Efficacy of tyrosine-kinase-2 and phosphodiesterase-4 inhibitors for scalp psoriasis: a systematic review and meta-analysis.

OBJECTIVES: Psoriasis of the scalp is challenging to manage. The only approved oral tyrosine kinase 2 and phosphodiesterase 4 inhibitors for psoriasis are deucravacitinib and apremilast. The aim of this study was to explore their efficacy for scalp psoriasis utilizing data from randomized controlled trials. METHODS: We searched Medline, Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov up to August 4, 2023. To determine risk of bias, the revised Risk of Bias assessment tool 2.0 was used. Inverse variance random effects meta-analyses were executed. Heterogeneity was assessed utilizing Q and I2 statistics. Pre-determined outcomes included the proportion of participants with cleared scalp skin (Scalp Physician's Global Assessment [ScPGA] of 0/1), mean change in Psoriasis Scalp Severity Index (PSSI), and mean improvement in Dermatology Life Quality Index (DLQI). RESULTS: Ten RCTs fulfilled inclusion criteria. Both apremilast (RR = 2.41, 95% CI = 2.08-2.79, Tau2 = 0, I2 = 0) and deucravacitinib (RR = 3.86, 95% CI = 3.02-4.94, Tau2 = 0, I2 = 0) were more effective in inducing ScPGA of 0/1 at 16 weeks compared to placebo. Furthermore, deucravacitinib was more effective than apremilast (RR = 1.70, 95% CI = 1.44-2.00, Tau2 = 0, I2 = 0). An analysis could not be executed for the rest of the outcomes. CONCLUSIONS: Apremilast and deucravacitinib are effective for scalp psoriasis. Deucravacitinib may be more efficient in clearing the scalp.

ZORYVETM (Roflumilast) Cream: A Topical Phosphodiesterase-4 Inhibitor for the Treatment of Psoriasis.

ZORYVETM (roflumilast) cream is a topical phosphodiesterase-4 (PDE-4) inhibitor that has been recently approved for the treatment of plaque psoriasis. It is also indicated for use in intertriginous areas. Roflumilast, the active ingredient, inhibits PDE-4, leading to the suppression of pro-inflammatory immune responses in psoriatic lesions. Two phase 3 clinical trials have demonstrated the efficacy of once daily application of roflumilast to treat plaque psoriasis in patients aged 12 years and older. At week 8, an investigator's global assessment score of 0 or 1 with a grade 2 improvement from baseline, the primary efficacy end point, was observed in 39.1% (225/576) of patients applying roflumilast, compared to 6.6% (20/305) of patients applying vehicle. Common adverse events reported were diarrhea, headache, insomnia, nausea, pain at application site, upper respiratory tract infection, and urinary tract infection.

New Non-Steroidal Topical Therapies for Inflammatory Dermatoses-Part 3: Roflumilast.

Topical corticosteroids have remained the initial and long-term topical treatment option for inflammatory dermatitis conditions since the 1950s. A number of non-steroidal topicals for treatment of inflammatory dermatoses have been developed in the recent decades, such as topical calcineurin inhibitors (tacrolimus ointment and pimecrolimus cream), vitamin D analogues, and phophodiesterase-4 inhibitors (crisaborole), but none had the combination of broad therapeutic range, relatively rapid onset of action, tolerability, and wide-spread clinical success that allowed topical glucocorticosteroids to remain the mainstay of therapy. This situation has shifted dramatically with three non-steroidal new molecular entities, each with completely different mechanisms of action, receiving approval of the Food and Drug Administration (FDA) in the past year. Topical ruxolitinib, a Janus kinase (JAK) inhibitor, was the first to receive FDA approval, specifically for treating atopic dermatitis, and was the subject of the first report in this series. Subsequently, topical tapinarof, an aryl hydrocarbon receptor modulating agent, was approved by the FDA for treating plaque psoriasis in May 2022 and was the focus of the second report in this series. Finally, and most recently in July 2022, topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, has received FDA approval for treating plaque psoriasis, and is the subject of the third and final report in this series. In addition to their unique mechanisms of action and spectra of activity, each of these agents has unique clinical characteristics, including degree of efficacy, rapidity of onset of efficacy, potential remittive effects, and safety and tolerability profiles. In this three-part series, we reviewed and summarized the data surrounding each agent, providing a comprehensive overview that would allow dermatologists to integrate them confidently and appropriately into treatment paradigms. Part three focuses on topical roflumilast, a highly potent phosphodiesterase-4 inhibitor.

