Search PubMed⌕ Search

Biomedical subjects

H F Merk

Publications and source records attributed to H F Merk.

At least 91 records · Page 5Linked to original sources
PubMed1996

Immunologic mechanisms of cutaneous drug reactions.

Idiosyncratic reactions (type B) are a major complication of drug therapy, because they are related to both the drug and to individual factors in the host. In comparison with other organs, the skin is quite frequently a target of allergic reactions, which are mainly elicited by small molecular weight compounds. This is the case in allergic contact dermatitis as well as in drug allergic reactions. In contrast to allergic contact dermatitis however, drug-induced hypersensitivity reactions of the skin have enormous variability with regard to their pathophysiological pathways, clinical signs of symptoms, severity, and the drugs which can elicit these reactions. Allergic reactions are mediated either by specific antibodies or a cellular immunocompetent immune response. About 25% to 30% of type B reactions are estimated to be allergic drug reactions, which are classified by the latency period between the ingestion of the responsible allergen and the onset of clinical symptoms. Studying the mechanisms of these hypersensitivity reactions improves our understanding of these diseases in general, and shows the importance of the skin as a signaling organ in these reactions.

Drug Eruptions↗
PubMed1995

Lymphocyte activation in cutaneous drug reactions.

Peripheral blood lymphocytes from both drug-induced immediate and delayed cutaneous hypersensitivity reactions frequently can be stimulated in vitro with the particular culprit drug. Immunohistochemical analysis has identified CD8+ T cells as the predominant epidermal T-cell subset in drug-induced maculopapular and bullous eruptions and in patch-test reactions to beta-lactam antibiotics. Beta-lactam-specific peripheral and epidermal T lymphocytes from bullous exanthems were predominantly T-cell receptor alpha/beta+, CD8+, CD4-. Three CD8+ epidermal T-cell clones from penicillin-induced bullous exanthems displayed a TH1-like cytokine pattern and proliferated in an antigen- and major histocompatibility complex-specific manner. These epidermal T-cell clones were cytotoxic against autologous B cells upon stimulation through the T-cell receptor and against epidermal keratinocytes in lectin-induced cytotoxicity assays. In contrast, peripheral T-cell lines from patients with penicillin-induced urticarial exanthems were predominantly T-cell receptor alpha/beta+, CD4+, CD8- and displayed a Th2-like cytokine pattern. CD8+ dermal T cells from a sulfamethoxazole-induced bullous exanthem proliferated in vitro in response to sulfamethoxazole. This T-cell proliferation was significantly increased in the presence of microsomes, which suggests that microsomal enzymes, such as cytochrome P450 enzymes, generate highly reactive metabolites which are the nominal antigens for T-cell activation. In summary, drugs may be processed and presented in different ways, which is reflected by the observation that Th1-like CD8+ T cells are primarily activated in delayed cutaneous hypersensitivity reactions, whereas Th2-like T-cell responses are present in patients with drug-induced urticarial exanthems.

Antigens↗
PubMed1995

CD8+ dermal T cells from a sulphamethoxazole-induced bullous exanthem proliferate in response to drug-modified liver microsomes.

There is evidence that T lymphocytes play a critical role in the pathogenesis of drug-induced bullous exanthems. Sulphonamides are known to be among the most frequent aetiological agents in these severe drug-induced cutaneous hypersensitivity reactions. Several studies indicate that cytochrome P450-dependent metabolites of sulphonamides act as the nominal allergens. A 70-year-old woman with a severe blistering exanthem caused by cotrimoxazole (sulphamethoxazole and trimethoprim) was studied. We employed an in vitro approach to determine whether cytochrome P450-dependent enzymes activated drug-specific T lymphocytes from this patient. Immunohistochemical analysis of involved skin revealed a majority of epidermal CD8+ T lymphocytes, whereas the dermal infiltrate was composed of both CD4+ and CD8+ T cells. Dermal T lymphocytes isolated from lesional skin proliferated in response to sulphamethoxazole, but not to trimethoprim, in the presence of autologous mononuclear cells used as antigen-presenting cells. The antigen-specific response of sulphamethoxazole-specific T cells was significantly augmented in the presence of murine liver microsomes with P450-dependent catalytic activities. Our observations suggest that some cutaneous hypersensitivity reactions to sulphamethoxazole are due to drug-specific T lymphocytes. Cytochrome P450-dependent enzymes may play a critical role in the formation of the nominal antigen, which is recognized by antigen-specific T cells.

