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Biomedical subjects

H F Merk

Publications and source records attributed to H F Merk.

At least 55 records · Page 3Linked to original sources
PubMed2001

Standard treatment: the role of antihistamines.

Histamine-1 (H1) antihistamines are the first-line drug for the treatment of urticaria. Major progress has been achieved in recent years both in the understanding of their ligands, the H1-histamine receptors, and therefore in the mechanisms of their pharmacologic effects, as well as in the development of safer antihistamines with low or no sedating effects and no interactions on the level of potassium channels leading to QT-prolongations and interactions on the level of cytochrome P450 isoenzymes. This development has brought antihistamines very close to the ideal antihistamines that are desired by clinicians to treat most types of urticaria in patients who have to take these drugs for a long time.

Cyclizine↗
PubMed2001

In vitro drug allergy detection system incorporating human liver microsomes in chlorazepate-induced skin rash: drug-specific proliferation associated with interleukin-5 secretion.

BACKGROUND: Chlorazepate is a benzodiazepine often used for pre-operative anxiolysis. The central metabolite responsible for the pharmacological and probably for the adverse effects of most benzodiazepines, including chlorazepate, is N-desmethyldiazepam. We report a woman who developed a generalized exanthem 1 day after receiving chlorazepate and four other drugs related to anaesthesia for surgery of the larynx. Patch tests pointed to chlorazepate as the culprit drug for the skin rash. OBJECTIVES: The purpose of this study was to detect drug allergy to chlorazepate or a metabolite in vitro by means of the lymphocyte transformation test (LTT), and to determine the concentrations of the T-helper (Th) 2-type cytokine interleukin (IL)-5 and the Th1-type cytokine interferon (IFN) -gamma in the culture supernatants. METHODS: We performed an LTT with peripheral blood mononuclear cells from the patient and a control, employing human liver microsomes containing cytochrome P450 enzymes as a metabolizing system, in parallel cultures. IL-5 and IFN-gamma concentrations in the culture supernatants were assessed by enzyme-linked immunosorbent assay. RESULTS: In the LTT, no T-cell reactivity was observed to the parent compound chlorazepate, whereas coincubation of the drug with human liver microsomes yielded proliferative T-cell reactivity, which was associated with secretion of IL-5 but not of IFN-gamma. CONCLUSIONS: We conclude that addition of a metabolizing system may be advantageous for in vitro detection of T-cell reactivity to drug metabolites in the LTT.

Adult↗
PubMed2001

Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.

Cytochrome P450 enzymes metabolize various endogenous and exogenous small molecular weight compounds. Transport-associated proteins, such as P-glycoprotein, multidrug resistance-associated protein and lung resistance protein are overexpressed in drug-resistant cell lines, as well as in human tumors from various histologic origins, including malignant melanoma. Little is known about the expression and function of cytochrome enzymes and multidrug resistance-associated transport proteins in human skin; therefore, the aim of this study was to analyze the expression pattern of cytochrome enzymes and multidrug resistance-associated transport proteins in proliferating human epidermal keratinocytes under constitutive conditions and after induction with various inducers. Reverse transcription-polymerase chain reaction revealed constitutive expression of cytochromes 1A1, 1B1, 2B6, 2E1, and 3A5 in keratinocytes and showed expression of cytochrome 3A4 after incubation with dexamethasone. The expression of cytochrome 1A1 was enhanced on the mRNA level after induction with benzanthracene. Reverse transcription-polymerase chain reaction analysis of the multidrug resistance-associated transport proteins revealed constitutive expression of multidrug resistance-associated proteins 1 and 3-6, and lung resistance protein in human epithelial keratinocytes and was negative for multidrug resistance 1 and 2. Expression of 1 was seen after induction with dexamethasone. Reverse transcription-polymerase chain reaction results were confirmed by immunoblots which showed expression of cytochromes 1A1, 2B6, 2E1, and 3A, multidrug resistance-associated proteins 1, 3, and 5 as well as multidrug resistance 1 after induction with dexamethasone. Immunohistology showed positive immunofluorescence in skin specimens for cytochromes 1A1, 2B6, 2E1, and 3A and multidrug resistance-associated protein 1 and multidrug resistance 1. Constitutive activity of cytochrome 1A1, 2B, 2E1, and 3A enzymes was measured by catalytic assays. These results show that keratinocytes of the human skin express various transport-associated enzymes and detoxifying metabolic enzymes. Previous studies have revealed that cytochrome enzymes and transport-associated proteins play complementary parts in drug disposition by biotransformation (phase I) and anti-transport (phase III) and act synergistically as a drug bioavailability barrier.