Serum IL-8 as a Determinant of Response to Phosphodiesterase-4 Inhibition in Chronic Obstructive Pulmonary Disease.

Rationale: Phosphodiesterase-4 (PDE4) inhibitors have demonstrated increased efficacy in patients with chronic obstructive pulmonary disease who had chronic bronchitis or higher blood eosinophil counts. Further characterization of patients who are most likely to benefit is warranted. Objective: To identify determinants of response to the PDE4 inhibitor tanimilast. Methods: A PDE4 gene expression signature in blood was developed by unsupervised clustering of the ECLIPSE study dataset (ClinicalTrials.gov ID: NCT00292552; Gene Expression Omnibus Series ID: GSE76705). The signature was further evaluated using blood and sputum transcriptome data from the BIOMARKER study (NCT03004417; GSE133513), enabling validation of the association between PDE4 signaling and target biomarkers. Predictivity of the associated biomarkers against clinical response was then tested in the phase-2b PIONEER tanimilast study (NCT02986321). Measurements and Main Results: The PDE4 gene expression signature developed in the ECLIPSE dataset classified subgroups of patients associated with different PDE4 signaling in the BIOMARKER cohort with an area under the receiver operator curve of 98%. In the BIOMARKER study, serum IL-8 was the only variable that was consistently associated with PDE4 signaling, with lower levels associated with higher PDE4 activity. In the PIONEER study, the exacerbation rate reduction mediated by tanimilast treatment increased up to twofold in patients with lower IL-8 levels; 36% versus 18%, reaching statistical significance at ⩽20 pg/ml (P = 0.035). The combination with blood eosinophils ⩾150 µl-1 or chronic bronchitis provided further additive exacerbation rate reduction: 45% (P = 0.013) and 47% (P = 0.027), respectively. Conclusions: Using selected heterogeneous datasets, this analysis identifies IL-8 as an independent predictor of PDE4 inhibition, as tanimilast had a greater effect on exacerbation prevention in patients with chronic obstructive pulmonary disease who had lower baseline serum IL-8 levels. Testing of this biomarker in other datasets is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT00292552 [Gene Expression Omnibus Series ID: GSE76705], NCT03004417 [GSE133513], and NCT02986321).

Phosphodiesterase-4 Inhibition in Parkinson's Disease: Molecular Insights and Therapeutic Potential.

Clinicians and researchers are exploring safer and novel treatment strategies for treating the ever-prevalent Parkinson's disease (PD) across the globe. Several therapeutic strategies are used clinically for PD, including dopamine replacement therapy, DA agonists, MAO-B blockers, COMT blockers, and anticholinergics. Surgical interventions such as pallidotomy, particularly deep brain stimulation (DBS), are also employed. However, they only provide temporal and symptomatic relief. Cyclic adenosine monophosphate (cAMP) is one of the secondary messengers involved in dopaminergic neurotransmission. Phosphodiesterase (PDE) regulates cAMP and cGMP intracellular levels. PDE enzymes are subdivided into families and subtypes which are expressed throughout the human body. PDE4 isoenzyme- PDE4B subtype is overexpressed in the substantia nigra of the brain. Various studies have implicated multiple cAMP-mediated signaling cascades in PD, and PDE4 is a common link that can emerge as a neuroprotective and/or disease-modifying target. Furthermore, a mechanistic understanding of the PDE4 subtypes has provided perceptivity into the molecular mechanisms underlying the adverse effects of phosphodiesterase-4 inhibitors (PDE4Is). The repositioning and development of efficacious PDE4Is for PD have gained much attention. This review critically assesses the existing literature on PDE4 and its expression. Specifically, this review provides insights into the interrelated neurological cAMP-mediated signaling cascades involving PDE4s and the potential role of PDE4Is in PD. In addition, we discuss existing challenges and possible strategies for overcoming them.

