RESUMEN
BACKGROUND: The papules and pustules of rosacea can be effectively treated with topical metronidazole. The optimal concentrations of metronidazole and optimum frequencies of application are uncertain. Traditionally, twice-daily applications have been advised, based on the pharmacokinetic profile of metronidazole. Once-daily applications may be safer and less expensive, and they may enhance patient compliance. OBJECTIVE: We compared the efficacy and safety of 2 commercially available topical metronidazole formulations (0.75% metronidazole cream formulation and 1.0% metronidazole cream formulation) when both were used in a once-daily regimen. METHODS: A multicenter, randomized, investigator-blind, parallel group trial was conducted at 3 separate clinical sites located in 3 US cities. The study enrolled 72 rosacea patients with at least 8 to 50 inflammatory facial lesions (pustules and papules) and moderately severe facial erythema. Patients were randomly assigned to receive either 0.75% metronidazole cream or 1.0% metronidazole cream and instructed to apply the medication once daily for 12 weeks. Patients' lesions were evaluated at baseline and at weeks 3, 6, 9, and 12. RESULTS: There were no significant differences between treatment groups for any of the efficacy parameters evaluated. The overall median percentage change in lesion count at end point for patients in the 0.75% metronidazole cream treatment group was -62% compared with -60% for the 1.0% metronidazole cream treatment group. The overall percentage change in erythema scores at endpoint for patients in the 0.75% metronidazole cream treatment group was -26% compared with -30% for patients in the 1.0% metronidazole cream treatment group. Regarding physician assessment of global severity, 57% of subjects (20/35) in the 0.75% metronidazole cream group compared with 37% of subjects (13/35) in the 1.0% metronidazole cream group were rated as having a clear to mild condition at end point. Both drugs were well tolerated; there was no significant difference in the number of drug-related adverse events between the two agents. CONCLUSION: This controlled trial demonstrates that both 0.75% metronidazole cream and 1.0% metronidazole cream, when used once daily, provide well-tolerated efficacy for moderate to severe rosacea.
Asunto(s)
Antiinfecciosos/farmacología , Metronidazol/farmacología , Rosácea/tratamiento farmacológico , Administración Tópica , Adulto , Anciano , Antiinfecciosos/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Eritema/tratamiento farmacológico , Eritema/patología , Femenino , Humanos , Masculino , Metronidazol/administración & dosificación , Persona de Mediana Edad , Método Simple Ciego , Resultado del TratamientoAsunto(s)
Anticuerpos/uso terapéutico , Inmunoglobulinas Intravenosas , Pénfigo/tratamiento farmacológico , Pénfigo/inmunología , Determinación de Punto Final , Medicina Basada en la Evidencia , Humanos , Inmunosupresores/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de InvestigaciónAsunto(s)
Nicotina/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Pénfigo/terapia , Fumar , HumanosAsunto(s)
Aminoquinolinas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inductores de Interferón/uso terapéutico , Verrugas/tratamiento farmacológico , Condiloma Acuminado/tratamiento farmacológico , Condiloma Acuminado/inmunología , Condiloma Acuminado/virología , Humanos , Imiquimod , Inmunidad Celular , Replicación Viral/efectos de los fármacos , Verrugas/inmunología , Verrugas/virologíaRESUMEN
Mucocutaneous involvement occurs predominantly in primary systemic amyloidosis as well as in myeloma-associated systemic amyloidosis. It is rarely observed in other types of amyloidoses. Signs of such involvement may aid in the early diagnosis of the disease process. Herein, we describe a 64-year-old white male patient with myeloma-associated systemic amyloidosis in whom the disease presented with unique cutaneous lesions consisting of chronic paronychia and palmodigital erythematous swelling and induration of the hands. Following weekly regimens with prednisone (20 mg/day) and melphalan (2 mg/day) administered every 16 weeks, almost complete resolution of the cutaneous lesions was observed after 1 year of therapy. Also, in response to chemotherapy, modest regression of the myelomatous bone lesions and complete resolution of the underlying gammopathy occurred.