ATP-Binding Cassette Transporters↗
PubMed2001

Comparison of patch test results with a standard series among white and black racial groups.

BACKGROUND: Environmental, cultural, occupational, genetic, individual, and racial differences are important factors in the study of contact dermatitis. Some epidemiologic studies have compared overall sensitization rates among different racial groups, but similar data are lacking on individual allergens. OBJECTIVE: Determine differences in sensitization rates between 2 racial groups in North America undergoing patch testing over a period of 4 years at the Cleveland Clinic Foundation (CCF), Ohio. METHODS: Retrospective computer review of the standard screening tray results of 991 patients with an average age of 45.9 years consisting of 877 (88.5%) whites and 114 (11.5%) blacks. RESULTS: Nickel sulfate and thiomersal (both 8.0%) and nickel sulfate and p-phenylenediamine (both 10.6%) were the 2 most common sensitizers among whites and blacks respectively. There was a statistically significant difference (P =.00599) in the sensitization rate for p-phenylenediamine in blacks (10.6%) compared with whites (4.5%). There were also statistically significant differences in sensitization rates for p-phenylenediamine (21.2%; P =.00005) and imidazolidinyl urea in petrolatum (pet.) (9.1%; P =.04103) in black men compared with white men (p-phenylenediamine [4.2%] and imidazolidinyl urea [2.6% pet.]). CONCLUSION: The differences in sensitization rates, especially for p-phenylenediamine, may reflect variations in allergen exposure among racial groups or interindividual variations in the N-acetylation (N-acetyltransferase 1 [NAT1] and 2 [NAT2]) capacities of human skin for p-phenylenediamine.

Allergens↗
PubMed2001

Drug metabolism in the skin.

The skin performs a wide range of active metabolic functions including xenobiotic metabolism involving metabolizing enzymes specific to the skin. In this review we focus on the role of drug metabolism: (i) in allergic reactions to substances of low molecular weight; (ii) in cutaneous vitamin A and D3 metabolism and its modulation; (iii) in the interaction of transport and metabolic enzymes in skin cells; and (iv) on novel tools for the measurement of drug metabolism in various compartments of the human skin.

Drug Hypersensitivity↗
PubMed2001

Pharmacotherapy of ectoparasitic infections.

Epizoonoses such as scabies, lice and cimicosis are common, vexing disorders that occur worldwide. Historically, many treatment modalities have been employed in the management of these disorders, and most of the drugs described in this review are of historical interest and no longer recommended or in widespread use because of their wide spectrum of adverse effects. More recently, reports documenting resistance against various antiectoparasite drugs, complicated and severe courses of the diseases, and adverse effects of drug therapy have prompted the development of new treatment strategies and drugs for optimal disease management. Because the strategies currently recommended for the treatment of ectoparasites differ worldwide, this review proposes a rational approach to selecting the best therapeutic agent by comparing the pharmacokinetics, pharmacodynamics, drug efficacy and adverse effects. A literature search of the currently Internet accessible libraries PubMed, Medline and Ideal library, of citations of articles found there, and from communications with the Federal Institute for Drugs and Medical Devices, Germany, was conducted based on this approach. One major observation of this literature search is that permethrin is the treatment of choice for lice and scabies in the US and in Great Britain, whereas lindane is still recommended for scabies in most other European countries because of its longer-standing record of effectiveness. Although permethrin has not yet been proven to be more effective than lindane in treating infections with these ectoparasites, it currently appears to have the best efficacy versus safety profile of topical treatments for scabies and lice. Ivermectin is a newer oral drug for the treatment of ectoparasites, which has been used with great success in the treatment of onchocercosis and other endoparasites. Although ivermectin appears to be a promising drug, its role in the treatment of ectoparasitic infections will be clarified as more study data become available. Finally, it is important to emphasise the clinical aspects of ectoparasite therapy and that providing the patient with optimal instructions on the use of topical therapeutics is of great importance in avoiding adverse effects and assuring complete removal of the ectoparasite, thereby avoiding the development of drug-resistance.

Administration, Oral↗
PubMed2000

Disparate cytotoxic activity of nickel-specific CD8+ and CD4+ T cell subsets against keratinocytes.

