Phosphodiesterase 4 Inhibitor Research Articles

Sorbitol Destroyed Intestinal Microfold Cells (M Cells) Development through Inhibition of PDE4-Mediated RANKL Expression.

Microfold cells (M cells) are specific intestinal epithelial cells for monitoring and transcytosis of antigens, microorganisms, and pathogens in the intestine. However, the mechanism for M-cell development remained elusive. Real-time polymerase chain reaction, immunofluorescence, and western blotting were performed to analyze the effect of sorbitol-regulated M-cell differentiation in vivo and in vitro, and luciferase and chromatin Immunoprecipitation were used to reveal the mechanism through which sorbitol-modulated M-cell differentiation. Herein, in comparison to the mannitol group (control group), we found that intestinal M-cell development was inhibited in response to sorbitol treatment as evidenced by impaired enteroids accompanying with decreased early differentiation marker Annexin 5, Marcksl1, Spib, sox8, and mature M-cell marker glycoprotein 2 expression, which was attributed to downregulation of receptor activator of nuclear factor kappa-В ligand (RANKL) expression in vivo and in vitro. Mechanically, in the M-cell model, sorbitol stimulation caused a significant upregulation of phosphodiesterase 4 (PDE4) phosphorylation, leading to decreased protein kinase A (PKA)/cAMP-response element binding protein (CREB) activation, which further resulted in CREB retention in cytosolic and attenuated CREB binds to RANKL promoter to inhibit RANKL expression. Interestingly, endogenous PKA interacted with CREB, and this interaction was destroyed by sorbitol stimulation. Most importantly, inhibition of PDE4 by dipyridamole could rescue the inhibitory effect of sorbitol on intestinal enteroids and M-cell differentiation and mature in vivo and in vitro. These findings suggested that sorbitol suppressed intestinal enteroids and M-cell differentiation and matured through PDE4-mediated RANKL expression; targeting to inhibit PDE4 was sufficient to induce M-cell development.

An update on topical therapies for psoriasis.

Topical therapies are a mainstay of treatment for mild psoriasis and may be a useful adjunct in treatment of moderate-to-severe psoriasis. This review summarizes recent advances in topical therapies for psoriasis and currently available treatments. Topical aryl hydrocarbon receptor modulators (tapinarof) and topical phosphodiesterase-4 inhibitors (roflumilast) have been proven effective in randomized controlled trials for psoriasis. Although topical JAK inhibitors have also been studied, none are currently licensed for treatment of psoriasis. Topical corticosteroids and vitamin D analogues remain the most commonly used and widely available topical treatments for psoriasis. Cost may limit use of novel topical agents. Although the novel topical agents tapinarof and roflumilast are licensed for treatment of psoriasis by the FDA in the United States, they have not yet been licensed in Europe, and it remains to be seen whether they will be limited by cost.

Targeting phosphodiesterase 4 as a potential therapy for Parkinson's disease: a review.

Phosphodiesterases (PDEs) have become a promising therapeutic target for various disorders. PDEs are a vast and diversified family of enzymes that degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which have several biochemical and physiological functions. Phosphodiesterase 4 (PDE4) is the most abundant PDE in the central nervous system (CNS) and is extensively expressed in the mammalian brain, where it catalyzes the hydrolysis of intracellular cAMP. An alteration in the balance of PDE4 and cAMP results in the dysregulation of different biological mechanisms involved in neurodegenerative diseases. By inhibiting PDE4 with drugs, the levels of cAMP inside the cells could be stabilized, which may improve the symptoms of mental and neurological disorders such as memory loss, depression, and Parkinson's disease (PD). Though numerous studies have shown that phosphodiesterase 4 inhibitors (PDE4Is) are beneficial in PD, there are presently no approved PDE4I drugs for PD. This review presents an overview of PDE4Is and their effects on PD, their possible underlying mechanism in the restoration/protection of dopaminergic cell death, which holds promise for developing PDE4Is as a treatment strategy for PD. Methods on how these drugs could be effectively delivered to develop as a promising treatment for PD have been suggested.

