RESUMO
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.
Assuntos
Inibidores da Fosfodiesterase 4 , Doença Pulmonar Obstrutiva Crônica , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 3/uso terapêutico , Inibidores da Fosfodiesterase 3/farmacologia , Carbolinas/uso terapêutico , Carbolinas/farmacologia , Isoquinolinas , PirimidinonasAssuntos
Aminopiridinas , Benzamidas , Ciclopropanos , Dermatite Atópica , Inibidores da Fosfodiesterase 4 , Humanos , Dermatite Atópica/tratamento farmacológico , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Aminopiridinas/administração & dosagem , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/administração & dosagem , Ciclopropanos/uso terapêutico , Ciclopropanos/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Ciclopropanos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Creme para a Pele/administração & dosagem , Administração CutâneaRESUMO
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.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores da Fosfodiesterase 4 , Humanos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/química , Animais , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Ensifentrine, an inhaled, selective phosphodiesterase (PDE) 3 and PDE4 inhibitor, is being developed by Verona Pharma plc for the treatment of respiratory diseases, including chronic obstructive pulmonary disease (COPD). In June 2024, ensifentrine (OHTUVAYRE™) inhalation suspension was approved for the maintenance treatment of COPD in adult patients in the USA. This article summarizes the milestones in the development of ensifentrine leading to this first approval for the maintenance treatment of COPD.
Assuntos
Aprovação de Drogas , Inibidores da Fosfodiesterase 4 , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/administração & dosagem , Administração por Inalação , Isoquinolinas/uso terapêutico , Isoquinolinas/farmacologia , Isoquinolinas/administração & dosagem , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 3/uso terapêutico , Inibidores da Fosfodiesterase 3/administração & dosagem , Estados Unidos , PirimidinonasRESUMO
BACKGROUND: Chronic inflammatory skin diseases are of great social and medical importance and require effective drug therapy. Phosphodiesterase 4 (PDE4) inhibitors represent a possible therapeutic option by regulating inflammatory processes. PDEs cause the release of proinflammatory cytokines by interfering with signaling pathways. The PDE4 inhibitors apremilast (treatment of psoriasis and Behçet's disease), roflumilast (treatment of chronic obstructive pulmonary disease), and crisaborole (treatment of atopic dermatitis) are currently approved in Europe. PSORIASIS: Apremilast is used for second-line treatment of plaque psoriasis and psoriatic arthritis and has a favorable side effect profile. Topical PDE4 inhibitors are currently being researched and have not yet been approved by the European Medicines Agency (EMA). ATOPIC DERMATITIS: The topical PDE4 inhibitor crisaborole was approved by the EMA in 2020 as a topical treatment alternative to glucocorticoids and calcineurin inhibitors. Although the substance has shown good tolerability in studies and also alleviates the accompanying itching, it did not find its way onto the German market. BEHçET'S DISEASE: Apremilast is approved for the treatment of Behçet's disease in adults with refractory, severe oral ulcers. OUTLOOK: Case studies have also demonstrated the efficacy of systemic PDE4 inhibition in other skin diseases (including blistering autoimmune dermatoses, lichen planus, and acantholytic genodermatoses). The substances are also being researched and used to treat extracutaneous inflammatory diseases.
Assuntos
Inibidores da Fosfodiesterase 4 , Psoríase , Talidomida , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/farmacologia , Talidomida/efeitos adversos , Psoríase/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Compostos de Boro/uso terapêutico , Compostos de Boro/farmacologia , Síndrome de Behçet/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Ciclopropanos , Compostos Bicíclicos Heterocíclicos com PontesRESUMO
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 (>80â¯%) in vitro with IC50â¯â¼â¯1.4-6.2⯵M. 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 (30â¯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⯵M) and the NOAEL (no-observed-adverse-effect level) was found to be 100⯵M. 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.
Assuntos
Artrite Reumatoide , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores da Fosfodiesterase 4 , Psoríase , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/uso terapêutico , Psoríase/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Animais , Relação Estrutura-Atividade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Ratos , Estrutura Molecular , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Peixe-Zebra , Artrite Experimental/tratamento farmacológico , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , MasculinoRESUMO
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.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Descoberta de Drogas , Indazóis , Doenças Inflamatórias Intestinais , Inibidores da Fosfodiesterase 4 , Animais , Doenças Inflamatórias Intestinais/tratamento farmacológico , Relação Estrutura-Atividade , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/uso terapêutico , Camundongos , Indazóis/farmacologia , Indazóis/química , Indazóis/síntese química , Humanos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Estrutura Molecular , Relação Dose-Resposta a Droga , Masculino , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Aminopiridinas , Benzamidas , Ciclopropanos , Psoríase , Humanos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Aminopiridinas/uso terapêutico , Psoríase/tratamento farmacológico , Ciclopropanos/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Resultado do Tratamento , Administração Tópica , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Administração Cutânea , Resorcinóis , EstilbenosRESUMO
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.