Asunto(s)
Amiloidosis/etiología , Eritema/etiología , Dermatosis de la Mano/etiología , Mieloma Múltiple/complicaciones , Paroniquia/etiología , Amiloidosis/diagnóstico , Amiloidosis/tratamiento farmacológico , Antineoplásicos Alquilantes/administración & dosificación , Enfermedad Crónica , Quimioterapia Combinada , Eritema/diagnóstico , Eritema/tratamiento farmacológico , Glucocorticoides/administración & dosificación , Dermatosis de la Mano/diagnóstico , Dermatosis de la Mano/tratamiento farmacológico , Humanos , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Paroniquia/diagnóstico , Paroniquia/tratamiento farmacológico , Prednisona/administración & dosificación , Recurrencia , Factores de TiempoAsunto(s)
Acampada , Enfermedades de la Piel , Adolescente , Niño , Enfermedad Crónica , Femenino , Humanos , Masculino , PennsylvaniaRESUMEN
OBJECTIVES: To determine whether nondesmoglein (non-Dsg) autoantibodies are pathogenic and whether they recognize keratinocyte cholinergic receptors that control cell adhesion because antikeratinocyte autoimmunity in patients with pemphigus vulgaris is not limited to the development of autoantibodies to Dsg. DESIGN: To determine whether non-DSg autoantibodies are pathogenic, we sought to induce pemphigus in genetically engineered neonatal mice lacking Dsg 3 using pemphigus vulgaris IgGs that did not cross-react with Dsg 1. To determine whether pemphigus autoimmunity involves keratinocyte cholinergic receptors, the latter were separated from cell membranes of human keratinocytes, tagged with the covalent label [3H]propylbenzilylcholine mustard, and used as an antigen in a radioimmunoprecipitation assay of 34 pemphigus vulgaris and 6 pemphigus foliaceus serum samples. SETTING: The dermatologic clinics of the University of Minnesota, Minneapolis; the Mayo Clinic, Rochester, Minn; and the University of California-Davis Medical Center, Sacramento. PATIENTS: Serum samples were collected from 34 patients with pemphigus vulgaris and 6 patients with pemphigus foliaceus (aged 31-89 years) and from 7 age-similar patients of both sexes with nonpemphigus blistering or the following immune-mediated conditions: pemphigoid gestation, bullous drug eruption, lupus erythematosus, erythema nodosum, urticaria, acute contact dermatitis, and skin ulcers. MAIN OUTCOME MEASURES: Clinical, laboratory, and histopathologic findings. RESULTS: Extensive skin blistering accompanied by the Nikolsky sign and suprabasilar acantholysis was induced in the Dsg3null mice that received pemphigus, but not normal human IgGs. In the radioimmunoprecipitation assays for reactivity with cholinergic receptors, the mean radioactivity precipitated by pemphigus serum samples significantly exceeded both normal- and disease-control levels (P = .001-.02). The mean individual levels of radioactivity precipitated by 34 pemphigus vulgaris and pemphigus foliaceus serum samples (85%) exceeded control values by a mean of approximately 2.6 times. CONCLUSIONS: Autoantibodies to keratinocyte cell-surface molecules other than Dsg 1 and Dsg 3 can induce clinical features of pemphigus vulgaris. Patients with pemphigus vulgaris and those with pemphigus foliaceus develop IgG antibodies that precipitate radiolabeled cholinergic receptors. Because these receptors control keratinocyte adhesion and motility, their inactivation by autoantibodies may elicit intracellular signals that cause disassembly of desmosomes, leading to acantholysis and blistering.
Asunto(s)
Autoanticuerpos/biosíntesis , Moléculas de Adhesión Celular/inmunología , Queratinocitos/inmunología , Pénfigo/inmunología , Receptores Colinérgicos/inmunología , Acantólisis/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Estudios de Casos y Controles , Adhesión Celular/inmunología , Proteínas del Citoesqueleto/inmunología , Dermatitis por Contacto/inmunología , Desmoplaquinas , Desmosomas/inmunología , Eritema Nudoso/inmunología , Femenino , Ingeniería Genética , Humanos , Inmunoglobulina G/inmunología , Lupus Eritematoso Sistémico/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos , Persona de Mediana Edad , Penfigoide Ampolloso/inmunología , Pénfigo/clasificación , Enfermedades Cutáneas Vesiculoampollosas/inmunología , Úlcera Cutánea/inmunología , Urticaria/inmunologíaRESUMEN
