Asunto(s)

Aminopiridinas , Benzamidas , Ciclopropanos , Dermatitis Atópica , Inhibidores de Fosfodiesterasa 4 , Humanos , Dermatitis Atópica/tratamiento farmacológico , Aminopiridinas/uso terapéutico , Aminopiridinas/efectos adversos , Aminopiridinas/administración & dosificación , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Inhibidores de Fosfodiesterasa 4/efectos adversos , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Ciclopropanos/uso terapéutico , Ciclopropanos/efectos adversos , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacología , Ciclopropanos/farmacocinética , Benzamidas/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Crema para la Piel/administración & dosificación , Administración Cutánea

RESUMEN

Current treatments for chronic obstructive pulmonary disease (COPD) are relatively limited and cannot meet the needs of all patients. Ensifentrine (development code RPL554), a representative drug of cyclic nucleotide phosphodiesterase 3/4 (PDE 3/4) inhibitors, has shown promising developments in the treatment of COPD in recent years, which need to be summarized. This article reviews the mechanism and clinical research progress of ensifentrine, focusing on its chemical structure, pharmacokinetics, pathophysiological mechanism, efficacy, and safety. Additionally, we provide clinical application suggestions and future research prospects.

Asunto(s)

Inhibidores de Fosfodiesterasa 4 , Enfermedad Pulmonar Obstructiva Crónica , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Humanos , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 3/uso terapéutico , Inhibidores de Fosfodiesterasa 3/farmacología , Carbolinas/uso terapéutico , Carbolinas/farmacología , Isoquinolinas , Pirimidinonas

RESUMEN

BACKGROUND: Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis. METHODS: In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFß1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches. RESULTS: The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFß-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFß1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFß1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings. CONCLUSIONS: Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition.

Asunto(s)

Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Fibrosis , Queloide , Queratinocitos , Inhibidores de Fosfodiesterasa 4 , Humanos , Queloide/metabolismo , Queloide/patología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/farmacología , Animales , Ratones , Epidermis/metabolismo , Epidermis/patología , Factor de Crecimiento Transformador beta1/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Masculino

RESUMEN

Purpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). Patients and Methods: The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

Asunto(s)

Aminopiridinas , Benzamidas , Ciclopropanos , Bases de Datos Factuales , Inhibidores de Fosfodiesterasa 4 , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/mortalidad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Masculino , Femenino , Inhibidores de Fosfodiesterasa 4/efectos adversos , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Persona de Mediana Edad , Anciano , Aminopiridinas/uso terapéutico , Aminopiridinas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Factores de Riesgo , Estados Unidos/epidemiología , Bronquitis Crónica/tratamiento farmacológico , Bronquitis Crónica/mortalidad , Bronquitis Crónica/epidemiología , Medición de Riesgo , Alemania , Adulto , Suecia/epidemiología , Anciano de 80 o más Años

RESUMEN

Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and Lou Gehrig's diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties.

Asunto(s)

Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inhibidores de Fosfodiesterasa 4 , Humanos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Inhibidores de Fosfodiesterasa 4/química , Animales , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo

RESUMEN

BACKGROUND: Dyspnea is a critical component of chronic obstructive pulmonary disease (COPD). We report the effect of ensifentrine, a novel PDE3/PDE4 inhibitor, on dyspnea using pooled data from the Phase 3 ENHANCE-1/2 trials. METHODS: The pooled population (ensifentrine, n = 975; placebo, n = 574) included patients aged 40-80 years with post-bronchodilator FEV1/FVC <0.7, FEV1 30-70% predicted, mMRC Dyspnea Scale score ≥2, and a smoking history ≥10 pack-years. Patients taking dual LAMA/LABA or LAMA/LABA/ICS triple therapy were excluded. Dyspnea measures included the Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms (E-RS), and rescue medication use. RESULTS: After 24 weeks, ensifentrine significantly improved TDI scores (least-squares mean difference, 0.97; 95% CI, 0.64, 1.30; p < 0.001) and across all TDI subdomains. Ensifentrine-treated patients were more likely to be TDI responders at week 24 (p < 0.001), which was consistent across clinically relevant subgroups. Ensifentrine-treated patients had improved E-RS breathlessness subdomain scores (p = 0.053) and reduced rescue medication use (p = 0.002). CONCLUSION: Ensifentrine produced clinically meaningful improvements in multiple dyspnea measures in patients with symptomatic, moderate-to-severe COPD. A limitation of this study was the exclusion of patients taking dual LAMA/LABA and LAMA/LABA/ICS triple therapy. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are ENHANCE-1: NCT04535986; ENHANCE-2: NCT04542057.

