Phosphodiesterase 4 Inhibitor Research Articles

Recalcitrant Scalp Psoriasis Successfully Treated with Once-Daily Roflumilast Cream 0.3%

Scalp psoriasis is a chronic, immune-mediated skin disease with varying phenotypes and is estimated to affect up to 80% of individuals suffering from psoriasis [1]. The physical symptoms, along with social and emotional impacts of scalp psoriasis can significantly reduce quality of life, necessitating long-term treatment for most patients [3]. Numerous topical and systemic treatments are available for scalp psoriasis, yet the condition remains challenging to manage, underscoring a persistent unmet need for safe and effective therapies [2]. Treatment of the scalp and other hair bearing areas is challenging and can affect the ability to apply topical products and hinder their efficacy [2, 3]. Roflumilast cream 0.3% is a highly selective, non-steroidal and potent topical phosphodiesterase 4 (PDE4) inhibitor approved in 2022 by the FDA for the treatment of psoriasis, including intertriginous disease; in 2023 as a foam for the treatment of seborrheic dermatitis and in 2024, roflumilast cream 0.15% was approved for the treatment of atopic dermatitis. Roflumilast has demonstrated a higher affinity for binding to PDE4 relative to other approved PDE4 inhibitors resulting in greater potency [4, 5]. The results of a phase 3 study investigating roflumilast foam 0.3% in patients with scalp and body psoriasis showed that once daily treatment produced significant clearance of affected areas, rapid improvement in pruritus, and was well-tolerated [6]. Here we report a case involving a 28-year-old female with recalcitrant scalp psoriasis following 10 years of unsuccessful treatment with topical products. Due to the severity of adverse effects experienced with prior therapies, the patient was reluctant to initiate systemic therapy and a trial of once daily topical roflumilast cream 0.3% was initiated. The patient demonstrated rapid improvement after 3 days and clearance of the scalp lesion following daily application for 5 days without any reported adverse effects. Lesions on the patient’s torso also cleared. Upon clearance of lesions, the patient discontinued application of roflumilast cream, and lesions remained clear for several weeks and applies only as needed with any recurrence. Our patient’s case demonstrates the significant potential of roflumilast cream 0.3% in addressing the inflammatory etiology of scalp psoriasis.

PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review

Chronic Obstructive Pulmonary Disease (COPD) is associated with cough, sputum production, and a reduction in lung function, quality of life, and life expectancy. Currently, bronchodilator combinations (β2-agonists and muscarinic receptor antagonists, dual therapy) and bronchodilators combined with inhaled corticosteroids (ICS), triple therapy, are the mainstays for the management of COPD. However, the use of ICS in triple therapy has been shown to increase the risk of pneumonia in some patients. These findings have laid the foundation for developing new therapies that possess both anti-inflammatory and/or bronchodilation properties. Phosphodiesterase-4 (PDE4) inhibitors have been reported as an effective therapeutic strategy for inflammatory conditions, such as asthma and COPD, but their use is limited because of class-related side effects. Efforts have been made to mitigate these side effects by targeting the PDE4B subtype of PDE4, which plays a pivotal role in the anti-inflammatory effects. Unfortunately, no selective oral PDE4B inhibitors have progressed to clinical trials. This has led to the development of inhaled PDE4 inhibitors to minimize systemic exposure and maximize the therapeutic effect. Another approach, the bronchodilation property of PDE3 inhibitors, is combined with anti-inflammatory PDE4 inhibitors to develop dual inhaled PDE4/PDE3 inhibitors. A few of these dual inhibitors have shown positive effects and are in phase 3 studies. The current review provides an overview of various PDE4 inhibitors in the treatment of COPD. The possibility of studying different selective PDE4 inhibitors and dual PDE3/4 inhibitors in combination with currently available treatments as a way forward to increase their therapeutic effectiveness is also emphasized.

Design, Synthesis, and Biological Evaluation of New Selective PDE4 Inhibitors for Topical Treatment of Psoriasis.