Roflumilast foam (Zoryve) for seborrheic dermatitis.

The FDA has approved a 0.3% foam formulation of the phosphodiesterase-4 (PDE4) inhibitor roflumilast (Zoryve – Arcutis) for topical treatment of seborrheic dermatitis in patients ≥9 years old. Roflumilast is the first PDE4 inhibitor to be approved in the US for this indication.

Evaluation of preclinical efficacy of apremilast-loaded liquid crystalline nanoparticulate gel in amelioration of atopic dermatitis

Apremilast is a phosphodiesterase-4 inhibitor currently under investigation for managing atopic dermatitis, but it is associated with poor physicochemical properties, majorly affecting its bioavailability. To improve the topical delivery, we have encapsulated apremilast into the liquid crystalline nanoparticles and evaluated its preclinical efficacy against atopic dermatitis. The liquid crystalline nanoparticles were manufactured by the melt emulsification method followed by probe sonication. The prepared nanoparticles were evaluated for particle size, zeta potential, encapsulation efficiency and in vitro release. Further, the apremilast liquid crystalline nanoparticles were loaded into the gel base by magnetic stirring. The gel formulation was evaluated for viscosity, textural profile, drug content, ex vivo permeation, and retention in mice skin. The preclinical efficacy of optimized gel formulation was assessed in 2,4-dinitrochlorobenzene induced atopic dermatitis in mice model followed by histopathological examination of skin sections. The apremilast was successfully loaded into the liquid crystalline nanoparticles with an average particle size of 180 ± 0.45 nm and entrapment efficiency of 89.42 ± 4.27 %. The optimized nanoparticles were successfully loaded into gel base showing pseudoplastic shear thinning behaviour. In vivo preclinical efficacy of the optimized gel formulation revealed improved skin structure in comparison with negative control group. The histopathological examination of mice skin treated with optimized gel formulation resulted in decreased epidermal hyperplasia and intactness of outer keratinized epidermal layer with the inner layer. The outcomes of the apremilast-loaded liquid crystalline nanoparticulate gel demonstrated anti-atopic dermatitis potential.

A phosphodiesterase 4 (PDE4) inhibitor, amlexanox, reduces neuroinflammation and neuronal death after pilocarpine-induced seizure

Epilepsy, a complex neurological disorder, is characterized by recurrent seizures caused by aberrant electrical activity in the brain. Central to this study is the role of lysosomal dysfunction in epilepsy, which can lead to the accumulation of toxic substrates and impaired autophagy in neurons. Our focus is on phosphodiesterase-4 (PDE4), an enzyme that plays a crucial role in regulating intracellular cyclic adenosine monophosphate (cAMP) levels by converting it into adenosine monophosphate (AMP). In pathological states, including epilepsy, increased PDE4 activity contributes to a decrease in cAMP levels, which may exacerbate neuroinflammatory responses. We hypothesized that amlexanox, an anti-inflammatory drug and non-selective PDE4 inhibitor, could offer neuroprotection by addressing lysosomal dysfunction and mitigating neuroinflammation, ultimately preventing neuronal death in epileptic conditions. Our research utilized a pilocarpine-induced epilepsy animal model to investigate amlexanox's potential benefits. Administered intraperitoneally at a dose of 100 ​mg/kg daily following the onset of a seizure, we monitored its effects on lysosomal function, inflammation, neuronal death, and cognitive performance in the brain. Tissue samples from various brain regions were collected at predetermined intervals for a comprehensive analysis. The study's results were significant. Amlexanox effectively improved lysosomal function, which we attribute to the modulation of zinc's influx into the lysosomes, subsequently enhancing autophagic processes and decreasing the release of inflammatory factors. Notably, this led to the attenuation of neuronal death in the hippocampal region. Additionally, cognitive function, assessed through the modified neurological severity score (mNSS) and the Barnes maze test, showed substantial improvements after treatment with amlexanox. These promising outcomes indicate that amlexanox has potential as a therapeutic agent in the treatment of epilepsy and related brain disorders. Its ability to combat lysosomal dysfunction and neuroinflammation positions it as a potential neuroprotective intervention. While these findings are encouraging, further research and clinical trials are essential to fully explore and validate the therapeutic efficacy of amlexanox in epilepsy management.