Asunto(s)

Disnea , Inhibidores de Fosfodiesterasa 4 , Enfermedad Pulmonar Obstructiva Crónica , Índice de Severidad de la Enfermedad , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Disnea/tratamiento farmacológico , Disnea/fisiopatología , Anciano , Masculino , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Resultado del Tratamiento , Adulto , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Broncodilatadores/administración & dosificación , Inhibidores de Fosfodiesterasa 3/uso terapéutico , Inhibidores de Fosfodiesterasa 3/administración & dosificación , Inhibidores de Fosfodiesterasa 3/efectos adversos , Volumen Espiratorio Forzado , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Ensayos Clínicos Fase III como Asunto

RESUMEN

There is a pressing medical need for improved treatments in skin fibrosis including keloids and hypertrophic scars (HTS). This study aimed to characterize the role of phosphodiesterase 4 (PDE4), specifically PDE4B in fibrotic skin remodeling in vitro and in vivo. In vitro, effects of PDE4A-D (Roflumilast) or PDE4B (siRNA) inhibition on TGFß1-induced myofibroblast differentiation and dedifferentiation were studied in normal (NHDF) and keloid (KF) human dermal fibroblasts. In vivo, the role of PDE4 on HOCl-induced skin fibrosis in mice was addressed in preventive and therapeutic protocols. PDE4B (mRNA, protein) was increased in Keloid > HTS compared to healthy skin and in TGFß-stimulated NHDF and KF. In Keloid > HTS, collagen Iα1, αSMA, TGFß1 and NOX4 mRNA were all elevated compared to healthy skin confirming skin fibrosis. In vitro, inhibition of PDE4A-D and PDE4B similarly prevented TGFß1-induced Smad3 and ERK1/2 phosphorylation and myofibroblast differentiation, elevated NOX4 protein and proliferation in NHDF. PDE4A-D inhibition enabled myofibroblast dedifferentiation and curbed TGFß1-induced reactive oxygen species and fibroblast senescence. In KF PDE4A-D inhibition restrained TGFß1-induced Smad3 and ERK1/2 phosphorylation, myofibroblast differentiation and senescence. Mechanistically, PDE4A-D inhibition rescued from TGFß1-induced loss in PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced skin fibrosis in mice in preventive and therapeutic protocols. The current study provides novel evidence evolving rationale for PDE4 inhibitors in skin fibrosis (including keloids and HTS) and delivered evidence for a functional role of PDE4B in this fibrotic condition.

Asunto(s)

Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Fibroblastos , Fibrosis , Queloide , Inhibidores de Fosfodiesterasa 4 , Piel , Factor de Crecimiento Transformador beta1 , Queloide/patología , Queloide/metabolismo , Humanos , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Ratones , Inhibidores de Fosfodiesterasa 4/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Piel/patología , Piel/metabolismo , Piel/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Masculino , Células Cultivadas , NADPH Oxidasa 4/metabolismo , NADPH Oxidasa 4/antagonistas & inhibidores , NADPH Oxidasa 4/genética , Ácido Hipocloroso/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína smad3/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino

RESUMEN

Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N2-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC50 = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models.

Asunto(s)

Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Descubrimiento de Drogas , Indazoles , Enfermedades Inflamatorias del Intestino , Inhibidores de Fosfodiesterasa 4 , Animales , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Relación Estructura-Actividad , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Ratones , Indazoles/farmacología , Indazoles/química , Indazoles/síntesis química , Humanos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Estructura Molecular , Relación Dosis-Respuesta a Droga , Masculino , Ratones Endogámicos C57BL

RESUMEN

Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis. Among the series, 8 compounds i.e. 1e, 1l, 1m, 1n, 1o, 2m, 2o and 3o showed promising PDE4B inhibition (>80 %) in vitro with IC50 ∼ 1.4-6.2 µM. The compound 1l was identified as an initial hit and was pursued for further studies. According to structure-activity relationship (SAR), an allyl group at C-4 position improved PDE4B inhibition. The correlation between in vitro activity data and binding affinities obtained via molecular docking suggested that the high-affinity binding to PDE4B is a prerequisite for the effective inhibition of PDE4B. Notably, the hit 1l showed selectivity towards PDE4B over PDE4D in vitro. Furthermore, 1l treatment (30 mg/kg) in the adjuvant-induced arthritis (AIA) rat model induced by complete Freund's adjuvant (CFA) demonstrated anti-arthritic potential via ameliorating paw swelling and body weight, narrowing joint space, reducing excessive immune cells infiltration and pannus formation in addition to reducing mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-6 in synovial tissues of experimental rats. Additionally, 1l reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes. The treatment of these cells with 1l markedly reduced the protein levels of Ki67 and mRNA levels of pro-inflammatory cytokines e.g. IL-17A and TNF-α suggesting its potent anti-psoriatic potential. Furthermore, 1l did not show any significant adverse effects when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at the tested concentrations (1-100 µM) and the NOAEL (no-observed-adverse-effect level) was found to be 100 µM. Thus, with promising anti-inflammatory effects both in vitro and in vivo along with PDE4B selectivity with an acceptable safety margin, 1l emerged as a new and promising inhibitor for further studies.