BI 1015550: an investigational phosphodiesterase 4B (PDE4B) inhibitor for lung function decline in idiopathic pulmonary fibrosis (IPF).

INTRODUCTION: The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. Therefore, several agents with specific molecular targets have been recently investigated to find a cure for IPF. Phosphodiesterase 4 (PDE4) inhibition is known for its anti-inflammatory and antifibrotic properties. BI 1015550, an oral preferential inhibitor of the isoform PDE4B, could express complementary activity to current therapies in IPF and other forms of progressive pulmonary fibrosis. AREAS COVERED: In this review, we first provide an overview toof the current IPF treatment market, followed by the description of pharmacokinetics and pharmacodynamics of BI 1015550. The main preclinical and early clinical evidence on BI 1015550 is then described, as well as its potential as an IPF treatment. EXPERT OPINION: Oral treatment with BI 1015550 was shown to stabilize lung function as compared to placebo over 12 weeks, both among patients with and without background antifibrotic use, with an acceptable safety profile in a phase 2 trial, and a phase 3 trial has been initiated. To date, this represents to date the largest effect size for an IPF investigational drug tested in a phase 2 trial with the shortest duration.

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS.

Apremilast exerts protective effects on stroke outcomes and blood-brain barrier (BBB) dysfunction through regulating Rho-associated protein kinase 2 expression.

AIMS: Stroke is a devastating event and a huge public health concern worldwide. Apremilast (APR) is a selective inhibitor of phosphodiesterase-4 involved in various neurological diseases, including stroke. However, the protective effects of APR on stroke have not been investigated. Here, we explored the effects of APR on stroke outcomes and blood-brain barrier (BBB) dysfunction using a middle cerebral artery occlusion (MCAO) stroke mice model. RESULTS: The results show that APR attenuated neurological injury in MCAO mice with decreased neurological deficit scores and infarct size, as well as increased hanging grip time. The increased BBB permeability and decreased expression of the tight junction protein Claudin-5 in MCAO mice were attenuated by APR treatment. APR treatment also mitigated neuroinflammation in MCAO mice, as shown by the decreased levels of inflammatory cytokines. In vitro assays also proved that APR ameliorated the oxygen/glucose deprivation/reoxygenation (OGD/R)-induced increase in endothelial permeability and restored the expression of Claudin-5 in bEnd.3 brain endothelial cells. Moreover, overexpression of ROCK2 in bEnd.3 cells abolished the protective effects of APR on endothelial permeability against OGD/R induction. CONCLUSION: Taken together, our results demonstrate that APR showed significant efficacy on ischemic stroke outcomes by alleviating enhanced BBB permeability and neuroinflammation by inhibiting ROCK2. These findings suggest a novel therapeutic window for ischemic stroke.

Curative effects of fucoidan on acetic acid induced ulcerative colitis in rats via modulating aryl hydrocarbon receptor and phosphodiesterase-4.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease. Fucoidan, sulfated polysaccharide of brown seaweed, demonstrates various pharmacological actions as anti-inflammatory, anti-tumor and anti-bacterial effects. Therefore, we opt to investigate the potential curative effects of fucoidan in experimentally induced UC in rats through modulating aryl hydrocarbon receptor (AhR), phosphodiesterase-4 (PDE4), nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme Oxygenase-1 (HO-1). METHODS: UC was induced in rats using intracolonic 2 ml of 4% acetic acid. Some rats were treated with 150 mg/kg fucoidan. Samples of colon were used to investigate gene and protein expression of AhR, PDE4, Nrf2, HO-1 and cyclic adenosine monophosphate (cAMP). Sections of colon were stained with hematoxylin/eosin, Alcian blue or immune-stained with anti-PDE4 antibodies. RESULTS: Investigation of hematoxylin/eosin stained micro-images of UC rats revealed damaged intestinal glands, severe hemorrhage and inflammatory cell infiltration, while sections stained with Alcian Blue revealed damaged and almost absent intestinal glands. UC results in elevated gene and protein expression of PDE4 associated with reduced gene and protein expression of AhR, IL-22, cAMP, Nrf2 and HO-1. Finally, UC increased the oxidative stress and reduced antioxidant activity in colon tissues. All morphological changes as well as gene and protein expressions were ameliorated by fucoidan. CONCLUSION: Fucoidan could treat UC induced in rats. It restored the normal weight and length of colon associated with morphological improvement as found by examining sections stained with hematoxylin/eosin and Alcian Blue. The curative effects could be explained by enhancing antioxidant activity, reducing the expression of PDE4 and increasing the expression of AhR, IL-22 and cAMP.