BACKGROUND: Rosacea is a chronic skin disease that requires long-term therapy. Oral antibiotics and topical metronidazole successfully treat rosacea. Because long-term use of systemic antibiotics carries risks for systemic complications and adverse reactions, topical treatments are preferred. OBJECTIVE: To determine if the use of topical metronidazole gel (Metrogel) could prevent relapse of moderate to severe rosacea. DESIGN: A combination of oral tetracycline and topical metronidazole gel was used to treat 113 subjects with rosacea (open portion of the study). Successfully treated subjects (n = 88) entered a randomized, double-blind, placebo-controlled study applying either 0.75% topical metronidazole gel (active agent) or topical metronidazole vehicle gel (placebo) twice daily (blinded portion of the study). SETTING: Subjects were enrolled at 6 separate sites in large cities at sites associated with major medical centers. SUBJECTS: One hundred thirteen subjects with at least 6 inflammatory papules and pustules, moderate to severe facial erythema and telangiectasia entered the open phase of the study. Eighty-eight subjects responded to treatment with systemic tetracycline and topical metronidazole gel as measured by at least a 70% reduction in the number of inflammatory lesions. These subjects were randomized to receive 1 of 2 treatments: either 0.75% metronidazole gel or placebo gel. INTERVENTIONS: Subjects were evaluated monthly for up to 6 months to determine relapse rates. MAIN OUTCOME MEASURES: Inflammatory papules and pustules were counted at each visit. Relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. Prominence of telangiectases and dryness (roughness and scaling) were also observed. RESULTS: In the open phase, treatment with tetracycline and metronidazole gel eliminated all papules and pustules in 67 subjects (59%). The faces of 104 subjects (92%) displayed fewer papules and pustules after treatment, and 82 subjects (73%) exhibited less erythema. In the randomized double-blind phase, the use of topical metronidazole significantly prolonged the disease-free interval and minimized recurrence compared with subjects treated with the vehicle. Eighteen (42%) of 43 subjects applying the vehicle experienced relapse, compared with 9 (23%) of 39 subjects applying metronidazole gel (P<.05). The metronidazole group had fewer papules and/or pustules after 6 months of treatment (P<.01). Relapse of erythema also occurred less often in subjects treated with metronidazole (74% vs 55%). CONCLUSION: In a majority of subjects studied, continued treatment with metronidazole gel alone maintains remission of moderate to severe rosacea induced by treatment with oral tetracycline and topical metronidazole gel.
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Fármacos Dermatológicos/uso terapéutico , Metronidazol/uso terapéutico , Rosácea/tratamiento farmacológico , Rosácea/prevención & control , Administración Cutánea , Adulto , Anciano , Antibacterianos/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Tetraciclina/uso terapéutico , Resultado del TratamientoRESUMEN
Around 90% of chronic dermatophyte infections are caused by the fungi Trichophyton mentagrophytes and Trichophyton rubrum. One of the causes of the chronic infection resides in the immunosuppressive effects of the cell-wall components of these organisms. Therefore we have attempted to identify the chemical structure of galactomannan, one of the major cell-wall components. The cell-wall polysaccharides secreted by T. mentagrophytes and T. rubrum were isolated from the culture medium and fractionated into three subfractions by DEAE-Sephadex chromatography. Analysis of each subfraction by NMR indicated that there are two kinds of polysaccharides present, i.e. mannan and galactomannan. The mannan has a linear backbone consisting of alpha1,6-linked mannose units, with alpha1,2-linked mannose units as side chains. The core mannan moiety of the galactomannan was analysed by a sequential NMR assignment method after removing the galactofuranose units by acid treatment. The result indicates that the mannan moiety has a linear repeating structure of alpha1,2-linked mannotetraose units connected by an alpha1,6 linkage. The H-1 signals of the two intermediary alpha1, 2-linked mannoses of the tetraose unit showed a significant upfield shift (Deltadelta=0.05-0.08 p.p.m.), due to the steric effect of an alpha1,6-linked mannose unit. The attachment point of the galactofuranose units was determined at C-3 of the core mannan by the assignment of the downfield-shifted 13C signals of the galactomannan compared with those of the acid-modified product. In these galactomannans there were no polygalactofuranosyl chains which have been found in Penicillium charlesii and Aspergillus fumigatus.