Aged↗
PubMed1994

Evidence for multiple inducible cytochrome P450 isozymes in SENCAR mouse skin by pyridine.

Pyridine, an amphipathic solvent, is widely used in industry and is also a constituent of tobacco and its smoke. Since, in addition to inhalation and ingestion, pyridine is also readily absorbed through skin, we assessed the effect of skin application of pyridine on monooxygenase activities and cytochrome P450 (CYP) isozymes and CYP mRNA levels in the skin of SENCAR mice. Compared to controls, a single topical application of pyridine (30 or 50 mg/100 g body weight) resulted in induction of cutaneous 7-ethoxyresorufin O-deethylase, 7-pentoxyresorufin O-depentylase, and erythromycin N-demethylase activities. Pyridine treatment also resulted in an increase in reactivity with monoclonal antibodies directed against CYP 1A1, 2B1 and 3A. In Northern blot analysis, treatment of pyridine also showed a significant increase in mRNA for Cyp1a-1 in the skin. These data indicate that murine skin contains multiple inducible CYP isozymes, and that pyridine results in the induction of at least three families of CYP in murine skin.

Animals↗
PubMed1994

Multiple cytochrome P450 isozymes in murine skin: induction of P450 1A, 2B, 2E, and 3A by dexamethasone.

Cytochrome P450s (P450s) are a supergene family of enzymes responsible for the metabolism of a wide range of endogenous and foreign compounds. P450 isozymes possess overlapping substrate specificity. Systemic administration of dexamethasone, a widely used topical agent in dermatologic practice, to animals is known to result in the induction of multiple P450 isozymes in liver. In this study the effect of topical application of dexamethasone to mice on P450-dependent monooxygenase activities, expression of P450 isozymes, and P450 mRNA levels in skin was assessed. The treatment of mice with dexamethasone resulted in significant induction of 7-ethoxyresorufin O-deethylase (2.3 times), 7-pentoxyresorufin O-depentylase (19.2 times), para-nitrophenol hydroxylase (7.5 times), and erythromycin N-demethylase (2.2 times) activities; the monooxygenases catalyzed preferentially by P450 isozymes 1A1, 2B1, 2E1, and 3A, respectively. Immunoblot analysis of cutaneous microsomes, employing antibodies directed against purified P450s 1A1/2, 2B1/2, 2E1, and 3A, showed that dexamethasone treatment results in an increased immunoreactivity (1.8-13.9 times). In immunohistochemical staining of skin with antibody against P4502B1/2, topical application of dexamethasone resulted in an increased reactivity towards microsomal protein in the suprabasal layer of the epidermis and with the cells of the hair follicles. Whereas constitutive expression of mRNAs for CYP1A1 and CYP2E1 was evident in murine skin, any change in the levels of these mRNAs following treatment with dexamethasone was not apparent. The results of our study indicate that the application of dexamethasone to murine skin results in the induction of several families of P450 isozymes, suggesting that murine skin contains multiple inducible P450 isozymes capable of participating in the metabolism of a wide range of xenobiotics and endogenous compounds.

Administration, Topical↗
PubMed1994

[Progress in understanding and therapy of allergic immediate hypersensitivity with antihistaminics].

Mast cells and basophils play a central role in the pathophysiology of immediate type allergic reactions. After binding of at least 2 IgE-antibodies with the antigen, the mediators of inflammation of these cells are released. Major progress in our understanding of this mechanism changed our knowledge about the pharmacologic properties of histamine antagonists. It could be demonstrated that some of them possess antiallergic properties, that means that they inhibit the release of mediators of inflammation of mast cells and basophils.

Acute-Phase Reaction↗
PubMed1993

[An anaphylactic shock reaction caused by latex from medical protective gloves].