Allergic contact dermatitis (ACD) is the result of an exaggerated immune reaction to haptens mediated by skin-homing T cells, but the effector mechanisms responsible for the tissue damage are poorly understood. Here we studied the capacity of distinct subsets of hapten-specific T cells to induce apoptosis in autologous keratinocytes. Skin- and blood-derived nickel-specific CD8+ T cytotoxic 1 (Tc1) and Tc2 clones as well as CD4+ Th1 and Th2 expressed the cutaneous lymphocyte-associated Ag and exhibited strong MHC-restricted cytotoxicity against nickel-coupled B lymphoblasts, as detected by the [3H]TdR release assay. Both Tc1 and Tc2 clones, but not CD4+ T cells, displayed a significant cytotoxic activity against resting nickel-modified keratinocytes. Following IFN-gamma treatment, keratinocytes expressed MHC class II and ICAM-1 and became susceptible to Th1-mediated, but not Th2-mediated, cytotoxicity. The molecules of the two major cytotoxic pathways, Fas ligand (FasL) and perforin, were expressed by Tc1, Tc2, and Th1 cells, whereas Th2 cells expressed only FasL. Experiments performed in the presence of specific inhibitors of the perforin (concanamycin A) and FasL (brefeldin A) pathway indicated that perforin-mediated killing dominated in Tc1 and Tc2, and FasL-mediated cytotoxicity prevailed in Th2 clones, with a more heterogeneous behavior in the case of Th1 cells. Finally, perforin mRNA was expressed in ACD lesional skin, as assessed by RT-PCR analysis. In aggregate, our results indicate that keratinocytes can be target of multiple hapten-specific CTL responses, that may have distinct roles in the epidermal injury during ACD.

B-Lymphocytes↗
PubMed2000

IgG, IgA and IgE autoantibodies against the ectodomain of BP180 in patients with bullous and cicatricial pemphigoid and linear IgA bullous dermatosis.

BACKGROUND: Bullous pemphigoid (BP), linear IgA bullous dermatosis (LABD) and cicatricial pemphigoid (CP) are clinically distinct autoimmune bullous skin diseases characterized by autoantibodies against components of the epidermal basement membrane. Like most patients with BP, a significant subgroup of patients with CP has circulating IgG specific for BP180, a transmembraneous protein of hemidesmosomes. Moreover, sera of patients with LABD contain IgA autoantibodies reactive with a 97/120-kDa protein, LABD antigen 1, which is highly homologous to the extracellular portion of BP180. OBJECTIVES: We aimed to determine whether, in these diseases, autoantibody reactivity to BP180 is restricted to distinct immunoglobulin subtypes. METHODS: Utilizing a baculovirus-encoded form of the ectodomain of BP180, sera from patients with BP (n = 10), CP (n = 9), LABD (n = 10) and normal human control sera (n = 10) were analysed by immunoblot for IgG, IgA and IgE reactivity against BP180. RESULTS: All of 10 BP sera displayed IgG, IgA and IgE reactivity with BP180. Six and seven of nine CP sera, respectively, contained IgG and IgA autoantibodies reactive with BP180, but none of nine sera contained BP180-specific IgE. Nine of 10 LABD sera contained IgA, and six of 10 IgG, which was reactive with BP180, but none of 10 sera showed IgE reactivity to BP180. CONCLUSIONS: The presence of IgG and IgA autoantibody responses to BP180 in patients with three clinically distinct autoimmune bullous diseases indicates that an autoimmune response to the same distinct adhesion protein may lead to different clinical manifestations. It is therefore conceivable that variable epitopes of BP180 are targeted by the different autoantibody isotypes, resulting in the distinct clinical pictures.

Adult↗
PubMed2000

13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors.

Despite its potent biologic effect on human sebocytes, 13-cis retinoic acid exhibits low binding affinity for cellular retinoic acid binding proteins and nuclear retinoid receptors. Hence, 13-cis retinoic acid may represent a pro-drug possibly acting through all-trans isomerization. In this study, marked isomerization of 13-cis retinoic acid has been confirmed in cultured SZ95 sebocytes showing 2- to 15-fold higher levels of all-trans retinoic acid at 12-72 h, as measured by high performance liquid chromatography. In contrast, only low amounts of all-trans retinoic acid were converted intracellularly to its 13-cis isoform. 9-cis retinoic acid was not detected after either 13-cis retinoic acid or all-trans retinoic acid treatment. The rapid isomerization of 13-cis retinoic acid to high levels of all-trans retinoic acid was a sebocyte-specific event, as no significant isomerization of 13-cis retinoic acid to all-trans retinoic acid occurred in HaCaT keratinocytes. De novo mRNA expression of cytochrome P450 1A1, a major xenobiotic metabolizing enzyme, in SZ95 sebocytes was induced by all-trans retinoic acid, but not by 13-cis retinoic acid. In addition, mRNA levels of cellular retinoic acid-binding protein II, which is supposed to regulate the concentration of intracellular all-trans retinoic acid, rapidly increased under all-trans retinoic acid treatment (30 min-6 h), whereas the 13-cis retinoic acid effect was markedly weaker and delayed. Both 13-cis retinoic acid and all-trans retinoic acid suppressed mRNA expression of cytochrome P450 1A2. In parallel experiments, 13-cis retinoic acid significantly reduced SZ95 sebocyte proliferation at 10-7 M, show- ing 30-40% inhibition after 9 d. All-trans retinoic acid and 9-cis retinoic acid exhibited similar anti-proliferative effects. AGN 193109, a pan-antagonist of the retinoic acid receptors, antagonized the anti-proliferative activity of all retinoic acid isomers tested in a concentration-dependent manner with complete abolishment at ratios of 1:10 13-cis retinoic acid and 1:1 all-trans retinoic acid. Coincubation of SZ95 sebocytes with 13-cis retinoic acid and AGN 193109 did not alter the intracellular concentration of 13-cis retinoic acid and its isomerization profile. In contrast, the retinoid X receptor antagonist CD 3507 did not affect the inhibition of SZ95 sebocyte proliferation induced by retinoic acids. Our findings indicate: (i) a selective 13-cis retinoic acid isomerization to all-trans retinoic acid in the intracellular compartment of SZ95 sebocytes; (ii) a reduced all-trans retinoic acid inactivation process after 13-cis retinoic acid treatment as compared with treatment with all-trans retinoic acid; and (iii) a retinoic acid receptor-mediated inhibition of SZ95 sebocyte proliferation. These data explain the sebocyte-specific activity of 13-cis retinoic acid and support a pro-drug/drug relation between 13-cis retinoic acid and all-trans retinoic acid.

Cell Division↗
PubMed2000

Delayed readings of a standard screening patch test tray: frequency of "lost," "found," and "persistent" reactions.

BACKGROUND: Several studies have shown that patch test results vary depending on the time at which the patch test sites are evaluated. OBJECTIVE: This study aims to determine the frequency of "lost," "found," and "persistent" reactions to a standard screening tray by comparing initial and delayed readings of the same patch tests. METHODS: We performed a retrospective review of patch test reactions for 587 patients tested with the standard screening tray at The Cleveland Clinic Foundation (Cleveland, OH) between January 1, 1988, and December 31, 1991, for which an initial day-3 and delayed day-4 to day-8 readings were available. RESULTS: For the 587 patients, we identified 81 found (15%), 342 persistent (62%), and 127 lost (23%) reactions, for a total of 550 reactions (100%). The three most common found reactions were to neomycin sulfate (n = 19; 53%), p-phenylenediamine (n = 10; 29%), and thiomersal (n = 10; 18%). The three most common persistent reactions were to thiomersal (n = 41; 73%), nickel sulfate (n = 33; 73%), and quaternium 15 (n = 32; 74%). The three most common lost reactions were to balsam of Peru (n = 14; 39%), benzoyl peroxide (n = 12; 63%), and nickel sulfate (n = 9; 20%). CONCLUSION: Two patch test readings are necessary, followed by a final interpretation.

Dermatitis, Allergic Contact↗
PubMed2000

Important drug interactions in dermatology.

Drug interactions can occur at any step from absorption to elimination of a drug, and can induce adverse as well as beneficial effects. Since systemic drugs are increasingly available and important in the treatment of dermatological diseases, a variety of possible interactions between concomitantly administered drugs have to be considered by dermatologists. The xenobiotic-metabolising enzyme system cytochrome P450 (CYP) is involved in the metabolism of many drugs, regulating their plasma concentrations and activities. Furthermore, the adverse effects of many drugs depend on the basal activity and inducibility of particular CYP isoenzymes in an individual patient. Since drug therapy in dermatological practice is of increasing complexity, and an increasing number of potent systemic drugs have become commonly used therapeutic agents, this review focuses on the following topics with the aim of optimising dermatological drug therapy. In the first section, all the different types of drug interactions that can occur through pharmacokinetic and pharmacodynamic mechanisms are introduced briefly, and then discussed systematically with special reference to drugs important for dermatologists. Then, the network of drug interactions that may occur from absorption to elimination is presented. The most important drug interactions mediated by CYP isoenzymes are listed. Finally, the importance of pharmacogenetics for the development of new drugs and its potential impact on the optimisation of individual therapy regimens is discussed.

Absorption↗
PubMed2000

N-Acetylation of paraphenylenediamine in human skin and keratinocytes.