Asunto(s)
Mananos/química , Trichophyton/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Galactosa/análogos & derivados , Espectroscopía de Resonancia Magnética , Datos de Secuencia MolecularRESUMEN
Human epidermal keratinocytes synthesize, secrete, and degrade acetylcholine and use their cell-surface nicotinic and muscarinic cholinergic receptors to mediate the autocrine and paracrine effects of acetyl-choline. Because acetylcholine modulates transmembrane Ca2+ transport and intracellular metabolism in several types of cells, we hypothesized that cholinergic agents might have similar effects on keratinocytes. Nicotine increased in a concentration-dependent manner the amount of 45Ca2+ taken up by keratinocytes isolated from human neonatal fore-skins. This effect was abolished in the presence of the specific nicotinic antagonist mecamylamine, indicating that it was mediated by keratinocyte nicotinic acetylcholine receptor(s). The sequences encoding the alpha 5 and alpha 7 nicotinic receptor subunits were amplified from cDNA isolated from cultured keratinocytes. These subunits, as well as the alpha 3, beta 2, and beta 4 subunits previously found in keratinocytes, can be components of Ca(2+)-permeable nicotinic receptor channels. To learn how activation of keratinocyte nicotinic receptors affected the rate of cell differentiation, we measured the nicotinic cholinergic effects on the expression of differentiation markers by cultured keratinocytes. Long-term incubations with micromolar concentrations of nicotine markedly increased the number of cells forming cornified envelopes and the number of cells staining with antibodies to suprabasal keratin 10, transglutaminase type I, involucrin, and filaggrin. The increased production of these differentiation-associated proteins was verified by Western blotting. Because nicotinic cholinergic stimulation causes transmembrane Ca2+ transport into keratinocytes, and because changes in concentrations of intracellular Ca2+ are known to alter various keratinocyte functions, including differentiation, the subcellular mechanisms mediating the autocrine and paracrine actions of epidermal acetylcholine on keratinocytes may involve Ca2+ as a second messenger.
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Calcio/metabolismo , Queratinocitos/citología , Queratinocitos/metabolismo , Receptores Nicotínicos/metabolismo , Acetilcolina/farmacología , Canales de Calcio/fisiología , Diferenciación Celular/efectos de los fármacos , Electrofisiología , Proteínas Filagrina , Humanos , Activación del Canal Iónico , Canales Iónicos/metabolismo , Mecamilamina/farmacología , Nicotina/metabolismo , Nicotina/farmacología , Permeabilidad , Receptores Nicotínicos/efectos de los fármacosAsunto(s)
Acampada , Enfermedades de la Piel , Adolescente , Actitud Frente a la Salud , Niño , Conducta Infantil , Femenino , Humanos , Masculino , MinnesotaRESUMEN
We have reported previously that human keratinocytes synthesize and secrete acetylcholine and that muscarinic cholinergic drugs have effects on keratinocyte proliferation, adhesion, and migration. This study defines the location of muscarinic acetylcholine receptors in human epidermis and describes some pharmacologic and molecular properties of these receptors. Confocal microscopy employing the anti-muscarinic receptor monoclonal antibody M35 visualized the receptors in the intercellular areas of normal human epidermis. Using immunoelectron microscopy, the receptors appeared to be attached to the keratinocyte plasma membranes. Functional, high-density (Bmax = 8.3 nmol/2 x 10(6) cells) and high-affinity (Kd = 21.5 nM) muscarinic receptors were demonstrated by saturable binding of the reversible radioligand [3H]quinuclidinyl benzilate to the surfaces of freshly isolated epidermal cells at 0 degrees C. Receptor proteins were separated by gel electrophoresis. An apparent isoelectric point of pH 4.3 was determined in immunoblots of sodium-cholate-solubilized receptors separated on isoelectric-focusing gels. Three protein bands, two at approximately 60 kDa and one at 95 kDa, were visualized in immunoblots of membrane-bound or solubilized receptors separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis. The covalent, irreversible ligand [3H]propylbenzilylcholine mustard confirmed these results. Thus, human keratinocytes express a heterogeneous population of muscarinic cholinergic receptors. Because human keratinocytes also express nicotinic cholinergic receptors, endogenously secreted acetylcholine may control different biologic processes in these cells by activating different types of their cholinergic receptors.
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Queratinocitos/química , Receptores Muscarínicos/análisis , Anticuerpos Monoclonales , Western Blotting , Técnica del Anticuerpo Fluorescente , Humanos , Queratinocitos/ultraestructura , Ligandos , Microscopía Inmunoelectrónica , Peso Molecular , Coloración y EtiquetadoAsunto(s)
Dermatología , Medicina General , Piel/anomalías , Piel/fisiología , Piel/fisiopatología , Piel/inmunología , Piel/microbiología , Piel/patología , Dermatitis , Eccema , Glándulas Sebáceas/anomalías , Pigmentación de la Piel/fisiología , Psoriasis , Terapéutica , Trastornos de la PigmentaciónRESUMEN
Dermatophytes are eliminated from the skin by a cell-mediated immune reaction. Immunity is acquired by active infection. The inflammatory reaction that ensues may increase the proliferatory activity of keratinocytes, causing the fungus to be sloughed from the skin surface. Nonspecific mechanisms of defense prevent invasion into the dermis and bloodstream even in the absence of immunity. Serum inhibitory factor robs fungi of iron, an essential nutrient. The cell walls of the organism activate complement through the alternative pathway and inhibit fungal growth. Polymorphonuclear leukocytes adhere to opsonized and unopsonized hyphae to inhibit growth of the dermatophyte and perhaps damage or kill it. The fungas secrets keratinases and other enzymes that allow the dermatophyte to burrow deeper into the stratum corneum. Mannan from the cell wall of Trichophyton rubrum and a lipophilic toxin associated with it might inhibit cell-mediated immunity and keratinocyte proliferation.
