RESUMO
OBJECTIVE: In this study the safety and efficacy of imiquimod 5% cream for the treatments of actinic keratoses in kidney, heart and liver transplant recipients is evaluated. BACKGROUND: Growing populations of organ transplant recipients face increased risk of developing actinic keratosis (AK) and skin cancer secondary to continuous systemic immunosuppressive therapy. Imiquimod 5% cream is an effective option for the treatment of AK, but the safety of topical immune stimulation in immunocompromised patients has not been widely evaluated. METHODS: A total of 43 patients in six European transplant centres applied two sachets of topical imiquimod or vehicle cream three times per week to a 100 cm(2) field. Dosing continued for 16 weeks regardless of lesion clearance. Patients were assessed for safety variables that included adverse events, local skin reactions, laboratory results, vital signs, dosage of immunosuppressive medication and indication of graft rejection. A blinded independent expert committee was responsible for safety monitoring and final safety assessment. RESULTS: No graft rejections or trends for a deterioration of graft function were detected. No meaningful trends were observed in laboratory results. Among patients randomized to imiquimod, the complete clearance rate was 62.1% (18/29); for vehicle patients, the complete clearance rate was 0% (0/14). Clinical clearance was confirmed histologically in all cases. CONCLUSIONS: Imiquimod appears to be a safe alternative for the treatment of multiple actinic keratoses in patients with solid organ transplants. Efficacy was within the range previously observed in nontransplanted populations.
Assuntos
Aminoquinolinas/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Ceratose/tratamento farmacológico , Transplante de Órgãos , Neoplasias Cutâneas/tratamento farmacológico , Administração Cutânea , Adulto , Idoso , Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/imunologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Imiquimode , Hospedeiro Imunocomprometido , Ceratose/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/tratamento farmacológico , Neoplasias Induzidas por Radiação/imunologia , Neoplasias Cutâneas/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: The molecular events leading to actinic keratosis (AK) are not well understood. OBJECTIVE: To identify and compare gene expression changes in AK lesions and in sun-exposed nonlesional skin and to determine the effect of imiquimod 5% cream on these changes. METHOD: A double-blind, vehicle-controlled, randomized study was conducted to evaluate the molecular changes in AK treated with imiquimod. Seventeen male subjects with >/= 5 AK lesions on the scalp applied vehicle or imiquimod three times a week for 4 weeks. Gene expression analysis using Affymetrix oligonucleotide arrays was performed on shave biopsies of lesions taken before and after treatment. Confocal microscopy was performed on the study area as an adjunctive diagnostic procedure. RESULTS: We identified gene expression changes which occur in sun-exposed, nonlesional skin as well as in AK lesions. These changes include, but are not limited to, the overexpression of oncogenic and proliferative genes and diminished expression of tumour suppressor genes. The gene expression changes observed in AK lesions and in sun-exposed, nonlesional skin were consistent with the confocal microscopy observations, which showed abnormalities in the sun-exposed, nonlesional skin, similar in nature but less pronounced than abnormalities seen in AK. Imiquimod partially or totally reversed the aberrant expression of some of the genes observed in AK, consistent with clearing of lesions and normalization of confocal cellular images. CONCLUSIONS: The data show that profound gene expression changes occur in sun-exposed, nonlesional skin which progress further in AK lesions. The data also suggest that imiquimod may play a role in normalizing gene expression and cellular morphology in sun-damaged skin.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Aminoquinolinas/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Ceratose/genética , Transtornos de Fotossensibilidade/genética , Dermatoses do Couro Cabeludo/genética , Receptor 7 Toll-Like/agonistas , Administração Tópica , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Seguimentos , Humanos , Imiquimode , Ceratose/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Transtornos de Fotossensibilidade/tratamento farmacológico , Dermatoses do Couro Cabeludo/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Imiquimod 5% cream is a topically applied immune response modifier that has been shown to give effective treatment of actinic keratosis (AK). The therapeutic effects of imiquimod are likely to involve the provocation of a cutaneous immune response against abnormal cells, an assumption based on a strong correlation between complete clearance rates and the severity of the local skin reactions (erythema, oedema, erosion/ulceration, weeping/exudation and scabbing/crusting); however, no clinical studies have conclusively proved this mechanism. OBJECTIVES: To determine the nature of cellular infiltrates induced by the application of imiquimod to AK lesions and to study cells involved in the cutaneous immune response. METHODS: Eighteen patients participated in this phase I, randomized, double-blind, parallel group, vehicle-controlled study. Enrolled patients were randomized in a 2 : 1 ratio to receive imiquimod cream or vehicle cream and applied study cream to five lesions on the scalp, forearm or upper trunk once daily, three days per week for up to 16 weeks. Each patient had punch biopsies of two distinct AK lesions: a lesion was biopsied before treatment to obtain baseline biomarker levels, and a different lesion was biopsied after 2 weeks of treatment. Biopsy specimens were examined using routine and immunohistochemical staining. RESULTS: The imiquimod group showed statistically significant increases from baseline to week 2 in tissue biomarker levels for CD3, CD4, CD8, CD11c, CD86/CD11c, CD68, HLA-DR and TUNEL. No significant differences were seen for the vehicle group. Complete clearance of all treated AK lesions was achieved in five of 11 (45%) imiquimod patients and in none of six vehicle patients. CONCLUSIONS: Imiquimod stimulates a cutaneous immune response characterized by increases in activated dendritic cells and CD4+ and CD8+ T cells.
Assuntos
Aminoquinolinas/uso terapêutico , Células Dendríticas/efeitos dos fármacos , Ceratose/tratamento farmacológico , Transtornos de Fotossensibilidade/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Idoso , Aminoquinolinas/efeitos adversos , Biomarcadores/metabolismo , Movimento Celular/imunologia , Células Dendríticas/imunologia , Método Duplo-Cego , Toxidermias/etiologia , Eritema/induzido quimicamente , Feminino , Humanos , Imiquimode , Imunofenotipagem , Indutores de Interferon/efeitos adversos , Indutores de Interferon/uso terapêutico , Ceratose/imunologia , Masculino , Pessoa de Meia-Idade , Transtornos de Fotossensibilidade/imunologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Resultado do TratamentoRESUMO
Imiquimod is presumed to clear basal cell carcinoma (BCC) through apoptosis mediated by cytokines and lymphocytes, with erosion often observed correlating with complete clearance. The objective was to determine the cellular immune response early in the course of treatment in order to examine whether cell mediated immunity could be responsible for imiquimod mediated regression of BCC. Sixteen adults with clinically diagnosed BCC were openly assigned to 5 days per week of drug (1, 2 or 4 weeks) or placebo (2 weeks) in groups of four. No baseline biopsy was performed. Post-treatment excision specimens were examined by routine and immunohistochemical staining. Treatment was associated with the early appearance of CD4 cells, activated dendritic cells and macrophages, with later infiltration by CD8 T cells. Dendritic cells continually increased with time, while macrophages reached a maximum at 1 week and then declined slightly. There were comparatively few neutrophils or gammadelta T cells. Early infiltrates were most prominent in the tumour and upper dermis. The results are consistent with a cell mediated immune response being responsible for the clearance of the BCC. Several immune-mediated tumour destruction mechanisms are likely to be involved.
Assuntos
Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Aminoquinolinas/efeitos adversos , Antineoplásicos/efeitos adversos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Carcinoma Basocelular/imunologia , Carcinoma Basocelular/patologia , Células Dendríticas/efeitos dos fármacos , Humanos , Imiquimode , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
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.
Assuntos
Aminoquinolinas/farmacologia , Condiloma Acuminado/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Indutores de Interferon/farmacologia , Transativadores/genética , Aminoquinolinas/uso terapêutico , Biópsia , Diferenciação Celular/efeitos dos fármacos , Condiloma Acuminado/tratamento farmacológico , Condiloma Acuminado/imunologia , Condiloma Acuminado/metabolismo , Proteínas de Ligação a DNA/metabolismo , Método Duplo-Cego , Humanos , Imiquimode , Indutores de Interferon/uso terapêutico , Interferons/genética , Interferons/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/fisiologia , Proteínas Inibidoras de STAT Ativados , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Transativadores/metabolismoRESUMO
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.
Assuntos
Aminoquinolinas/uso terapêutico , Condiloma Acuminado/tratamento farmacológico , Doenças dos Genitais Femininos/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Indutores de Interferon/uso terapêutico , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciação Celular , Divisão Celular , Condiloma Acuminado/imunologia , Condiloma Acuminado/virologia , Citocinas/genética , Citocinas/metabolismo , Método Duplo-Cego , Feminino , Doenças dos Genitais Femininos/imunologia , Doenças dos Genitais Femininos/virologia , Doenças dos Genitais Masculinos/imunologia , Doenças dos Genitais Masculinos/virologia , Humanos , Imiquimode , Queratinócitos/patologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/fisiologia , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Carga ViralRESUMO
Imiquimod (S-26308, R-837) (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4 amine), an immune response modifier, demonstrates potent antiviral and antitumor activity in animal models (see structure in Fig. 1). The drug exhibits no direct antiviral or antiproliferative activity when tested in a number of cell culture systems. Imiquimod's activity was discovered while screening for anti-herpes virus activity. One of the first analogs in the series, S-25059 was tested in the early 1980's and due to slight toxicity, caused slightly reduced herpes cytopathology in Vero cell cultures. Follow-up testing in herpes infected guinea pigs showed complete protection toward lesion development. Activity of these drugs results primarily from interferon alpha (IFN-alpha) induction and other cytokine induction. At least part of the cytokine induction is mediated through NF-kappaB activation. These cytokines stimulate several other aspects of the innate immune response. In addition, imiquimod stimulates acquired immunity, in particular the cellular arm which is important for control of viral infections and various tumors. This effect is mediated by drug induced IFN-alpha and Interleukin-12 (IL-12) and IFN-gamma induced by these cytokines. Imiquimod is expected to be effective where exogenous IFN-alpha has shown utility and where enhancement of cell-mediated immunity is needed. The following is a brief review of the preclinical pharmacology of imiquimod and the clinical results of genital wart trials. The mechanism of action of topically applied imiquimod will likely lead to benefits in several other chronic virus infections and tumors of the skin. Two other reviews on imiquimod that focus mainly on the clinical results have been published (Beutner & Geisse, 1997; Slade, Owens, Tomai & Miller, 1998).
Assuntos
Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/farmacologia , Antivirais/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Administração Tópica , Aminoquinolinas/administração & dosagem , Animais , Antivirais/administração & dosagem , Humanos , ImiquimodeRESUMO
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.
Assuntos
Aminoquinolinas/uso terapêutico , Condiloma Acuminado/tratamento farmacológico , Doenças dos Genitais Femininos/tratamento farmacológico , Doenças dos Genitais Masculinos/tratamento farmacológico , Indutores de Interferon/uso terapêutico , Administração Tópica , Adolescente , Adulto , Condiloma Acuminado/imunologia , Condiloma Acuminado/patologia , Condiloma Acuminado/virologia , Citocinas/análise , Citocinas/genética , Feminino , Doenças dos Genitais Femininos/imunologia , Doenças dos Genitais Femininos/patologia , Doenças dos Genitais Femininos/virologia , Doenças dos Genitais Masculinos/imunologia , Doenças dos Genitais Masculinos/patologia , Doenças dos Genitais Masculinos/virologia , Humanos , Imiquimode , Masculino , RNA Mensageiro , Resultado do TratamentoRESUMO
OBJECTIVE: As a secondary objective to a long-term study evaluating the bronchodilator effectiveness of Proventil HFA (albuterol), to assess the safety of Proventil HFA, Ventolin, and hydrofluoroalkane 134a (HFA-134a) placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy parallel group, placebo-controlled, multicenter trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment with Proventil HFA, Ventolin, or HFA-134a placebo, qid, for 12 weeks. MEASUREMENTS: Adverse events were reviewed at biweekly clinic visits. Between clinic visits, patients recorded morning and evening peak expiratory flow (PEF), asthma symptom and nighttime asthma sleep disturbance scores, and use of rescue beta-adrenergic bronchodilator on diary cards daily. Investigators provided a global assessment of asthma control at weeks 0, 4, 8, and 12. Vital signs were recorded over 6 h after dosing with study drug at weeks 0, 4, 8, and 12. Standard laboratory tests, CBC count, serum chemistries, and urinalysis were obtained at study start and end. RESULTS: Adverse event reporting rates were similar for the three treatment groups. The morning PEF tended to be lower for the Proventil HFA and Ventolin groups than the HFA-134a placebo group, but the evening PEF tended to be higher for the active treatment groups. Daytime asthma symptom scores tended to be lower (better) with active treatment than placebo, but nighttime asthma sleep disturbance scores were similar for all three treatment groups. Use of Ventolin Rotacaps as rescue medication was significantly greater for the HFA-134a placebo group than the Proventil HFA and Ventolin groups. Diary card data did not change within groups over time. Investigator global assessments of asthma scores clustered between fair and good for all three treatment groups throughout the study. Changes in heart rate and BP were small after dosing with study drug and tended to be similar for the active treatments and HFA-134a placebo groups. No clinically meaningful changes in results of standard laboratory tests were found in any treatment group during this study. CONCLUSIONS: Proventil HFA had a similar safety profile as Ventolin during regular use. A dosage of 16 puffs per day of propellant HFA-134a was well tolerated by asthmatics. Regular use of either Proventil HFA or Ventolin did not cause asthma control to deteriorate.
Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Administração por Inalação , Adolescente , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/efeitos adversos , Adulto , Propelentes de Aerossol , Idoso , Albuterol/administração & dosagem , Albuterol/efeitos adversos , Asma/sangue , Asma/fisiopatologia , Asma/urina , Contagem de Células Sanguíneas , Análise Química do Sangue , Pressão Sanguínea/efeitos dos fármacos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Método Duplo-Cego , Cefaleia/etiologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrocarbonetos Fluorados , Estudos Longitudinais , Prontuários Médicos , Pessoa de Meia-Idade , Pico do Fluxo Expiratório/efeitos dos fármacos , Pico do Fluxo Expiratório/fisiologia , Placebos , Infecções Respiratórias/etiologia , Rinite/etiologia , Segurança , Transtornos do Sono-Vigília/fisiopatologiaRESUMO
OBJECTIVE: To compare the bronchodilator effectiveness of albuterol reformulated in the chlorofluorocarbon-free propellant hydrofluoroalkane (HFA)134a (Proventil HFA) to that of Ventolin and HFA placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy, parallel group, placebo-controlled, multi-center trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment qid with Proventil HFA, Ventolin, or HFA-134a placebo for 12 weeks. MEASUREMENTS: At weeks 0, 4, 8, and 12, spirometry was performed predose and serially over 6 h after dosing with study drug. Bronchodilator efficacy variables, based on FEV1 response to study drug, were proportion of responders, time to onset of effect, peak percent change, time to peak effect, duration of effect, and area under the curve (AUC). RESULTS: Demographic and baseline characteristics were similar for patients randomized to Proventil HFA (193), Ventolin (186), and HFA-134a placebo (186). No significant differences were found between the Proventil HFA and Ventolin treatment groups for any FEV1 efficacy variable, either predose or during 6 h of serial spirometry, at weeks 0, 4, 8, and 12. For all efficacy variables, except time to onset of effect, the Proventil HFA and Ventolin results were significantly greater than placebo. Time to onset of effect for the HFA-134a placebo group is misleading; only 13 patients (7%) were found to be responders in the intent-to-treat database. These efficacy results were found to be consistent across subgroup analyses of inhaled and nasal corticosteroid use, age (18 to 35 and 36 to 66 years), sex, race, weight (<60, 60 to 100, and >100 kg), and baseline FEV1 (< or =55% and >55% predicted). The peak FEV1 effect, duration of FEV1 effect, and AUC for FEV1 were all significantly smaller at weeks 4, 8, and 12 than week 0 for both the Proventil HFA and Ventolin treatment groups. CONCLUSIONS: Proventil HFA provided bronchodilation comparable to Ventolin and superior effects to HFA-134a placebo over 12 weeks of regular dosing. There was a diminution in bronchodilator response to both Proventil HFA and Ventolin after 4 weeks of use.
Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Administração por Inalação , Adolescente , Agonistas Adrenérgicos beta/administração & dosagem , Adulto , Propelentes de Aerossol , Fatores Etários , Idoso , Albuterol/administração & dosagem , Área Sob a Curva , Peso Corporal , Broncodilatadores/administração & dosagem , Clorofluorcarbonetos , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Seguimentos , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Hidrocarbonetos Fluorados , Masculino , Pessoa de Meia-Idade , Placebos , Grupos Raciais , Indução de Remissão , Fatores Sexuais , EspirometriaRESUMO
Imiquimod is a novel synthetic molecule with potent immune-modifying activities. Formulated in a 5% vanishing cream as Aldara, this self-applied therapy has shown good efficacy and safety in the treatment of external genital and perianal warts caused by human papillomavirus (HPV) infection (Condyloma acuminata). The molecule does not demonstrate direct antiviral activity, but through induction of cytokines results in immune-based resolution of wart tissue and reduction of viral burden. Phase III trials of imiquimod have demonstrated that patients who experience complete clearance of either new or recalcitrant warts tend to remain clear, possibly related to Th1 immune recognition and memory. Self-application, good tolerability and a unique mechanism of action combine to make imiquimod a reasonable first-line therapy for genital warts. The effects of imiquimod on immune function suggest several potential uses. Preclinical studies of infection with herpes simplex virus (HSV), cutaneous leishmaniasis, Rift Valley Fever virus and vesiculostomatitis virus have shown reduced viral persistence, reduced recurrence (HSV) and diminished pathology (Leishmania donovani). In a murine tumour model using the FCB bladder cancer cell line, imiquimod behaves as a potent adjuvant leading to immune-based tumour cell eradication and immunity against subsequent FCB cell challenge. The ability of imiquimod to induce significant production of interferon alpha (IFN-alpha) by monocytes/macrophages suggests that diseases responsive to recombinant interferon therapy, such as basal cell carcinoma, may be reasonable clinical targets. The induction of tumour necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma) and interleukin-12 (IL-12) leads to inhibition of IL-5, with animal models demonstrating immune deviation away from Th2 immune responses. The observation that several patients with hepatitis C infection and eosinophilia showed normalisation of elevated eosinophil counts in association with oral imiquimod therapy encourages further exploration of the immune modifying properties of this novel molecule. This review is focused on the use of imiquimod for the treatment of external genital and perianal warts.
RESUMO
Imiquimod is the newest in a class of drugs known as immune response modifiers. In preclinical studies, imiquimod induced the production of cytokines - the principal cytokine for antiviral activity being interferon alpha. Imiquimod does not inhibit viruses directly, nor does it cause direct, non-specific cytolytic destruction [1]. Preclinical studies suggest that its antiviral action results from in vivo cytokine-induced activation of the immune system. This paper reviews a recent double blind, placebo-controlled study designed to evaluate this hypothesis. The results of this study showed that wart regression following treatment with imiquimod strongly correlated with a decrease in viral DNA and gene transcripts; a decrease in mRNA expression for proteins associated with cellular proliferation, and an increase in keratinocyte markers. These results support the hypothesis that stimulation of local cytokines by imiquimod leads to a reduction in human papilloma virus (HPV) load; to wart regression and to the normalisation of keratinocyte proliferation without evidence of scarring.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Aminoquinolinas/uso terapêutico , Citocinas/biossíntese , Indutores de Interferon/uso terapêutico , Papillomaviridae/imunologia , Infecções por Papillomavirus/tratamento farmacológico , Infecções Tumorais por Vírus/tratamento farmacológico , Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/farmacologia , Animais , Ensaios Clínicos Fase I como Assunto , Condiloma Acuminado/tratamento farmacológico , Condiloma Acuminado/imunologia , Citocinas/efeitos dos fármacos , DNA Viral/análise , DNA Viral/efeitos dos fármacos , Humanos , Imiquimode , Indutores de Interferon/farmacologia , Papillomaviridae/genética , Infecções por Papillomavirus/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções Tumorais por Vírus/imunologiaAssuntos
Vacinas contra a AIDS/genética , Infecções por HIV/virologia , HIV-1/genética , Recombinação Genética , Adulto , Sequência de Bases , Linhagem Celular Transformada , Células Cultivadas , DNA Viral , Feminino , Genes env , Genes gag , Infecções por HIV/imunologia , Infecções por HIV/terapia , HIV-1/classificação , HIV-1/imunologia , HIV-1/isolamento & purificação , Humanos , Dados de Sequência MolecularRESUMO
A 1-year study measured the effect of administration of an inactivated human immunodeficiency virus type 1 (HIV-1) immunogen in incomplete Freund's adjuvant (IFA) on HIV-1-specific immunity and viral burden in asymptomatic HIV-1-infected patients. A total of 103 patients were enrolled in this double-blind, randomized study comparing immunogen in adjuvant with adjuvant alone. This study was conducted at nine medical centers throughout the United States. Significant differences in cell-mediated immune responses to HIV-1 and p24 core antigen were observed between the treated and control groups (P < .01). Compared with controls, treated patients as a group had a significantly lower rate of increase in viral DNA as determined by quantitative HIV-1 DNA-polymerase chain reaction (P = .016). Significant differences in the rate of percent CD4 cell decline were also observed between the 2 groups (P = .024). These data suggest that augmentation of HIV-1-specific immunity via immunotherapy may alter the rate of increase of HIV-1 DNA in peripheral blood mononuclear cells and stabilize the percent of CD4 cell decline in relatively healthy HIV-1-infected persons.
Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/administração & dosagem , Adolescente , Adulto , Formação de Anticorpos , Linfócitos T CD4-Positivos/citologia , DNA Viral/análise , Método Duplo-Cego , Adjuvante de Freund , Anticorpos Anti-HIV/imunologia , Humanos , Imunidade Celular/imunologia , Contagem de Leucócitos , Leucócitos Mononucleares/microbiologia , Pessoa de Meia-Idade , Vacinação , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologiaRESUMO
We investigated mechanisms by which the soluble native envelope glycoprotein gp120 of the human immunodeficiency virus (HIV-1) suppresses antigen-driven T cell responses. For this study, exogenous interleukin-2 (IL-2)-independent, antigen-specific, CD4 positive, human T-cell clones were developed by cyclic restimulation with soluble tetanus toxoid antigen. In the presence of soluble antigen and antigen-presenting cells (APC), T-cell clones proliferated and secreted IL-2. Purified gp120 suppressed the proliferative responses of the T-cell clones with concomitant suppression of IL-2 secretion; proliferative responses of CD8+ T cells preincubated with gp120 were not inhibited. A short pulse of 20 minutes with gp120 was sufficient to inhibit the proliferative response of the T-cell clones. Anti-CD3 monoclonal antibody (MoAb)-driven proliferation of the T-cell clones was also suppressed by gp120, but responses elicited by mitogens, phorbol myristate acetate (PMA) plus calcium ionophore, ionomycin, anti-CD2 MoAbs, and a combination of anti-CD3 plus anti-CD28 MoAb driven responses remained unaffected. Investigation of signal transduction events showed that antigen-driven early activation signals via translocation of protein kinase C (PKC), increase in intracellular inositol phosphates, and increase in intracellular calcium were suppressed in gp120 pretreated, tetanus toxoid antigen-stimulated T-cell clones. One mechanism of immune suppression by gp120 may involve interference with the initiation of signal transduction through the T-cell receptor complex.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos CD2 , Antígenos CD28 , Cálcio/metabolismo , Células Clonais , Proteína gp120 do Envelope de HIV/isolamento & purificação , Proteína gp120 do Envelope de HIV/farmacologia , Humanos , Técnicas In Vitro , Fosfatos de Inositol/metabolismo , Interleucina-2/biossíntese , Ativação Linfocitária/efeitos dos fármacos , Proteína Quinase C/metabolismo , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores Imunológicos/imunologia , Receptores de Interleucina-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Toxoide Tetânico/imunologiaRESUMO
Asymptomatic congenital HIV infection cannot be diagnosed in infants less than 15 mo by routine serologic techniques because of the presence of passively acquired maternal antibody in the infants' circulation. Possibly, infants who synthesize antibody to highly conserved HIV proteins may be recognized by the detection in serum of clonally distinct IgG antibodies to HIV. To test this hypothesis, isoelectric focusing in thin-layer agarose gels was combined with affinity immunoblotting to antigen-coated nitrocellulose membranes. In all 10 cases examined, the presence or absence of clonotypically distinct bands of IgG antibodies was concordant with infectious status. Thus, this technique may provide an accurate serologic approach to the diagnosis of congenital HIV infection.