Real-world efficacy of 2% crisaborole ointment on chronic hyperplasia lesions in 49 patients with atopic dermatitis.

Crisaborole, as a phosphodiesterase 4 (PDE4) inhibitor (PDE4i), effectively inhibits inflammatory pathways, showing promising results in atopic dermatitis (AD), particularly in chronic hyperplasia lesions. Based on real-world data from China, this study assesses the effectiveness and safety of 2% PDE4i ointment as monotherapy for chronic hyperplastic AD lesions. A total of 49 AD patients aged 12 and above with chronic hyperplastic lesions and Investigator's Static Global Assessment scores of mild or moderate were enrolled. They received 2% PDE4i ointment twice daily until the lesions completely cleared. The effectiveness endpoints comprised the onset time of pruritus and lesion remission and the time of complete lesion clearance. PDE4i demonstrated high effectiveness with minimal irritation, notable improvement in hyperpigmentation, and early remission of pruritus and lesions. The response varied across age groups; elderly patients experienced quicker pruritus relief compared to adolescents and adults, while adolescents showed earlier lesion remission by about 3 days. No significant difference was observed across age groups in the time for complete lesion clearance. Additionally, AD duration (less or more than 3 years) did not significantly impact pruritus or lesion remission. PDE4i monotherapy is effective and safe for chronic hyperplasia lesions in AD across all age groups, and its effectiveness appears to be independent of AD duration.

Functional rescue of CFTR in rectal organoids from patients carrying R334W variant by CFTR modulators and PDE4 inhibitor Roflumilast

BackgroundMany disease-causing variants in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene remain uncharacterized and untreated. Restoring the function of the impaired CFTR protein is the goal of personalized medicine, particularly in patients carrying rare CFTR variants. In this study, functional defects related to the rare R334W variant were evaluated after treatment with CFTR modulators or Roflumilast, a phosphodiesterase-4 inhibitor (PDE4i). MethodsRectal organoids from subjects with R334W/2184insA and R334W/2183AA > G genotypes were used to perform the Forskolin-induced swelling (FIS) assay. Organoids were left drug-untreated or treated with modulators VX-770 (I), VX-445 (E), and VX-661 (T) mixed, and their combination (ETI). Roflumilast (R) was used alone or as a combination of I + R. ResultsOur data show a significant increase in FIS rate following treatment with I alone. The combined use of modulators, such as ETI, did not increase further swelling than I alone, nor in protein maturation. Treatment with R shows an increase in FIS response similar to those of I, and the combination R + I significantly increases the rescue of CFTR activity. ConclusionsEquivalent I and ETI treatment efficacy was observed for both genotypes. Furthermore, significant organoid swelling was observed with combined I + R used that supports the recently published data describing a potentiating effect of only I in patients carrying the variant R334W and, at the same time, corroborating the role of strategies that include PDE4 inhibitors further to potentiate the effect of I for this variant.

A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a significant contributor to morbidity and mortality in the United States. It contributes to over 140,000 annual deaths, to over 200 related diseases and health conditions globally, and accounts for 5.1% of the global disease burden. Despite its substantial impact, AUD remains undertreated, marked by a scarcity of approved medications. This paper explores the current treatment landscape and novel strategies for both alcohol withdrawal syndrome and AUD. Promising results, including the use of psychedelics alongside psychotherapy, noninvasive neural-circuit-based interventions, phosphodiesterase-4 inhibitors, and GLP-1 receptor agonists, have emerged from recent studies. While these advancements show potential, further research is crucial for a comprehensive understanding of their effectiveness. The clear shortage of approved medications and other treatment modalities underscores the pressing need for ongoing research.

