocyte phagocytosis along with diminished lymphokine production have been observed in patients with pg .
positive clinical results from treatment of pg with pimecrolimus and tacrolimus are probably due , in part , to a decrease in the release of tfn. tfn  release is considered to be very important in the development of the neutrophilic dermatoses .
pimecrolimus does not affect the differentiation , maturation , and functions of langerhans cells and does not induce their apoptosis .  
discoid lupus erythematosus ( dle ) is a chronic skin condition of sores with inflammation and scarring on the face , ears , and scalp , and at times , on other areas of the body .
localized dle typically manifests as skin lesions localized above the neck and mainly involves sites such as the scalp , bridge of nose , cheeks , lower lip , and ears .
lesions have elevated levels of il-2 , ifn , and tnf  mrna , as compared to normal skin .
elevated type i ifn ( ifn-/ ) has also been found in these skin lesions .
in addition , unlike cyclosporine and tacrolimus , the action of pimecrolimus is more selective for t - cells and mast cells , thus reducing the likelihood of systemic immunosuppression .
behet 's disease ( bd ) was named in 1937 after the turkish dermatologist hulusi behet who first described the triple - symptom complex of recurrent oral aphthous ulcers , genital ulcers , and uveitis .
painful genital ulcerations usually develop around the anus , vulva , or scrotum and cause scarring in 75% of the patients .
the cause is not well defined , but it is primarily characterized by autoinflammation of the blood vessels .
the primary mechanism of the damage is an overactive immune system that seems to target the patient 's own body .
in fact , as of now , no one knows why the immune system starts to behave this way in behet 's disease .
there does however seem to be a genetic component involved , as first degree relatives of the affected patients are often affected in more than expected proportion for the general population .
pimecrolimus is safe and effective for the treatment of bd genital ulcers and accelerates the healing process .
graft - versus - host disease ( gvhd ) is a common complication of an allogeneic tissue transplant .
gvhd is commonly associated with stem cell or bone marrow transplant , but the term also applies to other forms of tissue graft .
immune cells ( white blood cells ) in the tissue ( the graft ) recognize the recipient ( the host ) as  foreign . 
gvhd can also occur after a blood transfusion if irradiated blood products are not used . in the classical sense ,
acute gvhd is characterized by selective damage to the liver , skin ( rash ) , mucosa , and the gastrointestinal tract .
new research indicates that target organs of gvhd other than those mentioned above include the immune system ( the hematopoietic system , e.g. , the bone marrow and the thymus ) itself , and the lungs in the form of idiopathic pneumonitis .
further , chronic gvhd involves the above organs but can also cause damage to the connective tissue and exocrine glands over a long term .
t cells present in the graft , either as contaminants or intentionally introduced into the host , attack the tissues of the transplant recipient after perceiving host tissues as antigenically foreign .
the t cells produce an excess of cytokines , including tnf-  and interferon - gamma ( ifn ) .
a wide range of host antigens can initiate gvhd , such as the human leukocyte antigens ( hlas ) .
the only study in which the treatment of gvhd was reported was that by schmook .
tacrolimus ( figure 5 )   was first isolated in 1984 from a japanese soil fungus .
the macrolide antibiotic tacrolimus ( fk 506 ) was discovered as a naturally occurring metabolite of the fungus streptomyces tsukubaensis .
at least 4 fkbp are described : 12 , 13 , 25 , and 59 .
the main effect of tacrolimus appears to result from the inhibition of t - cell function . following the binding of an antigen - presenting cell to a t cell via the t cell receptor , intracytoplasmic levels of calcium rise , leading to calmodulin activation of the phosphorylase enzyme , calcineurin phosphatase .
the activation of calcineurin phosphatase leads to the dephosphorylation of a cytoplasmic protein - nfat .
once dephosphorylated , nfat translocates into the nucleus where it combines with a nuclear subunit ( nfatn ) .