ZL-n-91, a specific Phosphodiesterase-4 inhibitor, suppresses the growth of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that frequently develops resistance to chemotherapy. A new approach to treating TNBC is required to improve patient survival. Phosphodiesterase-4 (PDE4) is an enzyme that is predominantly involved in the modulation of intracellular signaling mediated by cAMP. Although the efficacy of PDE4 inhibitors in several human inflammatory diseases is well documented, their clinical utility has been limited by side effects, including nausea and emesis. Recently, PDE4 has been used as a potential therapeutic target for different cancer types. In the present study, we investigated the anticancer effects of a novel PDE4 inhibitor ZL-n-91 on TNBC and the underlying mechanism. We showed that ZL-n-91 inhibited the proliferation of TNBC cells, induced cell apoptosis, and caused cell cycle arrest. Western blot analysis showed that ZL-n-91 increased Bax level and reduced Bcl-2 expression. Furthermore, downregulation of the cell cycle-related proteins, such as CDK2, CDK4, cyclin D1, PCNA, p-RB, and ZL-n-91, significantly inhibited the transcription of DNA repair genes and triggered an intracellular DNA damage response. Moreover, ZL-n-91 prevented the growth of the transplanted MDA-MB-231 tumor xenograft in nude mice and increased the γ-H2AX expression. These data demonstrate the anticancer effects of ZL-n-91 on TNBC cells and suggest its potential use in anticancer therapy.

Selective inhibition of phosphodiesterase 4D increases tau phosphorylation at Ser214 residue.

Tau is a protein that normally participates in the assembly and stability of microtubules. However, it can form intraneuronal hyperphosphorylated aggregates that are hallmarks of Alzheimer's disease and other neurodegenerative disorders known as tauopathies. Tau can be phosphorylated by multiple kinases at several sites. Among such kinases, the cAMP-dependent protein kinase A (PKA) phosphorylates tau at Ser214 (pTAU-S214), an event that was shown to reduce the pathological assembly of the protein. Given that the neuronal cAMP/PKA-activated cascade is involved in synaptic plasticity and memory, and that cAMP-enhancing strategies demonstrated promising therapeutic potential for the treatment of cognitive deficits, we investigated the impact of cAMP on pTAU-S214 in N2a cells and rat hippocampal slices. Our results confirm that the activation of adenylyl cyclase increases pTAU-S214 in both model systems and, more interestingly, this effect is mimicked by GEBR-7b, a phosphodiesterase 4D inhibitor with proven pro-cognitive efficacy in rodents.

Phosphodiesterase­4 inhibitors: a review of current developments (2013-2021).

INTRODUCTION: Cyclic nucleotide phosphodiesterase 4 (PDE4) is responsible for the hydrolysis of cAMP, which has become an attractive therapeutic target for lung, skin, and severe neurological diseases. Here, we review the current status of development of PDE4 inhibitors since 2013 and discuss the applicability of novel medicinal-chemistry strategies for identifying more efficient and safer inhibitors. AREAS COVERED: This review summarizes the clinical development of PDE4 inhibitors from 2013 to 2021, focused on their pharmacophores, the strategies to reduce the side effects of PDE4 inhibitors and the development of subfamily selective PDE4 inhibitors. EXPERT OPINION: To date, great efforts have been made in the development of PDE4 inhibitors, and researchers have established a comprehensive preclinical database and collected some promising data from clinical trials. Although four small-molecule PDE4 inhibitors have been approved by FDA for the treatment of human diseases up to now, further development of other reported PDE4 inhibitors with strong potency has been hampered due to the occurrence of severe side effects. There are currently three main strategies for overcoming the dose limitation and systemic side effects, which provide new opportunities for the clinical development of new PDE4 inhibitors.