Effects on Lipid Profile after One Year of Apremilast Therapy in Patients with Psoriasis: A Monocentric Experience.

Apremilast, a phosphodiesterase-4 inhibitor, has shown promise to have a potential beneficial metabolic effect. We conducted a single-centre retrospective study on adult patients with moderate-to-severe psoriasis who underwent apremilast treatment over at least 12 and 52 weeks, respectively. Baseline characteristics, weight, lipid profile, and fasting glucose levels were collected at baseline and at 12, 24, and 52 weeks. Furthermore, we conducted a narrative review of the current scientific knowledge on the metabolic effects of apremilast in patients with psoriasis and psoriatic arthritis. We observed a significant reduction in average weight and body mass index (BMI) in patients treated with apremilast in both the initial and the subgroup analysis, a significant reduction in triglycerides levels at 24 and 52 weeks, and a significant increase in high-density lipoprotein (HDL) levels at 52 weeks, whereas there were no significant changes in total cholesterol or low-density lipoprotein (LDL) concentrations over the 52-week treatment period. These findings suggest a potential positive impact of apremilast on both weight management and lipid profile in individuals with moderate-to-severe psoriasis in the medium-long term.

The PDE4 Inhibitors Roflumilast and Rolipram Rescue ADO2 Osteoclast Resorption Dysfunction.

Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption caused by heterozygous missense mutations in the chloride channel 7 (CLCN7). Adenylate cyclase, which catalyzes the formation of cAMP, is critical for lysosomal acidification in osteoclasts. We found reduced cAMP levels in ADO2 osteoclasts compared to wild-type (WT) osteoclasts, leading us to examine whether regulating cAMP would improve ADO2 osteoclast activity. Although forskolin, a known activator of adenylate cyclase and cAMP levels, negatively affected osteoclast number, it led to an overall increase in ADO2 and WT osteoclast resorption activity in vitro. Next, we examined cAMP hydrolysis by the phosphodiesterase 4 (PDE4) proteins in ADO2 versus WT osteoclasts. QPCR analysis revealed higher expression of the three major PDE4 subtypes (4a, 4b, 4d) in ADO2 osteoclasts compared in WT, consistent with reduced cAMP levels in ADO2 osteoclasts. In addition, we found that the PDE4 antagonists, rolipram and roflumilast, stimulated ADO2 and WT osteoclast formation in a dose-dependent manner. Importantly, roflumilast and rolipram displayed a concentration-dependent increase in osteoclast resorption activity which was greater in ADO2 than WT osteoclasts. Moreover, treatment with roflumilast rescued cAMP levels in ADO2 OCLs. The key findings from our studies demonstrate that osteoclasts from ADO2 mice exhibit reduced cAMP levels and PDE4 inhibition rescues cAMP levels and ADO2 osteoclast activity dysfunction in vitro. The mechanism of action of PDE4 inhibitors and their ability to reduce the high bone mass of ADO2 mice in vivo are currently under investigation. Importantly, these studies advance the understanding of the mechanisms underlying the ADO2 osteoclast dysfunction which is critical for the development of therapeutic approaches to treat clinically affected ADO2 patients.