the binding of nfatn enables transcription of proinflammatory cytokines , including il-2 , il-4 , ifn , and tgf-  and upregulation of receptors , such as il-2r ( cd25 ) .
transcription of these cytokines initiates t - cell activation ( figure 2 ) [ 9 , 33 ] .
activated tacrolimus inhibits the action of calcineurin , thus preventing the dephosphorylation of nuclear factors and blocking this path to gene transcription . in stimulated t cells
inhibition of il-2 production blocks the activation of t - helper cells , t - regulatory cells ( autocrine loop ) , natural killer cells , and monocytes .
in addition to inhibiting il-2 transcription , other calcium - dependent events , including nitric oxide synthase activation ( figure 6 ) , cell degranulation , and apoptosis ( figure 7 )   are also inhibited . in stimulated mast cells ,
tacrolimus decreases histamine release , impairs langerhans ' cell function , and downregulates high - affinity ige receptors .
it also decreases the production of chemotactic protein-1 and il-8 in monocytes and affects other cell types , including neutrophils , eosinophils , and endothelial cells .
inhibition of calcineurin interferes with superantigen stimulation of t cells and may decrease the production of vascular endothelial growth factor .
tacrolimus also inhibits the function of b cells and the production of other cytokines such as il-3 , il-4 , il-5 , ifn , tnf , and granulocyte - macrophage colony stimulating factor ( gm - csf ) . when used to treat ad , tacrolimus inhibits the t lymphocytes , which release the cytokines that trigger the inflammation underlying ad .
tacrolimus also affects other cells including langerhans and mast cells . by downregulating t cells ,
the symptoms of ad begin to fade within a few days of applying a topical ointment that contains tacrolimus .
. however , the skin does not act as a reservoir for this drug , as discussed by kim and kono .
tacrolimus inhibits the production of many proinflammatory cytokines , such as il-6 , il-8 , and tnf , perhaps by suppressing the transcription factors nf-b or activator protein-1 .
however , topical tacrolimus that was applied under occlusion to descaled psoriatic plaques is an effective treatment .
there is good evidence that topical tacrolimus is a highly effective treatment for psoriasis of the face and flexures [ 3739 ] . in our clinical practice , treatment with 0.15  mg / kg b.d .
oral tacrolimus for 1 week resulted in a marked reduction in the erythema and scaling of severe psoriasis patients .
administration of tacrolimus at a dose of 0.3  mg / kg per day to 7 patients with recalcitrant psoriasis resulted in remission with minor metabolic effects , including minimal elevation of urea , creatinine , and glucose in the blood .
more recently , tacrolimus has been used to treat genital lichen sclerosus , a condition in which patches of the skin become thin and wrinkled .
thus , the skin tears easily , and bright red or purple bruises are common . sometimes , the skin becomes scarred .
tacrolimus blocks the proliferation of t lymphocytes and the release of inflammatory cytokines from these cells .
then the skin tears easily , and bright red or purple bruises are common . sometimes , the skin becomes scarred . if the disease is a mild case , there may be no symptoms .
tacrolimus ointment 0.1% may also be effective and well tolerated for the treatment of anogenital lichen sclerosus , both in adults and in prepubertal girls .
recent reports describe the use of 0.1% tacrolimus in a topical formulation for the management of olp .
therefore , there is a need for more effective and safer therapies for symptomatic olp .
the activation of il-2 production occurs after antigen , with a major histocompatibility complex type ii antigen , is presented to the t - cell receptor - cd3 complex .
antigen presentation results in the release of calmodulin , which binds and activates the protein calcineurin that is involved in the dephosphorylation of nfat .
tacrolimus and the intracellular immunophilin protein known as the fk - binding protein form a complex that binds to and inactivates the protein calcineurin . as a result ,
the t - cell receptor - mediated induction of il-2 production is inhibited , resulting in suppression of t - cell - dependent immune functions [ 43 , 44 ] .