Psoriasis is a complex and chronic inflammatory disease. Current drugs help control the symptoms of psoriasis but make no cure, urging discovery of novel drugs. We report in this paper the discovery of new phosphodiesterase 4 (PDE4) inhibitors for treatment of psoriasis. We designed and synthesized 45 new compounds, among which 14h exhibited IC50 of 0.57 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 14h inhibited release of inflammatory cytokines of TNF-α (IC50 = 34.2 μM) and IL-6 (IC50 = 40.9 μM) in Raw264.7 cells and reduced the expression of IL-1β and IL-17A in the skin of psoriasis mice. In addition, 14h alleviated IMQ-induced psoriasis in the mouse model and reduced the erythema level, scales, and thickness of the back skin of the mice. In short, our results suggested that PDE4 inhibitor 14h is a strong candidate for the topical treatment of psoriasis.

Anogenital psoriasis - clinical picture and therapy

Psoriasis presenting with anogenital lesions is an important medical and social problem that is not sufficiently covered in the literature. The genitals and perianal area are involved in severe plaque and inverse psoriasis. Occasionally, the disease can be localized only in the anogenital zone. Diagnosis of psoriasis with localization on the genitals and/or perianal area is difficult, which is associated with the anatomical and physiological characteristics of the affected area. The manifestations of psoriasis become exudative, infiltration of papules and plaques is expressed little, the borders of rashes lose clarity, peeling on the skin is expressed weakly, in the depth of the folds due to maceration and friction is absent. Subjectively significant localization of the process, its prolonged course, pruritus lead to significant violations of the quality of life of patients and serve as prerequisites for the formation of anxiety-depressive disorders and sexual dysfunction Diagnosis and treatment of anogenital psoriasis presents significant challenges. Clinical guidelines tend to emphasize external therapy with topical corticosteroids and calcineurin inhibitors; in recent years, the efficacy of genetically engineered biological agents, including interleukin-17 inhibitors and phosphodiesterase-4 inhibitors, has been considered. The presented review systematizes information about anogenital psoriasis, peculiarities of its epidemiology, clinical picture, diagnosis and approaches to therapy.

Structural optimization and bioactivity evaluation of 2-(Methylcarbonylamino) thiazole derivatives as novel PDE4B inhibitors

Phosphodiesterase-4 (PDE4) is a protease belonging to the phosphodiesterase family, with a specific function of hydrolyzing intracellular cyclic adenosine monophosphate (cAMP). PDE4 is widely distributed across various human tissues and cells, where it plays a pivotal role in modulating intracellular cAMP levels, particularly in immune and inflammatory cells. Consequently, PDE4 inhibitors have been proven to effectively dampen inflammatory responses in these cells, leading to a reduction in the release of pro-inflammatory factors such as lipid mediators, reactive oxygen species (ROS) hydrolases, cytokines, and chemokines. Despite the considerable interest from both academia and pharmaceutical industries in exploiting this target for drug development, only a handful of PDE4 inhibitors are available in the market. The aim of this study was to identify novel PDE4B inhibitors through a combined approach of computer-aided drug design, synthesis, and activity evaluation. The study implemented three phases of structure optimization from the hit compound MR9, which was previously obtained by virtual screening, with reference to structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches. The optimized compound MR9-302 (PDE4B IC50=2.02±0.2888 μM) exhibited enhanced inhibitory activity compared to MR9.

Pharmacokinetics and ADME Profiling of Tanimilast Following an Intravenous 14C-Microtracer co-administered with an Inhaled Dose in Healthy Male Individuals.