Crosstalk between purinergic receptor P2Y11 and chemokine receptor CXCR7 is regulated by CXCR4 in human macrophages

P2Y11 is a G protein-coupled ATP receptor that activates IL-1 receptor (IL-1R) in a cyclic AMP dependent manner. In human macrophages, P2Y11/IL-1R crosstalk with CCL20 as a prime target is controlled by phosphodiesterase 4 (PDE4), which mediates breakdown of cyclic AMP. Here, we used gene expression analysis to identify activation of CXCR4 and CXCR7 as a hallmark of P2Y11 signaling. We found that PDE4 inhibition with rolipram boosts P2Y11/IL-1R-induced upregulation of CXCR7 expression and CCL20 production in an epidermal growth factor receptor dependent manner. Using an astrocytoma cell line, naturally expressing CXCR7 but lacking CXCR4, P2Y11/IL-1R activation effectively induced and CXCR7 agonist TC14012 enhanced CCL20 production even in the absence of PDE4 inhibition. Moreover, CXCR7 depletion by RNA interference suppressed CCL20 production. In macrophages, the simultaneous activation of P2Y11 and CXCR7 by their respective agonists was sufficient to induce CCL20 production with no need of PDE4 inhibition, as CXCR7 activation increased its own and eliminated CXCR4 expression. Finally, analysis of multiple CCL chemokines in the macrophage secretome revealed that CXCR4 inactivation and CXCR7 activation selectively enhanced P2Y11/IL-1R-mediated secretion of CCL20. Altogether, our data establish CXCR7 as an integral component of the P2Y11/IL-1R-initiated signaling cascade and CXCR4-associated PDE4 as a regulatory checkpoint.

The Efficacy and Safety of Apremilast in the Management of Psoriatic Arthritis: A Systematic Review and Meta-Analysis.

Psoriasis is achronicautoimmune inflammatory skin disease that is associated with other conditions, one of them being psoriatic arthritis (PsA).Apremilast, a phosphodiesterase-4 inhibitor, displayed promising results in multiple trials for patients with PsA. This systematic review and meta-analysis aims to showcase its efficacy and safety when compared to placebo. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) was adopted after registration on the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023476245). Four databases were systematically searched from their inception until October 25, 2023. As a result, five randomized controlled trials were included with 1,849 participants, after thorough screening. The primary efficacy endpoint evaluated in this meta-analysis was the American College of Rheumatology Response Criteria 20 (ACR20). The results significantly favored apremilast (risk ratio [RR] = 1.92, 95% confidence interval [CI] 1.66-2.21; P < 0.00001; I2= 0%) as opposed to placebo. Similarly, secondary efficacy endpoints, ACR50 (RR = 2.34, 95% CI 1.79-3.06; P < 0.00001; I2 =0%), ACR70 (RR = 2.89, 95% CI 1.62-5.18; P = 0.0003; I2 =0%), and the Health Assessment Questionnaire and Disability Index (HAQ-DI; standardized mean difference [SMD] = -0.26, 95% CI -0.34 to -0.17; P < 0.00001; I2 =0%)were also in significant favor of apremilast. However, apremilast had a higher occurrence of gastrointestinal adverse events than placebo (RR = 1.21, 95% CI 1.12-1.30; P < 0.00001; I2 =19%). To conclude, apremilast shows promising efficaciousness with some nonserious side effects when compared to placebo, but further trials are needed for comparison with other management lines.

Targeting Aquaporin-5 by Phosphodiesterase 4 Inhibition Offers New Therapeutic Opportunities for Ovarian Ischemia Reperfusion Injury in Rats.

