Uptake and metabolism of cyclosporin a and SDZ IMM 125 in the human in vitro skin2TM dermal and barrier function models

Vickers, Alison E. M.; Biggi, W. A.; Dannecker, Robert; Fischer, Volker

doi:10.1016/0024-3205(95)00265-8

Cited by 13 publications

(6 citation statements)

References 21 publications

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“…Basal keratinocytes formed a characteristic columnar layer with several suprabasal squamous cell layers covered by a thin stratum corneum. The extent of epidermal differentiation and functional properties of KFCs are detailed elsewhere (13,50,51,56,63).…”

Section: Methodsmentioning

confidence: 99%

Haemophilus ducreyiInfection Causes Basal Keratinocyte Cytotoxicity and Elicits a Unique Cytokine Induction Pattern in an In Vitro Human Skin Model

et al. 1998

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Haemophilus ducreyi is the etiologic agent of the sexually transmitted genital ulcer disease chancroid. Predominantly a cutaneous pathogen, H. ducreyi is present in chancroid ulcers that are characterized by extensive neutrophil accumulation in intraepidermal lesions accompanied by a mononuclear infiltrate in the dermis. We used an in vitro human skin model composed of foreskin fibroblasts and keratinocytes to examine host skin cell interactions with H. ducreyi 35000. Bacteria replicated and persisted in artificial skin for at least 14 days. We observed H. ducreyi inside suprabasal keratinocytes using transmission electron microscopy. Although no bacteria were seen in the basal keratinocyte region, these cells were disrupted in infected cocultures.H. ducreyi infection stimulated increased secretion of interleukin-6 (IL-6) and IL-8 by skin cells. Conversely, tumor necrosis factor alpha and IL-1α levels were not elevated. IL-8 produced in response to H. ducreyi infection may be involved in recruiting polymorphonuclear leukocytes and other inflammatory cells, thereby contributing to the tissue necrosis and ulcer formation characteristic of chancroid.

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Section: Methodsmentioning

confidence: 99%

Haemophilus ducreyiInfection Causes Basal Keratinocyte Cytotoxicity and Elicits a Unique Cytokine Induction Pattern in an In Vitro Human Skin Model

et al. 1998

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“…CsA ointments were found ineffective when topically applied on psoriatic skin , but intralesional injections were able to clear psoriatic lesions, demonstrating that inappropriate drug delivery was responsible for the ineffectiveness of topical preparations . It was shown that CsA can be physically transferred into epidermal and dermal cells without apparent toxicity, either in a skin model in vitro or in psoriatic lesions, in vivo using a 5–10% ointment under occlusion . In the latter case, lesional concentrations of CsA were comparable to those obtained in systemic therapy, and marked changes were observed in the immune cell infiltrate, yet no clinical effects were seen.…”

Section: Introductionmentioning

confidence: 92%

Penetration and biological effects of topically applied cyclosporin A nanoparticles in a human skin organ culture inflammatory model

Frušić-Zlotkin

Soroka

Tivony

et al. 2012

Experimental Dermatology

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Systemic antipsoriatic therapies have potentially life-threatening, long-term side effects. The efficacy of topical drugs is poor, but may be improved by the use of delivery systems based on drug nanoparticles. To produce nanoparticles (NP) composed of cyclosporin A, a classical antipsoriatic drug, and to investigate their penetration and biological effects in human skin affected by psoriatic symptoms, poly-ε-caprolactone (PCL) and cyclosporin A (CsA) NP were prepared by the solvent evaporation method. Skin penetration was followed using fluorescently labeled NP in human skin organ cultures (hSOC). Psoriatic symptoms were mimicked in hSOC by the treatment with epidermal growth factor (EGF) and bacterial lipopolysaccharide (LPS). Cell viability in hSOC was evaluated by the resazurin test, and cytokine secretion into the growth medium was measured by immunodetection. We showed that topically applied NP diffused throughout the epidermis within two hours and through the dermis within the following day. They significantly reduced the secretion of inflammatory cytokines IL-1β, IL-6, IL-8, IL-20 and IL-23. At active doses, no cytotoxicity was detected. This type of NP display relevant properties for the use as topical anti-inflammatory agents and may help to resorb psoriatic lesions.

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“…The hydroxylation of cyclosporine A, a CYP3A4 substrate, has been observed in human dermis-derived cultures (Vickers et al, 1995). CYP3A5 has been shown to be constitutively expressed in keratinocytes (Merk et al, 2007), and mRNA has been identified (Bergstrom et al, 2007).…”

Section: Cyp3mentioning

confidence: 98%

Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions

Sharma¹,

Uetrecht²

2013

Drug Metabolism Reviews

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Drug-induced skin rashes are poorly understood idiosyncratic reactions, and current methods cannot predict their occurrence. Most idiosyncratic drug reactions are thought to be caused by chemically reactive metabolites, and the skin is a frequent site of idiosyncratic reactions; however, the skin has a very limited capacity to metabolize drugs. To balance this, the skin represents a protective barrier with a very active immune response against pathogens and other types of skin injury. Therefore its response to reactive metabolites is quite different from that of the liver. The purpose of this review is to integrate emerging findings into proposed mechanisms of drug and carcinogen metabolism in the skin that are likely responsible for rashes and other immune responses of the skin. Current evidence suggests the skin possesses significant sulfotransferase and flavin monooxygenases activities, but very low cytochromes P450 activity. However, there are skin-specific P450s that are not present in the liver. The manner in which the skin responds to neoantigens through local antigen presentation and innate immune sensing is reviewed with a focus on insights gained from the contact hypersensitivity (CHS) field. The roles of keratinocytes and Langerhans cells, and the emerging function of NOD-like receptors, are highlighted.

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Uptake and metabolism of cyclosporin a and SDZ IMM 125 in the human in vitro skin2TM dermal and barrier function models

Cited by 13 publications

References 21 publications

Haemophilus ducreyiInfection Causes Basal Keratinocyte Cytotoxicity and Elicits a Unique Cytokine Induction Pattern in an In Vitro Human Skin Model

Haemophilus ducreyiInfection Causes Basal Keratinocyte Cytotoxicity and Elicits a Unique Cytokine Induction Pattern in an In Vitro Human Skin Model

Penetration and biological effects of topically applied cyclosporin A nanoparticles in a human skin organ culture inflammatory model

Bioactivation of drugs in the skin: relationship to cutaneous adverse drug reactions

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