Tanimilast is an inhaled phosphodiesterase-4 inhibitor currently in phase 3 clinical development for treating chronic obstructive pulmonary disease (COPD) and asthma. This trial aimed to characterize the pharmacokinetics, mass balance, and metabolite profiling of tanimilast. Eight healthy male volunteers received a single dose of non-radiolabeled tanimilast via powder inhaler (NEXThaler® (3200μg)), followed by a concomitant intravenous (IV) infusion of a microtracer ([14C]-tanimilast: 18.5μg and 500nCi). Plasma, whole blood, urine, and feces samples were collected up to 240 hours post-dose to quantify non-radiolabeled tanimilast, [14C]-tanimilast, and total-[14C]. The inhaled absolute bioavailability of tanimilast was found to be approximately 50%. Following IV administration of [14C]-tanimilast, plasma clearance was 22 L/h, the steady-state volume of distribution was 201 L, and the half-life was shorter compared to inhaled administration (14 vs. 39 hours, respectively), suggesting that plasma elimination is limited by the absorption rate from the lungs. 79% (71% in feces; 8% in urine) of the IV dose was recovered in excreta as total-[14C]. [14C]-tanimilast was the major radioactive compound in plasma, while no recovery was observed in urine and only 0.3% was recovered in feces, indicating predominant elimination through metabolic route. Importantly, as far as no metabolites accounting for more than 10% of the circulating drug-related exposure in plasma or the administered dose in excreta were detected, no further qualification is required according to regulatory guidelines. This study design successfully characterized the absorption, distribution, and elimination of tanimilast, providing key pharmacokinetic parameters to support its clinical development and regulatory application. Significance Statement This trial investigates PK and ADME profile of tanimilast, an inhaled PDE4 inhibitor for COPD and asthma. Eight male volunteers received a dose of non-radiolabeled tanimilast via NEXThaler® and a microtracer IV dose. Results show pivotal PK results for the characterization of tanimilast, excretion route and quantification of significant metabolites, facilitating streamlined clinical development and regulatory approval.

Modern pharmacotherapy approaches to treating chronic obstructive pulmonary disease. Part 1: Main and additional groups of drugs used in COPD therapy

The review article contains current data on the main groups of drugs used in COPD. COPD pharmacotherapy includes pharmacological and non-pharmacological approaches. Phar macological treatments include bronchodilators, combined ICS and long-acting bronchodilators (LABD), phosphodiesterase-4 inhibitors, theophylline, and COPD prevention methods such as influenza and pneumococcal vaccination. The described approaches to COPD pharmacotherapy are based on current national and international guidelines for COPD treatment.

Development of selective heterocyclic PDE4 inhibitors for treatment of psoriasis

Psoriasis is a chronic autoimmune disease that badly affects the life quality of patients and their families. Inadequate efficacy, safety risks, high cost and low compliance of current psoriasis drugs urge development of novel small molecular drugs. In this study, two series of 37 novel compounds were designed and synthesized as inhibitors of phosphodiesterase 4 (PDE4) that specifically hydrolyzes second messenger cAMP and is an effective target for treatment of inflammatory diseases. Comprehensive structural-activity optimization led to finding of inhibitor 2e with IC50 = 2.4 nM for PDE4D and >4100-fold selectivity over other PDE families. Compound 2e inhibited the release of TNF-α (IC50 = 21.36 μM) and IL-6 (IC50 = 29.22 μM) in the LPS-stimulated Raw264.7 cells. Topical application of 2e exhibited remarkable therapeutic efficacy in imiquimod-induced psoriasis mice model, suggesting that 2e is a strong drug candidate for treatment of psoriasis.