contact dermatitis is a condition in which the skin becomes red , sore , or inflamed after direct contact with a substance .
tacrolimus has good anti - inflammatory effects and penetrates well through inflamed skin . in a human study , topical tacrolimus ( at concentrations of 0% , 0.01% , 0.1% , and 1% ) in ethanol
biopsies of the test patches showed no inflammation on the dncb - challenged skin sites that were pretreated with fk 506 , while there was intense dermatitis ethanol - only .
the ability to suppress reactions in previously sensitized patients is important because contact dermatitis patients do not present until after primary sensitization .
the ability to treat such sensitized individuals is crucial because many antigens , such as nickel , are ubiquitous and complete avoidance is often impossible .
topical tacrolimus also suppresses irritant reactions in animal models , suggesting that topical tacrolimus may also be useful for primary irritant contact dermatitis .
this may be applicable to the treatment of chronic hand dermatitis and occupational irritant dermatitis ( in which allergic contact often coexists ) .
the efficacy and safety of 0.1% tacrolimus ointment in vitiligo were compared favourably to that of 0.05% fluticasone propionate cream for the treatment of segmental vitiligo in a randomized controlled trial .
even diseases that are not considered to be classic t - cell - mediated inflammatory processes have been considered as targets for tacrolimus therapy .
goldman noted that the anti - inflammatory properties of topical tacrolimus that unlike steroids , tacrolimus may not have intrinsic rosacea - promoting properties .
he treated the patients who had steroid - induced rosacea and were previously unable to taper off and discontinue the use of steroid therapy .
the eruptions were controlled in all 3 patients , and they were able to successfully taper off tacrolimus therapy and switch to a long - term regimen of topical antibiotics [ 47 , 48 ] . while aa is another candidate disease for tacrolimus therapy , some authors have expressed reservations regarding its use for this purpose , as aa generally responds poorly to treatment .
thiers published a report of the failure of 0.3% tacrolimus ointment to treat aa in a 9-year - old .
steroid intralesionals in combination with topically applied tacrolimus yield better results than topical tacrolimus alone [ 50 , 51 ] . in 5075% of patients ,
pg is associated with inflammatory bowel disease , rheumatoid arthritis , chronic autoimmune hepatitis , or haematological solid tumours .
tacrolimus ointment ( 0.1% ) was applied to dle lesions twice daily and the erythematous plaques readily diminished after 48 weeks .
cutaneous le is a broad term , which includes a variety of lesions that may appear in the absence of the systemic manifestations of systemic lupus erythematosus [ 52 , 53 ] . in an open - label study of tacrolimus
( 0.1  mg / kg ) administered for 1 year with dosage adjustment showed that serum c3 level , and anti - ds dna antibody titre improved with tacrolimus treatment .
the mean titre of anti - ds dna antibodies provides a representative indicator of immunological parameters reflecting disease activity .
therefore , a t cell blockade is considered a reasonable therapeutic target for cutaneous and systemic le [ 54 , 55 ] .
tacrolimus can therefore be considered both effective and safe for treating mild manifestations of le , including skin dermatosis , in systemic le patients . however , for severe active conditions , its efficacy is limited at current dose settings and usage .
crohn 's disease ( cd ) , also known as regional enteritis , is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from the mouth to anus and causes a wide variety of symptoms .
cd is caused by interactions between environmental , immunological , and bacterial factors in genetically susceptible individuals .
this results in a chronic inflammatory disorder , in which the immune system of the body attacks the gastrointestinal tract possibly directed at microbial antigens .
one type of skin manifestation , erythema nodosum , presents as red nodules usually appearing on the shins .
erythema nodosum is due to inflammation of the underlying subcutaneous tissue and is characterized by septal panniculitis .
a new view is that cd results from an impaired innate immunity , in that impaired cytokine secretion by macrophages contributes to impaired innate immunity and leads to a sustained microbial - induced inflammatory response in the colon , where the bacterial load is high . despite the poor quality of the majority of trials examining the role of tacrolimus in cd
, there is some evidence suggesting that tacrolimus may be of some benefit in this disease .