This study aimed to examine the effect of Phosphodiesterase 4 (PDE4) inhibition on Aquaporin-5 (AQP5) and its potential cell signaling pathway in the ovarian ischemia reperfusion (OIR) model.Thirty adult female rats were divided into five groups: Group 1; Control: Sham operation, Group 2; OIR that 3 hour ischemia followed by 3 hour reperfusion, Group 3; OIR + Rolipram 1 mg/kg, Group 4; OIR + Rolipram 3 mg/kg, Group 5; OIR + Rolipram 5 mg/kg. Rolipram was administered intraperitoneally to the rats in groups 3-4 and 5 at determined doses 30 minutes before reperfusion. From ovary tissue; Tumor necrosis factor-a (TNF-α), Cyclic adenosine monophosphate (cAMP), Nuclear factor kappa (NF-κB), Interleukin-6 (IL-6), Phosphodiesterase 4D (PDE4D), Mitogen-activated protein kinase (MAPK) and AQP5 levels were measured by ELISA. We also measured the level of AQP5 in ovary tissue by real-time reverse-transcription polymerase chain reaction (RT-PCR).In the OIR groups; TNF-α, NF-κB, IL-6, MAPK inflammatory levels increased, and cAMP and AQP5 levels decreased, which improved with the administration of rolipram doses. Also histopathological results showed damaged ovarian tissue after OIR, while rolipram administration decrased tissue damage in a dose dependent manner.We propose that the protective effect of PDE4 inhibition in OIR may be regulated by AQP5 and its potential cell signaling pathway and may be a new target in OIR therapy. However, clinical studies are needed to appraise these data in humans.

Advancing Treatment in Atopic Dermatitis: A Comprehensive Review of Clinical Efficacy, Safety, and Comparative Insights Into Corticosteroids, Calcineurin Inhibitors, and Phosphodiesterase-4 Inhibitors as Topical Therapies.

Atopic dermatitis (AD) is a pervasive and multifaceted dermatological disorder causing daily distress to afflicted individuals worldwide. This comprehensive review synthesizes the historical and contemporary advancements in therapeutic strategies, offering a critical analysis of their efficacy, safety profiles, and adaptability. The enduring role of topical corticosteroids in managing AD is examined, acknowledging their potent anti-inflammatory properties alongside their potential adverse side effects, particularly in extended usage. The article explores the utilization of topical calcineurin inhibitors like tacrolimus and pimecrolimus, highlighting their novel anti-inflammatory pathways while also scrutinizing concerns over potential malignancies that relegate them to second-line therapy. The present investigation features the emergence of crisaborole, a phosphodiesterase four inhibitor. Its innovative mode of action, benign safety profile, and applicability to mild and moderate AD are thoroughly evaluated. The review also includes challenges, particularly cost considerations, which constrain accessibility and necessitate nuanced implementation in therapeutic regimens. This study underscores the need for persistent investigation, teamwork, and innovations in managing AD. In this regard, AD requires a united approach between clinicians, researchers, affected individuals, and policymakers to refine patient-focused treatment and develop precise, economical strategies to address this chronic and frequently life-altering health condition.

Executive Summary: From the Medical Board of the National Psoriasis Foundation: Perioperative management of immunomodulatory agents in patients with psoriasis and psoriatic arthritis

BackgroundSystemic immunomodulatory agents are indicated in the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis. Perioperative use of these medications may increase the risk of surgical site infection and complication. ObjectiveTo evaluate the risk of surgical site infection and complication in patients with chronic autoimmune inflammatory disease receiving immunomodulatory agents (tumor necrosis factor-alpha inhibitors, interleukin [IL]-12/23 inhibitor, IL-17 inhibitors, IL-23 inhibitors, cytotoxic T-lymphocyte–associated antigen-4 co-stimulator, phosphodiesterase-4 inhibitor, Janus kinase inhibitors, tyrosine kinase 2 inhibitor, cyclosporine, and methotrexate) undergoing surgery. MethodsWe performed a search of the MEDLINE PubMed database of patients with chronic autoimmune inflammatory disease on immune therapy undergoing surgery. ResultsWe examined 48 new or previously unreviewed studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. ConclusionFor low-risk procedures, TNF-alpha inhibitors, IL-17 inhibitors, IL-23 inhibitors, ustekinumab, abatacept, methotrexate, cyclosporine, and apremilast can safely be continued. For intermediate- and high-risk surgery, methotrexate, cyclosporine, apremilast, abatacept, IL-17 inhibitors, IL-23 inhibitors, and ustekinumab are likely safe to continue; however, a case-by-case approach is advised. Acitretin can be continued for any surgery. There is insufficient evidence to make firm recommendations on tofacitinib, upadacitinib, and deucravacitinib.

Ribociclib leverages phosphodiesterase 4 inhibition in the treatment of neutrophilic inflammation and acute respiratory distress syndrome

IntroductionOverwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation. MethodsPrimary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. In vitro and silico analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an in vivo ARDS model in lipopolysaccharide (LPS)-primed mice. ResultsWe found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS. ConclusionWe demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.

The Dosing Strategy to Improve Adherence to Roflumilast in Treatment for Chronic Obstructive Lung Disease: A Systemic Review and Meta-Analysis.

The clinical efficacy of roflumilast, an oral phosphodiesterase-4 inhibitor, has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD). However, roflumilast has shown frequent adverse drug reactions (ADRs). This study was performed to investigate the dosing strategy that will improve adherence to roflumilast in COPD. We conducted a systematic review and meta-analysis using PubMed, Embase, and Cochrane Central Register. The dosing strategy for roflumilast was classified into a dose-escalation group and a low-dose group. We investigated clinical outcomes according to dosing strategy. Five clinical trials involving 2424 patients were included. Both the dose-escalation and the low-dose groups showed a decrease in discontinuation rate compared to the standard dosing group for roflumilast (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.67-0.97; P = 0.02 and RR, 0.62; 95% CI, 0.48-0.80; P < 0.01, respectively). In the two strategies, the pooled proportions of discontinuation were 27.9% and 11.7%, respectively. Although the pooled proportion of any ADR was not statistically decreased in the two strategies, diarrhea was significantly reduced in the low-dose group compared to the standard group (RR, 0.58; 95% CI, 0.42-0.82; P < 0.01). The pooled incidence of acute exacerbations was similar between the low-dose and the standard groups (22.9% and 20.1%, respectively; P = 0.27). Our findings show that the two alternative dosing strategies might have the benefit of improving adherence to roflumilast in COPD. Further large-scale trials are required to support our findings.

Existing and Emerging Targeted Therapies in Juvenile Psoriatic Arthritis: Challenges and Unmet Needs.

Juvenile psoriatic arthritis (JPsA) is a heterogeneous type of non-systemic chronic inflammatory arthritis affecting children and young people. This review focuses on highlighting challenges in harmonising recommendations for the use of available therapies in JPsA, according to its distinct clinical phenotypes, and explores the similarities and differences between the disease classification and management across age. We further explore the emerging therapeutic landscape, summarising the recently completed clinical trials in JPsA, and ongoing studies in both JPsA and adults with psoriatic arthritis, highlighting unmet needs and barriers for translational research in JPsA. The novel therapeutic agents in clinical development in JPsA range from monoclonal antibodies targeting interleukin (IL)-17, IL-12/23 and IL-23 blockades to synthetic small molecules targeting Janus kinase and tyrosine kinase and phosphodiesterase-4 inhibition. In addition, there are head-to-head clinical trials comparing tumour necrosis factor-α blockade with both IL-17 and IL-23 inhibition. Most of these new therapies have been tested in adults with psoriatic arthritis and haveadvanced to the phase III stage of drug development or received license for use, suggesting promising signals for efficacy and potentially acceptable safety and tolerability for JPsA. Further translational research in JPsA is required to improve our understanding of the impact of age at onset on treatment efficacy, as well as to provide opportunities for better management of refractory disease and improved long-term outcomes in JPsA, for ultimate patient benefit.

Renal and cardiac effects of the PDE9 inhibitor BAY 73-6691 in 5/6 nephrectomized rats.

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3',5'-cyclic guanosine monophosphate (cGMP) degradation.5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73-6691) on the heart and kidney. Two doses of BAY 73-6691 (1mg/kg/day and 5mg/kg/day) were given for 95days.The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73-6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways.Two dosages of the PDE9 inhibitor BAY 73-6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.