7360 An Overlooked Cause of Hypoglycemia and Weight Loss: Phosphodiesterase-4 Inhibitors

Abstract Disclosure: J. Aurora: None. K. Cappetta: None. R.M. Lechan: None. Background: Phosphodiesterase-4 (PDE-4) inhibitors, apremilast and roflumilast, are anti-inflammatory agents used to treat psoriasis, psoriatic arthritis, and COPD. These agents are commonly associated with gastrointestinal intolerance. However, patients may also experience profound weight loss (>10%). We present a case of a patient with T2DM who developed significant hypoglycemia and weight loss on apremilast. Clinical Case: A 57-year-old female with T2DM, obesity, psoriasis, and postsurgical hypothyroidism due to papillary thyroid cancer developed symptoms of hypoglycemia and weight loss over 1 month. Prior to this, her A1c was 7.8% and weight 104 kg on stable doses of metformin, repaglinide, and insulin glargine. Insulin glargine and repaglinide were both discontinued given her symptoms, yet hypoglycemia persisted, and she continued to lose weight. Further investigations into the cause of this sudden change were carried out. Initial fasting labs: BG 53 mg/dL, C-peptide 4.48 ng/mL (RR 0.8-3.85 ng/mL), insulin 12.8 uIU/mL (RR <18.4 uIU/mL), proinsulin 29.8 pmol/L (RR <18.8 pmol/L), A1c 6.8%, cortisol 24.9 mcg/dL (RR 4-22 mcg/dL), IGF-1 95 ng/mL (Z-score -0.7), and IGF-2 434 ng/mL (RR 267-616 ng/mL). 1 month later, hypoglycemia symptoms improved but she continued to lose weight. Fasting labs were repeated: BG 84 mg/dL, C-peptide 5.62 ng/mL, insulin 24.3 uIU/mL, proinsulin 35 pmol/L, and beta-hydroxybutyrate (BHB) 0.17 mmol/L (RR <0.28 mmol/L); metformin was subsequently stopped. A MR abdomen revealed a 2 cm cystic pancreatic lesion that showed atypical mucinous epithelium by biopsy under endoscopic ultrasound guidance. Gallium-68 DOTATATE-PET scan was unremarkable for an insulin-producing tumor. Two months off metformin, she had no further episodes of hypoglycemia, but her weight loss continued. Fasting labs were repeated: BG 129 mg/dL, C-peptide 5.15 ng/mL, insulin 18.2 uIU/mL, proinsulin 40.5 pmol/L, and BHB 0.27 mmol/L. Review of her medications identified apremilast as a potential culprit contributing to both her hypoglycemia and weight loss, as her symptoms started 1 month after starting apremilast. Over 9 months using apremilast, her A1c decreased by 1% and weight decreased by 27%. Hypoglycemia resolved off all glucose-lowering agents. Conclusion: Significant weight loss with apremilast may be explained by PDE-4 inhibition increasing cyclic AMP, which triggers the release of GLP-1 with subsequent effects on pancreatic beta cells. Apremilast has also been shown to significantly increase fasting insulin levels in patients without insulin resistance, as seen in our patient (1). Given these effects, patients may be at higher risk of hypoglycemia with concurrent glucose-lowering agents, particularly secretagogues. BG and weight need careful monitoring for patients with T2DM using PDE-4 inhibitors. Reference: 1. Ikumi K, et al. J Dermatol. 2022;49(4):e125-e126. Presentation: 6/3/2024

Diminished nuclear-localized β-adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy.

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), which is characterized by mesangial matrix expansion that involves dysfunctional mesangial cells (MCs). However, the underlying mechanisms remain unclear. This study aims to delineate the spatiotemporal contribution of adrenergic signalling in diabetic kidney fibrosis to reveal potential therapeutic targets. A model of diabetic nephropathy was induced by in db/db mice. Gene expression in kidneys was profiled by RNA-seq analyses, western blot and immunostaining. Subcellular-localized fluorescence resonance energy transfer (FRET) biosensors determined adrenergic signalling microdomains in MCs. Effects of oral rolipram, a phosphodiesterase 4 (PDE4) inhibitor, on the model were measured. Our model exhibited impaired kidney function with elevated expression of adrenergic and fibrotic genes, including Adrb1, PDEs, Acta2 and Tgfβ. RNA-seq analysis revealed that MCs with dysregulated YAP pathway were crucial to the extracellular matrix secretion in kidneys from diabetic nephropathy patients. In cultured MCs, TGF-β promoted profibrotic gene transcription, which was regulated by nuclear-localized β-adrenoceptor signalling. Mechanistically, TGF-β treatment diminished nuclear-specific cAMP signalling in MCs and reduced PKA-dependent phosphorylation of YAP, leading to its activation. In parallel, db/db mouse kidneys showed increased expressions of PDE4B and PDE4D. Treatment with oral rolipram alleviated kidney fibrosis in db/db mice. Diabetic nephropathy impaired nuclear-localized β1-adrenoceptor-cAMP signalling microdomain through upregulating PDE4 expression, promoting fibrosis in MCs via PKA dephosphorylation-dependent YAP activation. Our results suggest PDE4 inhibition as a promising strategy for alleviating kidney fibrosis in diabetic nephropathy.

Phosphodiesterase4 inhibitors in dermatology : Role in the treatment of skin diseases

Chronic inflammatory skin diseases are of great social and medical importance and require effective drug therapy. Phosphodiesterase4 (PDE4) inhibitors represent apossible 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. Apremilast is used for second-line treatment of plaque psoriasis and psoriatic arthritis and has afavorable side effect profile. Topical PDE4 inhibitors are currently being researched and have not yet been approved by the European Medicines Agency (EMA). The topical PDE4 inhibitor crisaborole was approved by the EMA in 2020 as atopical 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. 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.

