RESUMEN
Imiquimod (IQ) has been successfully used in treatment of genital warts. In clinical settings, patients responded well but wart reduction rates varied. Our aim was to find a correlation between clinical responses and pretreatment (constitutive) levels of genes that might be involved in the molecular action of IQ. Since IQ is a cytokine inducer, we analyzed levels of expression of genes of the JAK/STAT signaling pathway and their inhibitors as well as interferon response factors (IRFs) in pretreatment biopsy specimens from complete responders (99 to 100% wart reduction rate) versus incomplete responders (75 to 92% wart reduction rate) by reverse transcription-PCR. We found that mRNA levels of signal transducer and activator of transcription 1 (STAT1) and IRF1 were higher in complete responders than in incomplete responders. Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment. We hypothesize that high-level expression of STAT1 and IRF1 is advantageous for a better IQ response. The observed differences in constitutive mRNA levels of these genes may be the consequence of alterations in cellular differentiation and/or variable expression of endogenous interferons. Previous in vitro studies showed that keratinocyte differentiation coordinates the balance between positive and negative signals along the JAK/STAT pathway by regulating the IRF1:IRF2 and STAT1:PIAS1 ratios and thus affecting induction of IQ-inducible genes. Specifically, differentiation supports constitutive expression of STAT1 and IRF1 mRNAs but not expression of IRF2 and PIAS1. Our data are in good agreement with studies that showed the importance of STAT1 in cytokine induction and activation of interferon-responsive genes by IQ.
Asunto(s)
Aminoquinolinas/farmacología , Condiloma Acuminado/genética , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/efectos de los fármacos , Inductores de Interferón/farmacología , Transactivadores/genética , Aminoquinolinas/uso terapéutico , Biopsia , Diferenciación Celular/efectos de los fármacos , Condiloma Acuminado/tratamiento farmacológico , Condiloma Acuminado/inmunología , Condiloma Acuminado/metabolismo , Proteínas de Unión al ADN/metabolismo , Método Doble Ciego , Humanos , Imiquimod , Inductores de Interferón/uso terapéutico , Interferones/genética , Interferones/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/fisiología , Proteínas Inhibidoras de STAT Activados , Proteínas/genética , Proteínas/metabolismo , ARN Mensajero/metabolismo , Factor de Transcripción STAT1 , Factor de Transcripción STAT3 , Transactivadores/metabolismoRESUMEN
The mechanism of action of imiquimod 5% cream applied topically to patients with genital warts was evaluated in a double-blind, placebo-controlled study. Imiquimod (16 patients) or placebo (three patients) was applied three times per week for up to 16 weeks. All imiquimod-treated patients had a > or =75% reduction in total wart area while only one of three placebo-treated patients had a similar reduction. Wart biopsies were taken at prestudy, week 6, and end of treatment. Polymerase chain reaction (PCR) for human papillomavirus (HPV) DNA and reverse transcriptase (RT)-PCR for messenger (m)RNAs were used to identify cytokines, cellular markers, viral gene products, and cell cycle markers in these biopsies. Treatment with imiquimod, an immune response modifier, stimulated significant increases in mRNA for interferon (IFN)-alpha, IFN-gamma and 2',5' oligoadenylate synthetase (2',5'-AS) as well as a tendency towards increases in tumor necrosis factor (TNF)-alpha and interleukin-12 p40. Significant increases in mRNA for CD4 and a trend toward increases in CD8 were also observed in imiquimod-treated patients, suggesting activation of a cell mediated immune response. Imiquimod administration was also associated with a significant decrease in viral load as measured by HPV DNA and L1 mRNA. The effects on HPV markers were accompanied by an apparent decrease in mRNA expression for markers of cell proliferation and an increase in mRNA for markers of keratinocyte differentiation and tumor suppressors.
Asunto(s)
Aminoquinolinas/uso terapéutico , Condiloma Acuminado/tratamiento farmacológico , Enfermedades de los Genitales Femeninos/tratamiento farmacológico , Enfermedades de los Genitales Masculinos/tratamiento farmacológico , Inductores de Interferón/uso terapéutico , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciación Celular , División Celular , Condiloma Acuminado/inmunología , Condiloma Acuminado/virología , Citocinas/genética , Citocinas/metabolismo , Método Doble Ciego , Femenino , Enfermedades de los Genitales Femeninos/inmunología , Enfermedades de los Genitales Femeninos/virología , Enfermedades de los Genitales Masculinos/inmunología , Enfermedades de los Genitales Masculinos/virología , Humanos , Imiquimod , Queratinocitos/patología , Masculino , Persona de Mediana Edad , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Papillomaviridae/fisiología , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Carga ViralRESUMEN
Imiquimod, an immune response modifier, has been demonstrated to be safe and effective in the treatment of external genital and perianal warts caused by human papillomavirus (HPV). To identify the molecular mechanism(s) by which condylomata acuminata clear during topical treatment with imiquimod, wart skin biopsies were taken from patients before treatment, at treatment week 6, and at the end of treatment. Tissues were analyzed for HPV DNA and for mRNA of several cytokines and HPV gene products. Wart clearance was associated with evidence of tissue production of interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha. Regression of warts was strongly associated with a decrease in HPV DNA and in mRNA expression for both early and late viral proteins. Thus, topical imiquimod treatment of anogenital warts led to significant increases in local production of multiple interferon mRNAs and a significant reduction in virus load as measured by decreases in HPV DNA and mRNA for early HPV proteins.
Asunto(s)
Aminoquinolinas/uso terapéutico , Condiloma Acuminado/tratamiento farmacológico , Enfermedades de los Genitales Femeninos/tratamiento farmacológico , Enfermedades de los Genitales Masculinos/tratamiento farmacológico , Inductores de Interferón/uso terapéutico , Administración Tópica , Adolescente , Adulto , Condiloma Acuminado/inmunología , Condiloma Acuminado/patología , Condiloma Acuminado/virología , Citocinas/análisis , Citocinas/genética , Femenino , Enfermedades de los Genitales Femeninos/inmunología , Enfermedades de los Genitales Femeninos/patología , Enfermedades de los Genitales Femeninos/virología , Enfermedades de los Genitales Masculinos/inmunología , Enfermedades de los Genitales Masculinos/patología , Enfermedades de los Genitales Masculinos/virología , Humanos , Imiquimod , Masculino , ARN Mensajero , Resultado del TratamientoRESUMEN
A recognized side effect of chemonucleolysis is life-threatening anaphylaxis to chymopapain. In the clinical trials of chymopapain, 13 cases of anaphylaxis were reported in 1585 administrations (0.82%). Two patients died. Data from a postmarketing survey (48,239 questionnaires) were reviewed to identify factors influencing the incidence and severity of anaphylaxis. The results indicate the incidence of anaphylaxis decreased to 0.44% in the 1983-1984 period (126/23,736), a level significantly (P less than or equal to 0.001) below the incidence of 0.82% observed in initial clinical trials. Only three deaths from complications related to anaphylaxis occurred in approximately 75,000 administrations (producing 252 anaphylactic episodes) reported since December 1982. The prophylactic use of antihistamines and pretreatment with intravenous fluids coincide with the dramatic reduction in mortality due to anaphylaxis. However, overdiagnosis of anaphylaxis in the clinical trials and avoidance of chemonucleolysis in patients with IgE antibodies to chymopapain may account, in part, for the reduction in incidence.
Asunto(s)
Anafilaxia/epidemiología , Quimopapaína/efectos adversos , Adulto , Anafilaxia/mortalidad , Anafilaxia/prevención & control , Anestesia Local , Femenino , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Masculino , Vigilancia de Productos Comercializados , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
To extent the safety information for Chymodiactin (chymopapain for injection), 37 neurologic and orthopedic surgeons conducted an open-label, multicenter, phase 3 clinical study. A total of 1,498 patients with one or two herniated lumbar intervertebral discs were enrolled. Therapeutic results were generally favorable, with the percentages of patients achieving either excellent or good (or successful) results ranging from 79.6% to 88.9%, depending on criteria employed in the tabulation. There were 13 cases of anaphylaxis, and 2 of these patients died of complications of anaphylaxis. Two additional patients experienced serious neurologic problems. The first of these two patients developed transverse myelitis and paraplegia approximately 3 weeks following chemonucleolysis. Transdural discograms at three levels had been done approximately 2 days prior to chemonucleolysis, in violation of the protocol. The second patient developed acute cauda equina syndrome, and, despite emergency laminectomy, had permanent neurologic sequelae. Back spasm and stiffness/soreness were the most frequently encountered adverse experiences.
Asunto(s)
Quimopapaína/uso terapéutico , Endopeptidasas/uso terapéutico , Desplazamiento del Disco Intervertebral/terapia , Adolescente , Adulto , Anafilaxia/inducido químicamente , Anafilaxia/mortalidad , Quimopapaína/administración & dosificación , Ensayos Clínicos como Asunto , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Desplazamiento del Disco Intervertebral/diagnóstico por imagen , Yotalamato de Meglumina , Masculino , Persona de Mediana Edad , Radiografía , Distribución Aleatoria , Espasmo/inducido químicamenteRESUMEN
Postmarketing surveillance data on 29,075 patients who received Chymodiactin (Smith Laboratories' formulation of chymopapain) intradiscal injections for a herniated lumbar intervertebral disc are summarized and tabulated. The serious adverse reactions reported include death, anaphylaxis, paraplegia, and discitis. Similar problems also have been reported for Discase (Baxter-Travenol's formulation of chymopapain). Of 11 deaths reported following Chymodiactin administration, only 3 appear to be related to the drug or procedure. Two of these three were due to anaphylaxis and the third to bacterial discitis with resultant meningitis. Paraplegia appeared to be primarily due to needle trauma or injection of contrast agent and enzyme into the subarachnoid space. Careful patient selection and needle placement are essential for avoiding serious problems.
Asunto(s)
Quimopapaína/efectos adversos , Endopeptidasas/efectos adversos , Desplazamiento del Disco Intervertebral/tratamiento farmacológico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anafilaxia/inducido químicamente , Infecciones Bacterianas/etiología , Quimopapaína/administración & dosificación , Quimopapaína/uso terapéutico , Cimetidina/uso terapéutico , Difenhidramina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/inducido químicamente , Premedicación , Vigilancia de Productos ComercializadosRESUMEN
This report summarizes the results of a randomized, double-blind, parallel group, multicenter study which compared the antiarrhythmic activity and safety of oral disopyramide phosphate and oral quinidine sulfate. A total of 124 outpatients, whose pretreatment rates of ventricular and/or supraventricular arrhythmias were documented by ambulatory ECG recordings, were randomly assigned to receive either oral disopyramide or oral quinidine for the eight-week course of the study. Every two weeks, ten-hour ambulatory ECG recordings were obtained from each patient and blood was drawn to determine serum concentrations of assigned drug.
Asunto(s)
Arritmias Cardíacas/tratamiento farmacológico , Disopiramida/uso terapéutico , Piridinas/uso terapéutico , Quinidina/uso terapéutico , Administración Oral , Adolescente , Adulto , Anciano , Ensayos Clínicos como Asunto , Disopiramida/administración & dosificación , Disopiramida/análogos & derivados , Disopiramida/sangre , Método Doble Ciego , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinidina/administración & dosificación , Quinidina/sangre , Distribución AleatoriaRESUMEN
Patients in congestive heart failure are known to have altered autonomic responses to circulatory stress. In this study, two different age groups of male coronary heart disease (CHD) patients, not in failure, as well as normal male subjects, underwent standard 20-min 70 degrees head-up tilt and Valsalva tests. Responses were monitored by noninvasive methods and cardiac output was estamated with a transthoracic impedance method. During tilt, the CHD patients and control subjects had similar heart rate and diastolic pressure responses. However, the CHD patients had a greater decline in pulse pressure during tilt, mainly due to a decrease in systolic pressure. CHD patients had lesser declines in stroke volume and cardiac index and lesser increases in total vascular resistance than did control subjects. In the Valsalva, the heart rate phase increments (and decrements) from control and rate increments (and decrements) between successive phases were less in the coronary patients. The results indicate that coronary patients, not in failure, have diminished circulatory responses to the tilt and Valsalva maneuver and suggest that these tests may be useful functional indices of cardiovascular capability in coronary disease.