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Arthrodermataceae/inmunología , Proteínas del Sistema Complemento/inmunología , Dermatomicosis/inmunología , Queratinocitos/inmunología , Neutrófilos/inmunología , Arthrodermataceae/metabolismo , Adhesión Bacteriana , División Celular , Activación de Complemento , Dermatomicosis/metabolismo , Dermatomicosis/microbiología , Dermatomicosis/patología , Humanos , Inmunidad Celular , Queratinocitos/metabolismo , Queratinocitos/microbiología , Queratinocitos/patología , Prueba de Inhibición de Adhesión Leucocitaria , Mananos/metabolismo , Mananos/farmacocinética , Monocitos/inmunología , Monocitos/metabolismo , Neutrófilos/metabolismo , Neutrófilos/microbiología , Neutrófilos/patología , Peroxidasa , Unión ProteicaRESUMEN
Resistance to dermatophyte infections has been shown to be mediated in part by T lymphocytes. The dermatophyte antigens recognized by human T lymphocytes and their degree of cross-reactivity were analyzed. Dermatophyte-responsive T-cell lines were generated by in vitro sensitization to crude fungal extracts obtained from Trichophyton rubrum, Trichophyton tonsurans, Microsporum canis and Epidermophyton floccosum. Proliferation was measured by incorporation of 3H-thymidine. The human T-cell lines responded to fungal extracts derived from these various dermatophyte species, demonstrating the recognition of cross-reactive antigens by human T cells. However, the T cells were dermatophyte-specific as they did not respond to herpes antigen, nor did herpes-specific T cells derived from the same donors respond to dermatophyte antigens. The mannose-rich glycoprotein fraction (mannan) isolated from T. rubrum was able to induce proliferation of T-cell lines generated by stimulation with various fungal extracts. Furthermore, a T-cell line generated by stimulation with mannan derived from T. rubrum proliferated in response to extracts from various fungal species, indicating that a major cross-reactive dermatophyte T-cell antigen was present in the mannose-rich glycoprotein fraction.
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Antígenos Fúngicos/inmunología , Arthrodermataceae/inmunología , Arthrodermataceae/fisiología , Glicoproteínas/química , Glicoproteínas/inmunología , Manosa/análisis , Linfocitos T/citología , Linfocitos T/inmunología , Adulto , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular , Reacciones Cruzadas , Epidermophyton/inmunología , Humanos , Masculino , Mananos/inmunología , Mananos/farmacología , Microsporum/inmunología , Persona de Mediana Edad , Fenotipo , Linfocitos T/metabolismo , Timidina/metabolismo , Trichophyton/inmunología , TritioRESUMEN
Effects of low concentrations of detergents on cultured human foreskin keratinocytes were assessed in vitro. The viability and activity of keratinocytes were assessed by measuring reduction of a tetrazolium dye as an indicator of mitochondrial metabolism. The keratinocyte proliferative responses after incubation with detergents were assessed by a spectrophotometric assay employing crystal violet dye and a fluorometric assay determining total DNA content. Both the cationic detergent cetyltrimethylammonium bromide [CTAB] and the anionic detergent sodium lauryl sulfate [SLS] showed toxic effects on keratinocytes at concentrations as low as 3 micrograms/mg, but SLS was less toxic. However, both SLS and CTAB activated keratinocytes at very low concentrations. Proliferative activity and mitochondrial metabolism increased. Serum partially protected keratinocytes against toxic and stimulatory activities of both detergents. We suggest that detergents may directly damage keratinocytes and thereby produce irritant contact dermatitis, but activation of keratinocytes by low concentrations may also produce dermatitis, perhaps by causing keratinocytes to release cytokines.