Safety, pharmacokinetics, and pharmacodynamics of ART-648, a PDE4 inhibitor in healthy subjects: A randomized, placebo-controlled phase I study.

Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an invitro whole-blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART-648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide-induced TNFα release in exvivo whole-blood assay. In the single rising dose study, ART-648 was safe and well tolerated with a dose-proportional increase in exposures up to 4 mg. Single doses of ART-648 demonstrated dose-dependent PD response, indicating target engagement at 2-8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART-648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.

Roflumilast-loaded nanostructured lipid carriers attenuate oxidative stress and neuroinflammation in Parkinson’s disease model

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited symptomatic treatment options. Targeting phosphodiesterase 4 (PDE4) has shown a promising result in several preclinical studies. In our study, we aim to repurpose US FDA-approved PDE4 inhibitor for PD. Through in-silico study, we identified roflumilast (ROF) as the potential candidate targeting PDE4B2. In Drosophila PD expressing the A30P mutant α-synuclein model, ROF exhibited anti-PD effects as indicated by negative geotaxis and antioxidant activities. Given the low brain distribution of ROF (<50%) at clinical doses, incorporation into nanostructured lipid carriers (NLCs) was carried out to enhanced blood-brain barrier permeability. In vitro release studies indicated sustained ROF release from NLCs (≈75%) over 24 h. Single-dose oral toxicity studies reported no mortality or toxicity signs. ROF-loaded NLCs significantly alleviated behavioural deficits, increased antioxidant parameters (p < 0.05), and reduced TNF-α and IL-6 levels (p < 0.5) in the striatum compared to pure ROF. ROF-loaded NLCs demonstrated potential anti-PD effects with high efficacy than pure ROF. Our study suggests that nanostructured lipid carriers (NLCs) can be a promising drug delivery system to overcome limitations associated with poor brain bioavailability of lipophilic drugs like ROF for PD treatment. Further investigation related to brain occupancy and underlying mechanisms of our formulation is warranted to confirm and strengthen our current findings.

Equine metabolic investigation of the phosphodiesterase-4 inhibitor ibudilast as a potential performance enhancer.

Phosphodiesterase 4 (PDE4) inhibitors are a newer class of drugs that induce bronchodilation and have anti-inflammatory effects, making them susceptible to misuse as performance enhancers in competitive sports. This study explores the metabolic conversion of PDE4 inhibitor ibudilast in thoroughbred horses after oral administration and in vitro using equine liver microsomes and Cunninghamella elegans. A liquid chromatography-high resolution mass spectrometry method was used to postulate the plausible structures of the detected metabolites. A total of 20 in vivo metabolites were identified under experimental conditions, including 12 Phase I and 8 Phase II conjugated metabolites. Phase I metabolites were predominantly formed through hydroxylation (mono-, di-, and tri-hydroxylation). Demethylated metabolites were also identified during this investigation. Additionally, the research detected Phase II metabolites conjugated with glucuronic and sulfonic acids. The data presented here can assist in detecting the PDE4 inhibitor ibudilast and uncover its illicit use in competitive sports.

Inhibition of Phosphodiesterase 4 Suppresses Neuronal Ferroptosis After Cerebral Ischemia/Reperfusion.

We have previously shown that inhibition of phosphodiesterase 4 (PDE4) protects against cerebral ischemia/reperfusion injury. However, it remains unclear whether and how PDE4 affects ferroptosis under cerebral ischemia/reperfusion conditions. In this study, we found that overexpression of PDE4B in HT-22 cells exacerbated the detrimental effects of oxygen-glucose deprivation/reoxygenation (OGD/R), including a decrease in cell viability and glutathione (GSH) levels and an increase in Fe2+ content. PDE4B knockdown mitigated the effects of OGD/R, as evidenced by decreased oxidative stress, lactate dehydrogenase (LDH) release, Fe2+ content, and nuclear receptor coactivator 4 (NCOA4) expression. PDE4B knockdown also enhanced the levels of GSH, ferroportin (FPN), and ferritin heavy chain 1 (FTH1). Consistently, inhibition of PDE4 by roflumilast (Roflu) produced similar effects as PDE4B knockdown. Roflu also ameliorated the morphology and membrane potential of the mitochondria. Glutathione peroxidase 4 (GPX4) knockdown blocked the effects of Roflu on cell viability and lipid peroxidation. Moreover, we found that nuclear factor erythroid 2-related factor 2 (Nrf-2) knockdown decreased GPX4 expression. In addition, Nrf-2 knockdown led to enhanced lipid peroxidation, LDH release, and iron levels, while the GSH and FPN levels decreased. More crucially, PDE4 inhibition decreased infarct volume, alleviated oxidative stress, and restored the expression levels of ferroptosis-associated proteins in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Interestingly, the GPX4 inhibitor RSL3 blocked the neuroprotective effects of Roflu in rats subjected to MCAO/R. Thus, PDE4 inhibition significantly inhibits neuronal ferroptosis by activating the Nrf-2/GPX4 pathway. These data indicate the existence of a novel mechanism underlying the neuroprotective effects of PDE4 inhibition.