In case of IgE-mediated latex allergy, the person wearing medical rubber gloves as well as the patient getting in contact with the gloves' outside may be affected. This is illustrated by the present case reports on two atopic young women. The first patient repeatedly underwent laparotomies and finally, 50 minutes after the onset of another operation, suffered an anaphylactic shock reaction due to transperitoneal latex resorption. The second patient was trained as an assistant in a dentist practice where she suffered more than once from latex contact urticaria as well as collapses. Since these were initiated by globus feeling, an aerogenic route of allergen penetration was assumed. Latex prick testing in this patient resulted in an anaphylactic shock reaction. With regard to these observations the general aspects of intraoperative allergen exposition and safety of latex skin testing are discussed. Recommendations are given for a) the latex test procedure in case of anamnestic suspicion of high-degree sensitisation, b) the issuing of a latex allergy pass, and c) the use of latex-free synthetic gloves.

Adolescent↗
PubMed1993

Predominance of epidermal CD8+ T lymphocytes in bullous cutaneous reactions caused by beta-lactam antibiotics.

The phenotype and functional characteristics of skin-infiltrating lymphocytes in beta-lactam antibiotic-induced vesiculobullous exanthemas were studied in vivo and in vitro. Immunohistochemical analysis demonstrated that CD8+ T lymphocytes were the predominant epidermal T-cell subset in these reactions. Epidermal T lymphocytes were isolated and expanded for in vitro studies. Fluorescence-activated cell sorter analysis showed the majority of epidermal T cells to be CD3+, T-cell receptor alpha/beta+, CD4-, CD8+, and HLA-DR+, which correlated with the predominance of epidermal CD8+ T lymphocytes found in situ. Three CD8+ epidermal T-cell clones derived from cutaneous lesions proliferated in response to penicillin-pulsed autologous antigen-presenting cells but not allogeneic antigen-presenting cells, indicating that those clones were antigen and major histocompatibility complex specific. All T-cell clones produced significant amounts of interleukin-2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. Additionally, the T-cell clones displayed cytotoxicity against epidermal cells in lectin-mediated cytotoxicity and against B-cell lines in T-cell receptor-triggered cytotoxicity. These data demonstrate the presence of epidermal drug-specific CD8+ T cells in bullous drug reactions. Because these CD8+ T cells have a cytotoxic potential, they may contribute to the necrosis of keratinocytes associated with drug-induced blister formation.

Anti-Bacterial Agents↗
PubMed1993

Selective generation of CD8+ T-cell clones from the peripheral blood of patients with cutaneous reactions to beta-lactam antibiotics.

The presence, phenotype, and functional characteristics of peripheral blood penicillin-specific T lymphocytes in individuals with cutaneous allergic reactions to penicillin were investigated using in vitro long-term culture techniques. Peripheral blood mononuclear cells from two penicillin-allergic patients were stimulated in vitro with penicillin, and T-cell blasts were clonally expanded by limiting dilution. Seven T-cell clones were derived, all of which were CD3+ CD4- CD8+ HLA-DR+, and produced IL-2 and IFN-gamma upon stimulation. T-cell proliferation required the presence of antigen and autologous, but not allogeneic, antigen-presenting cells. In addition to the parent compound, the T-cell clones also developed a proliferative response to penicilloyl, the major metabolite of penicillin. The cloned T-cell lines were found to exhibit marked suppressor activity for Con A mitogenesis. The observed suppressor activity required cell-to-cell contact, as supernatants from these T-cell clones had no comparable inhibitory effect. These findings indicate that there is a predominance of penicillin-specific CD8+ T cells in the peripheral blood of individuals sensitized to beta-lactam antibiotics.

Anti-Bacterial Agents↗
PubMed1993

Allergic contact reaction to dexpanthenol: lymphocyte transformation test and evidence for microsomal-dependent metabolism of the allergen.

In a patient with contact dermatitis, dexpanthenol was found to be the causative allergen. There was a positive reaction to dexpanthenol on patch testing. Controls did not show any positive reactions to dexpanthenol on patch testing. Additionally, an LTT was performed. After preincubation with dexpanthenol-modified microsomes, we observed an increase in lymphocyte proliferation to dexpanthenol, in comparison to dexpanthenol without microsomes, suggesting that microsomal metabolism plays a rôle in the pathogenesis of dexpanthenol sensitization, because microsomes are known to possess drug metabolizing enzymes such as cytochrome P450.

Cell Division↗