Skin is the major target of allergic reactions to paraphenylenediamine (PPD). Such small molecules require activation to become immunogenic. The balance between activation and/or detoxification processes is critical for immunogenic potentials of compounds. Therefore, we investigated N-acetylation (NAT) capacities of human skin for PPD to gain a better understanding of its mechanisms of action. PPD is acetylated to monoacetyl-PPD (MAPPD), which in turn is acetylated to N,N'-diacetyl-PPD (DAPPD). This was found using cytosolic fractions from human skin (n = 9) and cultured normal human epidermal keratinocytes (n = 7). The cutaneous activities for MAPPD formation ranged from 0.41 to 3.68 nmol/mg/min (9-fold variation) and DAPPD formation from 0.65 to 3.25 nmol/mg protein/min (5-fold), respectively. Similar results were obtained with keratinocytes. NAT activities toward both substrates, PPD and MAPPD, were correlated in keratinocytes (r = 0.930), suggesting that the reactions were catalyzed by the same enzyme. Formation of MAPPD and DAPPD was competitively inhibited in the presence of p-aminobenzoic acid (300 microM), a typical NAT1 substrate, but not by sulfamethazine. These kinetic characteristics suggest that the acetylation of PPD in human skin and keratinocytes is predominantly attributable to the polymorphic NAT1, although both mRNAs (NAT1 and NAT2) are synthesized in human skin and keratinocytes. The metabolism of PPD by NAT1 in human skin and keratinocytes as well as the virtual absence of NAT2 activity may have important toxicological implications. In the case of PPD, our results emphasize that N-acetylation status may be a susceptibility factor for the development of an allergy to PPD.

4-Aminobenzoic Acid↗
PubMed2000

Cytochrome P450 isoenzyme mRNA expression pattern in human urinary bladder malignancies and normal urothelium.

This study was designed to analyze the cytochrome P450 isoenzyme mRNA expression pattern of transitional cell carcinomas of the bladder (N = 19) and normal urothelium (N = 10). In addition, biopsies from normal urothelium (N = 32) taken at the time of transurethral resection of bladder cancer in eight patients from surrounding histologically normal urothelium also were characterized concerning their specific cytochrome P450 mRNA expression pattern. A total of 13 of 19 of the analyzed tumor specimens (68%) revealed expression of cytochrome P450 1B1. Cytochrome P450 4B1 and 1A1 mRNA expression were detected in 79% (15 of 19) and 53% (10 of 19) of the tumor specimens, with no correlation between tumor stage and grade of the neoplasm. Biopsies from macroscopically and histologically normal urothelium from tumor-invaded bladders also showed expression of cytochrome P450 1B1 in 75% (24 of 32), 4B1 in 62.5% (20 of 32), and 1A1 in 50% (16 of 32). Furthermore, a 75% homology concerning cytochrome P450 1B1 and 4B1 mRNA expression was observed between the bladder tumor and the biopsies from this bladder. The polymerase chain reaction analysis of normal urothelium from normal bladders that do not harbor a neoplasm revealed CYP450 mRNA expression for CYP450 1A1 in 6 of 10; 1B1 in 5 of 10; 4B1 in 6 of 10; 2D6 in 2 of 10; and 2E1 in 2 of 10. According to our data, CYP450 1B1 mRNA expression is not tumor-specific. The present findings are the first to compare CYP450 expression in bladder cancer with biopsies from the same tumor-bearing bladder, and they indicate that, from the enzymatic point of view, bladder cancer also is a panurothelial field disease present in even normal urothelium.

Aged↗
PubMed1999

Identification of N-acetyltransferase 2 genotypes by continuous monitoring of fluorogenic hybridization probes.

Three polymorphic sites in the N-acetyltransferase 2 (NAT2) gene were detected using rapid cycle DNA amplification with allele-specific fluorescent probes and melting curve analysis. Two fluorogenic adjacent hybridization probes were designed to NAT2*5A (C(481)T), NAT2*6A (G(590)A), and NAT2*7A (G(857)A). During amplification, probe hybridization is observed as fluorescence resonance energy transfer. The fluorescence increases every cycle as the product accumulates during amplification. A single base mismatch resulted in a melting temperature shift (T(m)) of 5 to 6 degrees C, allowing for the easy distinction of a wild-type allele from the mutant allele. The protocol is rapid, requiring 40 min for the completion of 45 cycles including the melting curves. It is also a simple and flexible method, since DNA templates prepared from different sources, including DNA from serum and paraffin-embedded tissue sections, could be used without adverse effects. Fluorescence genotyping of all three polymorphisms in a total of 155 DNA samples correlated perfectly with our previously validated genotyping by restriction enzyme digestion (PCR-RFLP). This new facile approach allows for the easy detection of NAT2 polymorphisms in hundreds of samples in only a day.

Arylamine N-Acetyltransferase↗