although systemic immunosuppressants are generally believed to increase the rate of cancer development , one study has shown that in female cd-1 mice there was a dose - related inhibition of 7,12-dimethylbenz[a]anthracene-(dmba- ) initiated and 12-tetradecanoylphorbol-13-acetate-(tpa- ) promoted skin papillomas when 0.1  mol tacrolimus was applied topically .
this antineoplastic effect may be unrelated to the suppression of t - cell functions and might occur after endogenous protein phosphorylation by tpa .
this study was contradicted by a later study of the occurrence of de novo neoplasms in organ transplant recipients .
cutaneous t cell lymphoma ( ctcl ) is a class of non - hodgkin 's lymphoma , which is a type of cancer of the immune system . the malignant t cells in the body initially migrate to the skin , which result in the development of various lesions .
these lesions change shape as the disease progresses , typically beginning as what appears to be a rash , which can be very itchy , and eventually forming plaques and tumors before metastasizing to other parts of the body .
ctcls are a heterogeneous group of lymphoproliferative disorders caused by clonally derived skin - invasive t cells .
few studies have reported the efficacy of topical tacrolimus for the treatment of ctcls [ 5961 ] .
topical application of 0.3% tacrolimus in isotonic solution or cream is a promising treatment modality for pathology ocular in bd .
pulmonary and intestinal lesions evanesced and skin lesions improved after the oral administration of fk506 at a dose of 0.1 - 0.2  mg / kg for 8 weeks [ 63 , 64 ] .   in a case of refractory gvhd
, the patient responded to a combination of oral tacrolimus , psoralen , and uv - a therapy .
this suggests that systemic tacrolimus may benefit recipients of solid organ or bone marrow transplants with gvhd that is refractory to cyclosporine , high - dose systemic steroids , and antithymocyte globulin .
the initial intravenous fk506 dose of 0.04  mg / kg per day and should be maintained for 7 days post - transplant .
after day 7 , intravenous fk506 doses should be decreased if serum creatinine is elevated to approximately 0.03  mg / kg per day .
suggested that tacrolimus and mycophenolate mofetil is a good option for prophylaxis in hla - matched nonmyeloablative transplants .  
the most common lesions are erythema nodosum , plaques , maculopapular eruptions , and subcutaneous nodules .
the current working hypothesis is that in genetically susceptible individuals , sarcoidosis is caused through an alteration in immune response after exposure to environmental , occupational , or infectious agents .
granulomatous inflammation is characterized primarily by accumulation of monocytes , macrophages , and activated t lymphocytes with increased production of key inflammatory mediators , tnf- , ifn , and il-12 , characteristic of a th1-polarized response ( t - helper lymphocyte-1 response ) .
sarcoidosis has contrasting effects on inflammatory processes ; it is characterized by increased macrophage and cd4 helper t - cell activation , which results in accelerated inflammation ; however , immune response to antigen challenges such as tuberculin is suppressed .
regulatory t lymphocytes in the periphery of sarcoid granulomas appear to suppress il-2 secretion , which is hypothesized to cause a state of anergy , by preventing antigen - specific memory responses .
topical tacrolimus has proved effective for the treatment of cutaneous sarcoidosis . in the recent years
, tacrolimus has been used to suppress the inflammation associated with diverse autoimmune or granulomatous diseases . 
as described by alijotas - reig ,  7 patients with severe and refractory late - onset inflammatory reactions , including large panniculitis , which complicate silicone gel injections were evaluated .
after an average of 18 months after tacrolimus administration ( in increasing doses , up to 0.08 to 0.1  mg / kg of body weight , 2 times per day ) , 5 patients experienced mild , sparse bouts of inflammatory processes , including nodules , plaques , and panniculitis .
