Nevirapine (NVP) can cause serious idiosyncratic drug reactions (IDRs); specifically, skin rash and hepatotoxicity. Treatment of rats or mice with NVP led to covalent binding to hepatic proteins. Studies of this covalent binding including the use of a deuterated analog of NVP leading to a decrease in oxidation of the methyl group indicated that the metabolite responsible for covalent binding in the liver is a quinone methide. Covalent binding in NVP-treated rats was also observed in the epidermis but by a different pathway. Incubation of 12-OH-NVP sulfate with homogenized human and rat skin led to extensive covalent binding. Inhibition of sulfation in the liver significantly decreased 12-OH-NVP sulfate in the blood, but it did not prevent covalent binding in the skin or the rash. In contrast, topical application of a sulfotransferase inhibitor prevented covalent binding in the skin as well as the rash, but only where it was applied. In contrast to rats, treatment of mice with NVP did not result in covalent binding in the skin or skin rash. These findings provide compelling evidence that 12-OH-NVP sulfate formed in the skin is responsible for the skin rash. IL-1β and IL-18 production in the skin of rats treated with NVP were increased. An anti-IL-1ß antibody significantly decreased rash severity. These cytokines were also produced by incubation of human keratinocytes with 12-OH-NVP sulfate. These data indicate that 12-OH-NVP sulfate activates the NLRP3 inflammasome, a pathway known to be responsible for contact hypersensitivity rashes. In summary, NVP was found to produce two different reactive metabolites, a quinone methide species in the liver, and a benzylic sulfate in the skin. Significant liver injury did not occur, presumably due to immune tolerance. Although it is usually assumed that reactive metabolites are responsible for most IDRs, this is the first example to actually demonstrate that a specific reactive metabolite is responsible for an IDR. This is also the first study to show that sulfotransferase in the skin is responsible for bioactivation of a drug leading to a skin rash. It is likely that there are other drugs that cause skin rashes by a similar mechanism.

Nevirapine (NVP) can cause serious idiosyncratic drug reactions (IDRs); specifically, skin rash and hepatotoxicity. Treatment of rats or mice with NVP led to covalent binding to hepatic proteins. Studies of this covalent binding including the use of a deuterated analog of NVP leading to a decrease in oxidation of the methyl group indicated that the metabolite responsible for covalent binding in the liver is a quinone methide. Covalent binding in NVP-treated rats was also observed in the epidermis but by a different pathway. Incubation of 12-OH-NVP sulfate with homogenized human and rat skin led to extensive covalent binding. Inhibition of sulfation in the liver significantly decreased 12-OH-NVP sulfate in the blood, but it did not prevent covalent binding in the skin or the rash. In contrast, topical application of a sulfotransferase inhibitor prevented covalent binding in the skin as well as the rash, but only where it was applied. In contrast to rats, treatment of mice with NVP did not result in covalent binding in the skin or skin rash. These findings provide compelling evidence that 12-OH-NVP sulfate formed in the skin is responsible for the skin rash. IL-1β and IL-18 production in the skin of rats treated with NVP were increased. An anti-IL-1ß antibody significantly decreased rash severity. These cytokines were also produced by incubation of human keratinocytes with 12-OH-NVP sulfate. These data indicate that 12-OH-NVP sulfate activates the NLRP3 inflammasome, a pathway known to be responsible for contact hypersensitivity rashes. In summary, NVP was found to produce two different reactive metabolites, a quinone methide species in the liver, and a benzylic sulfate in the skin. Significant liver injury did not occur, presumably due to immune tolerance. Although it is usually assumed that reactive metabolites are responsible for most IDRs, this is the first example to actually demonstrate that a specific reactive metabolite is responsible for an IDR. This is also the first study to show that sulfotransferase in the skin is responsible for bioactivation of a drug leading to a skin rash. It is likely that there are other drugs that cause skin rashes by a similar mechanism.

Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. There is strong evidence that the rash is due to 12-hydroxynevirapine (12-OH-NVP), which is further metabolized to a reactive benzylic sulfate in the skin. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver appears to involve oxidation of the methyl group leading to a reactive quinone methide. In this study we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH-NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up-regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the hypothesis that the 12-hydroxylation pathway is involved in causing the rash. Some genes up-regulated by 12-OH-NVP were Trim63, S100a7a, and IL22ra2, etc. Up-regulation of genes such as S100a7a, which is considered a danger signal, supports the danger hypothesis. Up-regulation of genes such as the ubiquitin ligase and Trim63 are consistent with protein-adduct formation. Up-regulation of IL-22ra2 gene suggests an immune response. These results provide important clues to how NVP causes induction of an immune response, in some cases leading to an idiosyncratic drug reaction.

Nevirapine (NVP) can cause serious skin rashes and hepatotoxicity. It also causes an immune-mediated skin rash in rats but not hepatotoxicity. There is strong evidence that the rash is due to 12-hydroxynevirapine (12-OH-NVP), which is further metabolized to a reactive benzylic sulfate in the skin. This could both act as a hapten and induce a danger signal. In contrast, most of the covalent binding in the liver appears to involve oxidation of the methyl group leading to a reactive quinone methide. In this study we examined the effects of NVP and 12-OH-NVP on gene expression in the liver and skin. Both NVP and 12-OH-NVP induced changes in the liver, but the list of genes was different, presumably reflecting different bioactivation pathways. In contrast, many more genes were up-regulated in the skin by 12-OH-NVP than by NVP, which is consistent with the hypothesis that the 12-hydroxylation pathway is involved in causing the rash. Some genes up-regulated by 12-OH-NVP were Trim63, S100a7a, and IL22ra2, etc. Up-regulation of genes such as S100a7a, which is considered a danger signal, supports the danger hypothesis. Up-regulation of genes such as the ubiquitin ligase and Trim63 are consistent with protein-adduct formation. Up-regulation of IL-22ra2 gene suggests an immune response. These results provide important clues to how NVP causes induction of an immune response, in some cases leading to an idiosyncratic drug reaction.

Hudutslag ären vanlig kontaktorsak inom primärvården och därför möter distriktssköterskan dagligen patienter med olika typer av hudutslag. Hudutslag oavsett diagnos eller etiologi, drabbar stora delar av världens befolkning och kan påverka människors livskvalitet negativt. I rollen som distriktssköterska innebär det att självständigt kunna bedöma och undersöka hudutslag. Genom förskrivningsrätten har distriktssköterskan möjlighet att förskriva behandling och därmed lindra patientens besvär men också kontakt med andra professiner för att remittera vidare. Syfte: Syftet med studien är att belysa distriktssköterskors erfarenheter av att bedöma personer med hudutslag inom primärvården. Metod: En kvalitativ intervjustudie med åtta distriktssköterskor inom primärvården i Hallands län. Data analyserades med en manifest kvalitativ innehållsanalys med induktiv ansats. Resultat: Tre kategorier med fem subkategorier indentifierades; Regelbundna bedömningar, Organisatoriska förutsättningar, Erfarenhetens betydelse. Slutsats: Studien belyser distriktssköterskans erfarenhet av att bedöma hudutslag och utmärkande för studien är att det är den yrkesverksamma tiden som skapar erfarenheten samt vikten av teamarbete vid bedömningar. Samtliga distriktssköterskor upplever att hudbedömningar är komplexomvårdnad och önskar mer utbildning inom området. En förbättrad kunskap inom området kan leda till minskat vårdbehov då flera korrekta bedömningar utförs.