Phosphodiesterase 4 inhibitors in diabetic nephropathy.

Phosphodiesterase subtype 4 (PDE4) hydrolyzes cyclic AMP, a secondary messenger that mediates intracellular signaling, and plays key roles in inflammatory and fibrotic responses. Based on these significant anti-inflammatory effects, oral administration of PDE4 inhibitor is approved for the treatment of chronic obstructive pulmonary disease, atopic dermatitis, and psoriasis. However, PDE4 inhibition also has adverse effects, such as diarrhea, vomiting, dyspepsia, and headache. Therefore, the application of PDE4 inhibitors for chronic diseases, such as diabetes and its complications, has not yet been approved. Recent studies have reported the clinical benefits of pentoxifylline, a non-selective PDE inhibitor, in patients with kidney disease. The PDE4 inhibitor, roflumilast, also clearly ameliorates the symptoms of diabetes mellitus by improving hyperglycemia and insulin resistance. However, the beneficial effects of PDE4 inhibition on diabetic nephropathy have not yet been evaluated, and its potential mechanisms of action remain unknown. In this review, we discuss the beneficial effects of PDE4 inhibitors and their mechanisms of action using diabetes and DN models.

Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults.

BACKGROUND: Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. OBJECTIVE: We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792). METHODS: Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. RESULTS: More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity. LIMITATIONS: Short study duration was a limitation. CONCLUSIONS: Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.

Protein-protein interactions of PDE4 family members - Functions, interactions and therapeutic value.

The second messenger cyclic adenosine monophosphate (cAMP) is ubiquitous and directs a plethora of functions in all cells. Although theoretically freely diffusible through the cell from the site of its synthesis it is not evenly distributed. It rather is shaped into gradients and these gradients are established by phospodiesterases (PDEs), the only enzymes that hydrolyse cAMP and thereby terminate cAMP signalling upstream of cAMP's effector systems. Miles D. Houslay has devoted most of his scientific life highly successfully to a particular family of PDEs, the PDE4 family. The family is encoded by four genes and gives rise to around 20 enzymes, all with different functions. M. Houslay has discovered many of these functions and realised early on that PDE4 family enzymes are attractive drug targets in a variety of human diseases, but not their catalytic activity as that is encoded in conserved domains in all family members. He postulated that targeting the intracellular location would provide the specificity that modern innovative drugs require to improve disease conditions with fewer side effects than conventional drugs. Due to the wealth of M. Houslay's work, this article can only summarize some of his discoveries and, therefore, focuses on protein-protein interactions of PDE4. The aim is to discuss functions of selected protein-protein interactions and peptide spot technology, which M. Houslay introduced into the PDE4 field for identifying interacting domains. The therapeutic potential of PDE4 interactions will also be discussed.

Treating COPD with PDE 4 inhibitors.

While the pathogenesis of chronic obstructive pulmonary disease (COPD) is incompletely understood, chronic inflammation is a major factor. In fact, the inflammatory response is abnormal, with CD8+ T-cells, CD68+ macrophages, and neutrophils predominating in the conducting airways, lung parenchyma, and pulmonary vasculature. Elevated levels of the second messenger cAMP can inhibit some inflammatory processes. Theophylline has long been used in treating asthma; it causes bronchodilation by inhibiting cyclic nucleotide phosphodiesterase (PDE), which inactivates cAMP. By inhibiting PDE, theophylline increases cAMP, inhibiting inflammation and relaxing airway smooth muscle. Rather than one PDE, there are now known to be more than 50, with differing activities, substrate preferences, and tissue distributions. Thus, the possibility exists of selectively inhibiting only the enzyme(s) in the tissue(s) of interest. PDE 4 is the primary cAMP-hydrolyzing enzyme in inflammatory and immune cells (macrophages, eosinophils, neutrophils). Inhibiting PDE 4 in these cells leads to increased cAMP levels, down-regulating the inflammatory response. Because PDE 4 is also expressed in airway smooth muscle and, in vitro, PDE 4 inhibitors relax lung smooth muscle, selective PDE 4 inhibitors are being developed for treating COPD. Clinical studies have been conducted with PDE 4 inhibitors; this review concerns those reported to date.