long - lasting implants of any type that interact with commensal or infectious microorganisms , trauma , or localized or generalized inflammatory processes could theoretically induce autoimmune disorders or granulomata .
these events may occur because of epigenetic alterations in dna expression in genetically susceptible hosts .
an excellent candidate for pathologic mischief on the face is propionibacterium acnes that under certain circumstances can act as an opportunistic pathogen , which stimulates the production of tnf- and polysaccharides [ 71 , 72 ] .
rapamycin acts through the inhibition of mammalian target of rapamycin ( mtor ) , a molecule that is activated via phosphoinositide 3-kinase ( pi3k ) and controls downstream proteins involved in the cell cycle . after binding with tacrolimus binding protein ( fk - bp ) immunophilin , the rapamycin complex inhibits the stimulatory effect of mtor on cell cycle protein translation , arresting the g1 to s transition ( figure 9 ) [ 8 , 73 ] .
this inhibitory effect can be partly explained because of a reduction of the phosphorylation of eif-4e binding protein 1 ( 4e - bp1 ) , a repressor of cap - mediated translation in mammalian cells . since 1999
, rapamycin has been broadly used in human skin transplantation because it carries a low risk of renal dysfunction and reduces the risk of allograft rejection in comparison with other [ 7577 ] .
rapamycin may potentially be used as an antiangiogenic agent to inhibit , for example , growth of pathological blood vessels in combination with laser treatment .
the application of a laser to an area of skin provokes the shutdown of major capillary vessels and results in the induction of a severely hypoxic microenvironment .
this can cause overexpression of hypoxia - inducible factor-1 alpha ( hif1 ) and promote the secretion of angiogenesis - stimulating factors like platelet - derived growth factor ( pdgf )   and vascular endothelial growth factor ( vegf ) .
rapamycin may prevent vascular reperfusion by acting as an inhibitor of this mtor - hif1-vegf pathway and through the inhibition of the pi3k - p70s6 kinase pathway in endothelial cells stimulated by vegf [ 81 , 82 ] .
there are some side effects to take into account , such as mild cholangitis   and delays in wound closure [ 75 , 83 ] .
these side effects may result from the multiple effects rapamycin may exert upon mtor inhibition in the epithelial and stromal tissues of the wound area .
this includes the important role of mtor in the wound healing process downstream from phosphatidylinositol 3 kinase ( pi3k ) and phosphatase and tensin homolog ( pten ) .  
a randomized , double blind , left - right comparative , dose - ranging clinical trial was carried out to determine the efficacy and safety of rapamycin applied to skin for the treatment of psoriasis .
the trial showed that rapamycin was able to penetrate human skin and exerted beneficial effects .
everolimus ( rad001 ) is a rapamycin derivative ( figure 10 )   with potent immunosuppressive effects , antiproliferative properties , and anticancer effects in many preclinical and clinical studies .
in addition , everolimus has shown in vivo antitumor activity with a significant cytostatic activity in a variety of preclinical models of haematological and solid tumours .
it has been reported that everolimus , while and effective treatment for psoriasis , became ineffective in 2 cases of severe atopic dermatitis when it was combined with prednisone or cyclosporine a .
temsirolimus ( cci-779 , torisel , wyeth ) is another rapamycin derivative ( figure 11 )   and has properties that are similar to everolimus .
it has been used for the treatment of metastatic renal cell carcinoma and mantle cell lymphoma .
rapamycin , everolimus , and temsirolimus all prevent tumour cell proliferation and angiogenesis through inhibition of the hif1/vegf pathway [ 8991 ] .
a new synthetic azythromycin - derivative - macrolide , called csy0073 , has anti - inflammatory and immune - modulatory effects , but no antibiotic effects .
csy0073 exerts counterregulatory activity on nuclear factor kappa b ( nf-b ) , activator protein-1 ( ap-1 ) and extracellular signal - regulated kinase 1/2 ( erk1/2 ) signalling .
the anti - inflammatory activity of csy0073 was demonstrated in rodent models of intestinal inflammation and hold potential as a treatment of inflammation - driven immune dysfunction .
csy0073 may reduce the colonic expression of cytokines involved in the development and maintenance of colon inflammation , such as tumour necrosis factor    ( tnf ) , interleukin 2 ( il-2 ) , and interferon    ( ifn ) .
this is consistent with studies of other macrolides that indicate that these compounds penetrate the cell membrane of macrophages and accumulate in subcellular compartments .
initial results indicate that treatment with csy0073 attenuates the development of several signs of arthritis .
recently , 2 new potential macrolides with anti - inflammatory and immunomodulatory characteristics were discovered .
these compounds , ( 8r,9s)-8,9-dihydro-6,9-anhydropseudoerythromycin a ( em900 ) and ( 8r,9s)-4,13-o - diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin a ( em911 ) , are derivatives of erythromycin a . em900 and em911 have so far only been used in vitro .
another newly developed molecule is ridaforolimus ( also known as deforolimus , ap23473 , mk-8669 , merck ) , a rapamycin analogue ( figure 12 ) , which has broad inhibitory effects on the cell growth , proliferation , division , metabolism , and angiogenesis of a broad panel of cell lines . in vitro and in vivo studies
inhibitory effects on vegf , endothelial cell growth ( egf ) , hif-1 , and glucose metabolism were also observed . in particular ,
ridaforolimus was found to arrest cell growth without evidence of cell death or apoptosis , accumulating cells in the g1 phase of the cell cycle .
this was due , in part , to a blockade of 4e - bp1/eif4e signalling [ 97 , 98 ] .
new uses are being developed for older macrolides , such as pimecrolimus and tacrolimus , due to their interesting anti - inflammatory properties .
these drugs work through the inhibition of the calcineurin promotion of several cytokines , such as interleukins , interferons , and tnf. this approach is opening a broad field of skin disease treatments that have minimal side effects ( table 1 ) . on the other hand , newer macrolides ( rapamycin , everolimus , and temsirolimus ) work through the downregulation of the mtor pathway .
these newer macrolides arrest the g1 to s transition , an important early event in the control of mammalian cell growth and proliferation .
there are many examples of successful applications for these compounds in cancer diseases and organ transplantation .
there were a variety of responses to these compounds , and some of them were not at all positive .
 
 background . inflammation - driven immune 
 dysfunction supports the development of several chronic human disorders including skin diseases . 
 nonantibiotic macrolides have anti - inflammatory and/or immunomodulatory activity that suggests the exploitation of these in the treatment of skin diseases characterized by inflammatory disorders . 
 materials and methods . 
 we performed an extensive review of the nonantibiotic macrolide literature published between 2005 and 2012 , including cross - references of any retrieved articles . 
 we also included some data from our own experience . results . 
 calcineurin antagonists such as tacrolimus and ascomycins ( e.g. , pimecrolimus ) act by inhibiting the activation of the nuclear factor for activated t cells ( nfat ) . 
 there are new applications for these macrolides that have been available for several years and have been applied to skin and hair disorders such as atopic dermatitis , oral lichen planus , vitiligo , chronic autoimmune urticaria , rosacea , alopecia areata , pyoderma gangrenosum , behcet 's disease , neutrophilic dermatosis , and lupus erythematosus . 
 we also reviewed new macrolides , like rapamycin , everolimus , and temsirolimus . 
 in addition to the literature review , we report a novel class of nonantibiotic 14-member macrocycle with anti - inflammatory and immunomodulatory effects . conclusions . this paper summarizes the most important clinical studies and case reports dealing with the potential benefits of nonantibiotic macrolides which have opened new avenues in the development of anti - inflammatory strategies in the treatment of cutaneous disorders . 
1. Introduction
2. Methodology
3. Results and Discussion
4. Conclusions