Asunto(s)

Artritis Reumatoide , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inhibidores de Fosfodiesterasa 4 , Psoriasis , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Psoriasis/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Animales , Relación Estructura-Actividad , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Ratas , Estructura Molecular , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Pez Cebra , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inducido químicamente , Artritis Experimental/patología , Masculino

RESUMEN

INTRODUCTION: Psoriasis is an immune-mediated inflammatory skin disease. First-line topical treatments include steroids, calcineurin inhibitors, vitamin D analogs, and anthralin. Recently, novel topical therapeutics like tapinarof and roflumilast have emerged with unique anti-inflammatory mechanisms and promising efficacy profiles. MATERIALS AND METHODS: This review utilized PubMed, SCOPUS, and Web of Science databases to identify recent studies on tapinarof and roflumilast. Criteria focused on efficacy, safety profiles, and therapeutic roles in psoriasis treatment. RESULTS: Four primary literature articles were identified for tapinarof and five for roflumilast. Both drugs demonstrated strong efficacy with minimal adverse events in treating mild-to-moderate plaque psoriasis. Tapinarof showed more frequent but mild adverse effects, while roflumilast had less frequent but more severe side effects. DISCUSSION: Tapinarof and roflumilast offer once-daily dosing and successful treatment in restricted areas, potentially enhancing patient adherence. Cost remains a limiting factor, necessitating future comparative studies to evaluate the efficacy, safety, and cost-effectiveness between the two drugs. CONCLUSION: Tapinarof and roflumilast present promising topical treatments for psoriasis, showing efficacy and manageable safety profiles. Further research is crucial to fully elucidate their comparative benefits and drawbacks in clinical practice.

Asunto(s)

Aminopiridinas , Benzamidas , Ciclopropanos , Psoriasis , Humanos , Aminopiridinas/administración & dosificación , Aminopiridinas/efectos adversos , Aminopiridinas/uso terapéutico , Psoriasis/tratamiento farmacológico , Ciclopropanos/efectos adversos , Ciclopropanos/administración & dosificación , Ciclopropanos/uso terapéutico , Benzamidas/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Resultado del Tratamiento , Administración Tópica , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/uso terapéutico , Administración Cutánea , Resorcinoles , Estilbenos

Asunto(s)

Aminopiridinas , Benzamidas , Ciclopropanos , Humanos , Aminopiridinas/efectos adversos , Aminopiridinas/administración & dosificación , Ciclopropanos/administración & dosificación , Ciclopropanos/efectos adversos , Ciclopropanos/uso terapéutico , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Femenino , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Crema para la Piel/administración & dosificación , Crema para la Piel/efectos adversos , Trastornos por Fotosensibilidad/tratamiento farmacológico , Trastornos por Fotosensibilidad/diagnóstico , Trastornos por Fotosensibilidad/inducido químicamente , Masculino , Persona de Mediana Edad

RESUMEN

Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)-nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR-NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.

Asunto(s)

Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Queratinocitos , Factor 2 Relacionado con NF-E2 , Inhibidores de Fosfodiesterasa 4 , Receptores de Hidrocarburo de Aril , Transducción de Señal , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Queratinocitos/metabolismo , Queratinocitos/efectos de los fármacos , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1/genética , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa 4/farmacología , Interleucina-33/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Línea Celular

RESUMEN

Lichen planus (LP), an idiopathic, multifaceted chronic inflammatory disease with a heterogeneous clinical presentation, affects approximately 0.5-1% of the population. The various clinical manifestations of LP fall into three broad categories, namely cutaneous, appendageal, and mucosal, with further subclassification depending on the morphology and distribution patterns of individual lesions. There is mounting evidence that LP has systemic associations, including autoimmune conditions, glucose intolerance, dyslipidemia, and cardiovascular disorders. Cutaneous hypertrophic and mucosal forms of LP are at a heightened risk for malignant transformation. Familiarity with these potential associations in conjunction with long-term follow-up and regular screening could lead to a timely diagnosis and management of concomitant conditions. In addition, the frequent quality of life (QoL) impairment in LP underscores the need for a comprehensive approach including psychological evaluation and support. Several treatment strategies have been attempted, though most of them have not been adopted in clinical practice because of suboptimal benefit-to-risk ratios or lack of evidence. More recent studies toward pathogenesis-driven treatments have identified Janus kinase inhibitors such as tofacitinib, phosphodiesterase-4 inhibitors such as apremilast, and biologics targeting the interleukin-23/interleukin-17 pathway as novel therapeutic options, resulting in a dramatic change of the treatment landscape of LP. This contemporary review focuses on the diagnosis and management of LP, and places emphasis on more recently described targeted treatment options.

Asunto(s)

Inhibidores de las Cinasas Janus , Liquen Plano , Calidad de Vida , Humanos , Liquen Plano/diagnóstico , Liquen Plano/terapia , Liquen Plano/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Productos Biológicos/uso terapéutico , Pirimidinas/uso terapéutico , Piperidinas/uso terapéutico , Piel/patología , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Terapia Molecular Dirigida/métodos

RESUMEN

Introduction: Although the treatment for pemphigus vulgaris (PV) has been revolutionized by the use of rituximab combined with corticosteroids, new effective therapies with a better safety profile are needed. Observation: A 67-year-old woman was diagnosed with severe mucosal PV, which was initially misdiagnosed as atypical Behçet's disease. Following an unsuccessful colchicine treatment, significant improvement was observed upon the introduction of apremilast: reduced pain, fewer lesions, and a stabilized weight. The discontinuation of apremilast led to a rapid relapse. Retrospective analysis through anti-Dsg3 ELISA indicated a gradual decrease in antibody levels during the apremilast treatment. Discussion: Apremilast, a phosphodiesterase 4 inhibitor approved for psoriasis and Behçet's disease's related oral ulcers treatment, demonstrated its efficacy in this PV case. This is the second case report highlighting the effectiveness of apremilast for PV treatment. Apremilast's ability to upregulate cyclic adenosine monophosphate (cAMP) levels appears to contribute to the stabilization of keratinocyte adhesion. Conclusion: Apremilast may be a promising therapeutic option for the treatment of pemphigus, with an innovative mechanism of action, no induced immunosuppression, and good tolerance. It could be a good alternative to steroids, in the treatment regimen of steroids combined with rituximab.

Asunto(s)

Pénfigo , Talidomida , Humanos , Pénfigo/tratamiento farmacológico , Pénfigo/diagnóstico , Femenino , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Anciano , Resultado del Tratamiento , Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico

RESUMEN

Folliculitis decalvans (FD) is a rare primary neutrophilic cicatricial alopecia that commonly displays resistance to traditional therapies and remains challenging to treat. Currently, data are lacking with recommendations for therapy-recalcitrant FD. A systematic review was conducted to analyze biologics, small molecule inhibitors, tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies utilized in the treatment of recalcitrant FD.

Asunto(s)

Productos Biológicos , Foliculitis , Inhibidores de Fosfodiesterasa 4 , Humanos , Foliculitis/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Alopecia/tratamiento farmacológico , Resultado del Tratamiento

RESUMEN

OBJECTIVE: Inflammatory Bowel Disease (IBD) poses a persistent challenge in the realm of gastroenterology, necessitating continual exploration of innovative treatment strategies. The limited efficacy and potential side effects associated with existing therapeutic modalities underscore the urgent need for novel approaches in IBD management. This study aims to examine potential therapeutic targets and recent advancements in understanding the disease's intricate pathogenesis, with a spotlight on the gut microbiome, immune dysregulation, and genetic predispositions. METHODS: A comprehensive review was conducted to delve into the pressing demand for new avenues in IBD treatment. The study examined potential therapeutic targets such as phosphodiesterase 4 (PDE4) inhibitors, immune system modulators, Tyrosine kinase receptors (TYK), Toll-like receptors (TLRs), modulation of the gut microbiota, stem cell therapy, fibrosis management, interleukins (ILs) regulation, and oxidative stress mitigation. Additionally, advances in precision medicine, biologics, small molecule inhibitors, and microbiome modulation techniques were explored. RESULTS: The investigation unveiled promising therapeutic targets and provided insights into recent breakthroughs that herald a transformative era in the therapeutic landscape for IBD. Advances in precision medicine, biologics, small molecule inhibitors, and the exploration of microbiome modulation techniques stood out as pivotal milestones in the field of gastroenterology. CONCLUSIONS: The findings offer renewed hope for enhanced efficacy, reduced side effects, and improved patient outcomes in the treatment of IBD. These innovative approaches necessitate continual exploration and underscore the urgent need for novel strategies in IBD management, potentially revolutionizing the realm of gastroenterology.

Asunto(s)

Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Animales , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Terapia Molecular Dirigida/métodos , Medicina de Precisión/métodos

RESUMEN

Phosphodiesterases (PDE) are involved in the regulation of cellular physiological processes and neurological functions, including neuronal plasticity, synapto-genesis, synaptic transmission, memory formation and cognitive functions by catalyzing the hydrolysis of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Many basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system (CNS) diseases by inhibiting cAMP hydrolysis, increasing cAMP content and enhancing its downstream effects. PDE4 inhibitors have long-term potentiation effect, which can enhance phosphorylation of cAMP response element binding protein (CREB) and upregulate expression of memory related Arc genes in hippocampal neurons, thereby improving cognitive impairment and Alzheimer's disease-like symptoms. They can also delay the occurrence and development of Parkinson's disease by reducing the cytotoxicity induced by α-syn and increasing the effect of miR-124-3p on cell functions. Alteration of PDE4 activity is the molecular basis for psychosis and some cognitive disorders, therefore it is considered as a therapeutic target for schizophrenia. PDE4 inhibitors play a role in depression by inhibiting the advanced glycation end product receptor (RAGE), TLR4 and NLRP3 pathways in the hippocampus, reducing the activation of microglia and the production of IL-1ß, down-regulating HMGB1/RAGE signaling pathway and inhibiting inflammatory factors. PDE4 inhibitor plays a role in the treatment of autism spectrum disorder by reducing the damage of cerebellar glial cells, increasing nociceptive threshold, and improving mutual learning and memory deficits. PDE4 inhibitors might be used in the treatment of fragile X syndrome by regulating the level of cAMP and affecting the expression of fragile X mental retardation protein (FMRP). PDE4 inhibitors can also promote the differentiation of oligodendrocyte progenitor cells and enhance myelination, which has potential in the treatment of multiple sclerosis. PDE4 is also related to bipolar disorder, which may be one of the therapeutic targets. At present, several PDE4 inhibitors are in clinical trials for the treatment of CNS diseases. This article reviews and discusses the progress on basic research and clinical trials of PDE4 inhibitors in CNS diseases, providing a reference for the prevention and treatment of CNS diseases and the development of new drugs.

Asunto(s)

Enfermedades del Sistema Nervioso Central , Inhibidores de Fosfodiesterasa 4 , Humanos , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Animales , AMP Cíclico/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo

RESUMEN

ABSTRACT: Atopic dermatitis (AD), a chronic inflammatory, pruritic skin disorder, is seen primarily in the pediatric population but can be found among all age groups. The symptoms of AD can cause embarrassment in patients and can interrupt daily activities and productivity, potentially resulting in avoidance of social situations. In addition to nonpharmacologic management, mainstay pharmacologic treatments for AD are topical medications including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and topical Janus kinase (JAK) inhibitors. Promising new drugs-oral JAK inhibitors and monoclonal antibodies-have emerged as new treatment options for moderate-to-severe AD.

Asunto(s)

Dermatitis Atópica , Dermatitis Atópica/enfermería , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/terapia , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Corticoesteroides/uso terapéutico , Inhibidores de la Calcineurina/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Enfermeras Practicantes

RESUMEN

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA ß3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA ß1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in ß1 subunit expression or phosphorylation at other residues. ß1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of ß1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.

Asunto(s)

Proteínas Quinasas Dependientes de AMP Cíclico , Etanol , Ratones Endogámicos C57BL , Inhibidores de Fosfodiesterasa 4 , Receptores de GABA-A , Talidomida , Animales , Talidomida/farmacología , Talidomida/análogos & derivados , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Masculino , Femenino , Etanol/farmacología , Ratones , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efectos de los fármacos , Técnicas de Sustitución del Gen , Fosforilación/efectos de los fármacos , Ataxia/genética , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/genética , Ratones Transgénicos , Diazepam/farmacología

RESUMEN

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.

Asunto(s)

Enfermedad de Alzheimer , Cognición , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Modelos Animales de Enfermedad , Ratones Transgénicos , Microglía , Inhibidores de Fosfodiesterasa 4 , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Cognición/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Presenilina-1/genética , Presenilina-1/metabolismo , Humanos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Masculino