Assuntos
Aminopiridinas , Benzamidas , Ciclopropanos , Bases de Dados Factuais , Inibidores da Fosfodiesterase 4 , Doença Pulmonar Obstrutiva Crônica , Humanos , Ciclopropanos/efeitos adversos , Ciclopropanos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Masculino , Feminino , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/uso terapêutico , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Pessoa de Meia-Idade , Idoso , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Fatores de Risco , Estados Unidos/epidemiologia , Bronquite Crônica/tratamento farmacológico , Bronquite Crônica/mortalidade , Bronquite Crônica/epidemiologia , Medição de Risco , Alemanha , Adulto , Suécia/epidemiologia , Idoso de 80 Anos ou maisRESUMO
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.
Assuntos
Inibidores de Janus Quinases , Líquen Plano , Qualidade de Vida , Humanos , Líquen Plano/diagnóstico , Líquen Plano/terapia , Líquen Plano/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Produtos Biológicos/uso terapêutico , Pirimidinas/uso terapêutico , Piperidinas/uso terapêutico , Pele/patologia , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Terapia de Alvo Molecular/métodosRESUMO
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.
Assuntos
Pênfigo , Talidomida , Humanos , Pênfigo/tratamento farmacológico , Pênfigo/diagnóstico , Feminino , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Idoso , Resultado do Tratamento , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêuticoRESUMO
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.
Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Animais , Inibidores da Fosfodiesterase 4/uso terapêutico , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodosRESUMO
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.
Assuntos
Produtos Biológicos , Foliculite , Inibidores da Fosfodiesterase 4 , Humanos , Foliculite/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Alopecia/tratamento farmacológico , Resultado do TratamentoRESUMO
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.
Assuntos
Doenças do Sistema Nervoso Central , Inibidores da Fosfodiesterase 4 , Humanos , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Animais , AMP Cíclico/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismoRESUMO
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.
Assuntos
Doença de Alzheimer , Cognição , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia , Inibidores da Fosfodiesterase 4 , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Cognição/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/administração & dosagem , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Presenilina-1/genética , Presenilina-1/metabolismo , Humanos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , MasculinoRESUMO
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.
Assuntos
Dermatite Atópica , Dermatite Atópica/enfermagem , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/terapia , Humanos , Inibidores de Janus Quinases/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Corticosteroides/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Profissionais de EnfermagemRESUMO
Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, even when starting 2 dpi, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores da Fosfodiesterase 4 , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Animais , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Camundongos , Feminino , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Camundongos Endogâmicos C57BL , Humanos , AMP Cíclico/metabolismo , Benzamidas , CiclopropanosAssuntos
Pênfigo , Talidomida , Humanos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Pênfigo/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Anti-Inflamatórios não Esteroides/uso terapêutico , Índice de Gravidade de Doença , Idoso , Adulto , Inibidores da Fosfodiesterase 4/uso terapêuticoRESUMO
This chapter thoroughly examines recent breakthroughs in atopic dermatitis (AD) treatment, with a primary focus on the medications in the development pipeline. Biologics agents targeting new interleukin receptors like interleukin-31, interleukin-22, and interleukin-2 are discussed along with the novel pathway looking at the OX40-OX40L interaction. Oral agents and small molecule therapies like Janus kinase inhibitors, sphingosine-1-phosphate modulators, and Bruton's tyrosine kinase inhibitors are also discussed along with the various new topical medications. Newly approved topicals like phosphodiesterase-4 and JAK inhibitors are highlighted while also discussing the potential of tapinarof and emerging microbiome-targeted therapies. Beyond conventional approaches, the chapter touches upon unconventional therapies currently being studied. The goal of this chapter is to discuss new advances in AD treatment from medications in the initial stages of development to those nearing FDA approval.
Assuntos
Dermatite Atópica , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/terapia , Dermatite Atópica/microbiologia , Dermatite Atópica/imunologia , Humanos , Produtos Biológicos/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Animais , Terapia de Alvo Molecular/métodos , Fármacos Dermatológicos/uso terapêuticoRESUMO
Significant research advances in our understanding of psoriatic disease have led to the development of several highly selective, effective, and safe topical and systemic treatments. These treatments have led to unprecedented levels of disease clearance and control for most patients with psoriasis with cutaneous disease. However, there remains a need for improved treatments for those patients with recalcitrant disease, psoriatic arthritis, or nonplaque disease variants. Recently approved therapies and investigational products in ongoing clinical development programs that target IL-17A/F, IL-23, TYK2, PDE4, AhR or IL-36 cytokine signaling are improving the clinician's ability to care for a broader range of patients affected by psoriasis.