Exploring Newer Topical Therapies for Inflammatory Skin Diseases: A Guide for Rheumatologists

Understanding the pathogenesis of many inflammatory skin diseases and their associated signalling pathways has revealed multiple promising therapeutic targets. Given the chronic nature of many of these conditions, products with long-term safety and efficacy are desired. While topical corticosteroids have been the mainstay of topical therapies for years, they are burdened by concerns over long-term safety (i.e., atrophy, striae, telangiectasias), risk of absorption with systemic glucocorticoid side effects, and patient apprehension regarding steroid use. Similarly, topical calcipotriol and retinoids may be ineffective and can cause irritation. Although topical calcineurin inhibitors (i.e., pimecrolimus, tacrolimus) have been approved for atopic dermatitis, their off-label use for many inflammatory conditions may be limited by tolerability issues such as stinging and burning, and lack of effectiveness. The emergence of newer targeted small molecules for topical application, including topical phosphodiesterase-4 inhibitors (PDE4i), topical Janus kinase inhibitors (JAKi), and a therapeutic aryl hydrocarbon modulating agent (TAMA), offer promising new options and will be reviewed here and summarized in Table 1.

Roflumilast cream (Zoryve) for atopic dermatitis.

The FDA has approved a 0.15% cream formulation of the phosphodiesterase-4 (PDE4) inhibitor roflumilast (Zoryve – Arcutis) for topical treatment of mild to moderate atopic dermatitis (AD) in patients ≥6 years old. Roflumilast is the second PDE4 inhibitor to be approved in the US for treatment of AD; crisaborole (Eucrisa), which can be used in patients ≥3 months old, was the first.

PET imaging in rat brain shows opposite effects of acute and chronic alcohol exposure on phosphodiesterase-4B, an indirect biomarker of cAMP activity.

The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [18F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [18F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [18F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption.

Successful Treatment of Seborrheic Dermatitis with Topical Roflumilast: A Case Series

Background: Seborrheic dermatitis (SD) is a common skin disease that presents with pink scaly patches in areas with higher sebaceous gland density, such as the scalp, glabella, retroauricular folds, nasolabial folds, chest, and groin. Case Reports: This is a case series of two patients with longstanding SD that did not respond adequately to topical corticosteroids or azoles, and were successfully treated monotherapy with roflumilast cream 0.3%. Both patients responded within two months and continue to respond to treatment with topical roflumilast monotherapy. Discussion: SD is commonly considered to be caused by Malassezia yeast proliferation and activity, however recent research has revealed that the inflammatory skin disease results from immune dysregulation and skin barrier disruption with Malassezia contributing as an exacerbating factor secondary to the primary pathogenesis. Thus treatment with topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, has been studied and demonstrated to be effective in treating the signs and symptoms of SD. Topical roflumilast 0.3% is formulated as a cream and a foam, with the foam approved for the treatment of SD. These cases demonstrate a successful treatment of patients with longstanding SD with roflumilast cream 0.3%. Conclusion: These cases demonstrate that SD, treated with either roflumilast cream 0.3% or roflumilast foam 0.3% may provide improvement in signs and symptoms of SD.

Phosphodiesterase 4 is overexpressed in keloid epidermal scars and its inhibition reduces keratinocyte fibrotic alterations

BackgroundEpidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis.MethodsIn vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFβ1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches.ResultsThe study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFβ-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFβ1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings.ConclusionsOverall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition.