Phosphodiesterase 4 Inhibitor Research Articles

Selective phosphodiesterase 4 inhibitor roflumilast reduces inflammation and lung injury in models of betacoronavirus infection in mice.

We aimed to understand the potential therapeutic and anti-inflammatory effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast in models of pulmonary infection caused by betacoronaviruses. Mice were infected intranasally with murine hepatitis virus (MHV-3) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Roflumilast was given to MHV-3-infected mice therapeutically at doses of 1mg/kg or 10mg/kg, or prophylactically at 10mg/kg. In SARS-CoV-2-infected mice, roflumilast was given therapeutically at a dose of 10mg/kg. Lung histopathology, chemokines (CXCL-1 and CCL2), cytokines (IL-1β, IL-6, TNF, IFN-γ, IL-10 and TGFβ), neutrophil immunohistochemical staining (Ly6G+ cells), macrophage immunofluorescence staining (F4/80+ cells), viral titration plaque assay, real-time PCR virus detection, and blood cell counts were examined. Therapeutic treatment with roflumilast at 10mg/kg reduced lung injury in SARS-CoV-2 or MHV-3-infected mice without compromising viral clearance. In MHV-3-infected mice, reduced lung injury was associated with decreased chemokines levels, prevention of neutrophil aggregates and reduced macrophage accumulation in the lung tissue. However, the prophylactic treatment strategy with roflumilast increased lung injury in MHV-3-infected mice. Our findings indicate that therapeutic treatment with roflumilast reduced lung injury in MHV-3 and SARS-CoV-2 lung infections. Given the protection induced by roflumilast in inflammation, PDE4 targeting could be a promising therapeutic avenue worth exploring following severe viral infections of the lung.

Evaluating Efficacy and Safety of Crisaborole in Managing Childhood Mild to Moderate Atopic Dermatitis: A Systematic Review and Meta-Analysis.

Aims/Background Atopic dermatitis (AD) is a common chronic inflammatory skin disorder globally. Crisaborole, a nonsteroidal topical phosphodiesterase 4 inhibitor (PDE4i), has been utilized in treating AD. Crisaborole regulates the production of inflammatory cytokines, which are usually overactive among AD patients. Therefore, this study aimed to explore the efficacy and safety of crisaborole in treating AD in patients aged ≤18 years. Methods A literature search was performed across PubMed, MEDLINE, Embase, Cochrane, and Google Scholar. The inclusion criteria involved primary studies evaluating the effect of crisaborole in treating dermatitis, articles exploring the use of crisaborole in AD patients below 18 years (>two years), and articles published in English between 2000 and 2022. However, the studies evaluating AD in adult patients, those reporting treatments other than crisaborole, those published before 2000, and articles written in languages other than English were excluded from this analysis. Furthermore, secondary data sources such as case reports, newspaper articles, magazines, and other systematic reviews and meta-analyses were excluded. A meta-analysis was conducted using RevMan 5.4. The risk of bias in the manuscripts was assessed using the Cochrane tool. The I-square test statistic was used to determine heterogeneity, and Egger's test was used to evaluate publication bias. Results Ten studies met the eligibility criteria and were included in the final analysis. Most of the studies exhibited a low risk of bias with no publication bias. Meta-analysis indicated a significant difference in the number of patients attaining Investigator Static Global Assessment (ISGA) success at day 29, with significantly higher patients in the crisaborole group than in the vehicle group (odds ratio (OR) 1.56, 95% CI 1.24 to 1.96; I2 = 77%; p = 0.0001). Similarly, pruritus improvement was significant between the two cohorts at day 29, indicating significantly higher heterogeneity (OR 1.70, 95% CI 1.10 to 2.63; I2 = 91%; p = 0.02). Furthermore, the safety profiling of the treatments was insignificant, demonstrating no statistical difference in the treatment-emergent adverse events (TEAEs) between the two groups with high heterogeneity (OR 0.53, 95% CI 0.14 to 1.98; I2 = 99%; p = 0.35). Conclusion Crisaborole demonstrates substantial efficacy in treating mild to moderate AD compared to vehicle therapies, as it reduces the signs and symptoms of the disease. Furthermore, crisaborole is well tolerated and has an acceptable safety profile in treating mild to moderate AD patients.

Design, Synthesis, and Evaluation of Selective PDE4 Inhibitors for the Therapy of Pulmonary Injury.

Pulmonary inflammation is the main cause of lung injury. Phosphodiesterase 4 (PDE4) is a promising anti-inflammatory target for the treatment of respiratory diseases. Herein, we designed and synthesized 43 compounds in two novel series of benzimidazole derivatives as PDE4 inhibitors. Among them, compound A5 showed highly selective inhibition of PDE4, good safety, and liver microsomal stability in vitro. A5 administration remarkably attenuated inflammatory infiltration and pathologic injury of the lung in models of acute lung injury in mice and chronic obstructive pulmonary disease (COPD) in mice. In addition, A5 enhanced sputum secretion, relieved cough in mice, and inhibited phosphorylation of p38 MAP kinase, an important protein in the regulation of lung injury. Overall, A5, as an effective PDE4 inhibitor without acute toxicity and gastrointestinal reaction, may be a potent candidate for the treatment of pulmonary injury.

P0942 Orismilast for the treatment of moderate to severe Ulcerative Colitis: Analysis of preliminary data from UCORIS, a phase 2a, open-label, single-arm exploratory clinical trial

Abstract Background Existing medications aim to induce and maintain remission in Ulcerative Colitis (UC), yet 30-55% of UC patients remain refractory in the induction phase, underscoring an unmet need for novel treatments1. Orismilast, an oral B/D selective phosphodiesterase-4 (PDE4) inhibitor, is currently in development for the treatment of atopic dermatitis, psoriasis, and hidradenitis suppurativa. PDE4 receptors have also been shown to be upregulated in UC2. This study (the UCORIS study) aims to explore the efficacy and safety of orismilast to guide future studies. Methods The UCORIS study is an ongoing phase 2a, open-label, single-arm exploratory clinical study assessing the efficacy and safety of orismilast in patients with moderate to severe UC. Patients with a UC diagnosis currently on stable 5-ASA treatment and experiencing moderate-severe disease activity (defined as a MAYO endoscopic subscore of 2 or 3) were eligible for inclusion. Orismilast was administered twice daily for 12 weeks, with investigators allowed to individualize the dose based on body weight, treatment response and side effects. Responding patients could extend treatment to a total duration of 52 weeks. The primary endpoint was clinical remission based on the total Mayo score at week 12, defined as 2 points or lower with no individual sub-score above 1. Results To date, nine patients have been enrolled in the study. Four patients have completed the initial 12-week trial period. Among these, one patient reached the primary endpoint, achieving remission with a total Mayo score of 0, a SCCAI <2 and a f-calprotectin <15. The remaining three patients who completed treatment did not achieve remission. Five patients discontinued treatment prematurely: three due to lack of efficacy and two due to adverse effects (headache and nausea). The two patients who discontinued due to adverse effects did achieve remission after six weeks of treatment, as indicated by a partial Mayo score of 0, a SCCAI < 2, and an f-calprotectin level < 15. The most common adverse events were nausea (67%), dizziness (22%), and headache (22%), aligning with previous findings. Conclusion In this preliminary analysis, 1 patient (14%) achieved the primary endpoint of clinical remission after 12 weeks of treatment with orismilast, defined as a total Mayo score of 2 or lower, with no individual sub-score exceeding 1. Across all patients included in the study, 3 out of 9 (33%) achieved remission following treatment with orismilast; however, two of these three patients discontinued treatment due to adverse events (headache and nausea). In conclusion, these preliminary data suggest that orismilast shows potential as a treatment for UC, with one patient reaching the primary endpoint and two others achieving remission.

Phosphodiesterase 4 Inhibition in Neuropsychiatric Disorders Associated with Alzheimer’s Disease

Cognitive disorders and psychiatric pathologies, particularly Alzheimer’s disease (AD) and Major depressive disorder (MDD), represent a considerable health burden, impacting millions of people in the United States and worldwide. Notably, comorbidities of MDD and anxiety are prevalent in the early stages of mild cognitive impairment (MCI), which is the preceding phase of Alzheimer’s disease and related dementia (ADRD). The symptoms of MDD and anxiety affect up to 80% of individuals in the advanced stages of the neurodegenerative conditions. Despite overlapping clinical manifestations, the pathogenesis of AD/ADRD and MDD remains inadequately elucidated. Until now, dozens of drugs for treating AD/ADRD have failed in clinical trials because they have not proven beneficial in reversing or preventing the progression of these neuropsychiatric indications. This underscores the need to identify new drug targets that could reverse neuropsychiatric symptoms and delay the progress of AD/ADRD. In this context, phosphodiesterase 4 (PDE4) arises as a primary enzyme in the modulation of cognition and mood disorders, particularly through its enzymatic action on cyclic adenosine monophosphate (cAMP) and its downstream anti-inflammatory pathways. Despite the considerable cognitive and antidepressant potential of PDE4 inhibitors, their translation into clinical practice is hampered by profound side effects. Recent studies have focused on the effects of PDE4 and its subtype-selective isoform inhibitors, aiming to delineate their precise mechanistic contributions to neuropsychiatric symptoms with greater specificity. This review aims to analyze the current advances regarding PDE4 inhibition—specifically the selective targeting of its isoforms and elucidate the therapeutic implications of enhanced cAMP signaling and the consequent anti-inflammatory responses in ameliorating the symptomatology associated with AD and ADRD.

Exploring the Therapeutic Landscape: A Narrative Review on Topical and Oral Phosphodiesterase-4 Inhibitors in Dermatology.

Phosphodiesterase-4 (PDE4) is involved in the synthesis of inflammatory cytokines that mediate several chronic inflammatory disorders, including psoriasis and atopic dermatitis. In recent years, the therapeutic armamentarium in dermatology has expanded with the introduction of PDE4 inhibitors, both in oral and topical formulations. PDE4 inhibitors have gained increasing interest due to their remarkable safety record and ease of prescription, as evidenced by the recent influx of literature detailing its off-label uses. Apremilast was the first PDE4 inhibitor approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for psoriasis, psoriatic arthritis, and oral ulcers of Behcet's disease. Off-label use has been reported in diverse dermatological conditions, including aphthous stomatitis, chronic actinic dermatitis, atopic dermatitis, cutaneous sarcoidosis, hidradenitis suppurativa, lichen planus, and discoid lupus erythematosus. Roflumilast is a PDE4 inhibitor that was approved by the FDA and the EMA as an oral treatment of chronic obstructive pulmonary disease. Since patent expiration, several generic formulations of oral roflumilast have become available, and various studies have documented its off-label use in psoriasis and other dermatological conditions such as hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet's disease. Topical roflumilast has received FDA approval for treatment of plaque psoriasis and seborrheic dermatitis. The favorable safety profile encourages its long-term use as an alternative to corticosteroids, addressing the chronic nature of many dermatological conditions. New oral PDE4 inhibitors are being developed, such as orismilast (LEO-32731), mufemilast (Hemay005), difamilast (OPA-15406) or lotamilast (E6005/RVT-501), among others. This narrative review provides a comprehensive synthesis of the pharmacology, clinical efficacy, safety profile, and practical considerations regarding the oral and topical use of PDE4 inhibitors in dermatology.

Roflumilast attenuates doxorubicin and cyclophosphamide combination-induced chemobrain in rats through modulation of NLRP3/ASC/caspase-1/GSDMD axis.

The aim of this study is to investigate the neuroprotective effect of roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor on cognitive impairment induced by doxorubicin (DOX)/cyclophosphamide (CP) combination therapy and to elucidate its modulatory effect on the pyroptosis pathway. Rats were allocated into five groups: a control group, a DOX/CP-intoxicated group, two groups receiving DOX/CP plus low-dose (0.5 mg/kg/day) or high-dose (1 mg/kg/day) roflumilast, and a roflumilast-only group. Behavioral assessments and brain tissue analyses were conducted, including histopathological staining and the measurement of inflammatory and oxidative stress markers. DOX/CP treatment resulted in cognitive impairment, abnormal brain histology. It significantly elevated the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and malondialdehyde (MDA). Concurrently, superoxide dismutase (SOD) activity was reduced. Pyroptosis-associated markers, including nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1, gasdermin-D (GSDMD), and interleukin-18 (IL-18) were upregulated. Apoptotic marker caspase-3 also exhibited increased expression. Conversely, administration of roflumilast (1 mg/kg/day) for four weeks ameliorated these pathological changes. Roflumilast improved cognitive function, reduced oxidative stress, and modulated inflammatory signaling. Additionally, it suppressed pyroptotic and apoptotic pathways within hippocampal tissue. These results suggest that roflumilast exerts neuroprotective effects against chemotherapy-induced cognitive dysfunction and neurodegeneration through inhibition of the NLRP3/caspase-1/GSDMD pyroptosis pathway.

Efficacy and Safety of Crisaborole 2% Ointment in the Treatment of Mild-to-moderate Atopic Dermatitis – A Prospective, Open-label Study at a Tertiary Care Centre in Eastern India

Objectives: Atopic dermatitis (AD) is a common occurrence worldwide, where topical corticosteroids and calcineurin inhibitors, along with antihistamines, are being used for the treatment of mild-to-moderate AD. Crisaborole 2% ointment, a phosphodiesterase-4 inhibitor, has been recently approved for AD treatment by the Food and Drug Administration. Crisaborole is proposed to have lesser side effects in comparison to its counterparts. However, the impact of crisaborole on the Indian population has only been studied in the paediatric population and has not been widely explored. We conducted this study to find the safety and efficacy of crisaborole 2% ointment in mild-to-moderate AD in the Indian population. Materials and Methods: Thirty consecutive mild-to-moderate AD patients were included in the study. The patients were advised to apply crisaborole 2% ointment at the site of involvement twice daily for 28 days. The evaluation was done at baseline and day 28 using the SCORing AD (SCORAD), investigator static global assessment (ISGA) and eczema-associated severity index (EASI) scores. The patients were followed up to report any side effects. Results: There was a statistically significant decrease in the mean SCORAD, ISGA and EASI scores after the end of treatment. According to SCORAD, there were 58.3% of patients with moderate AD which reduced to 41.6% at the end of treatment. ISGA defined treatment success as only being achieved by 36.6% of patients, out of which complete resolution was achieved only by 20% of patients at the end of treatment. The mean EASI scores showed a considerable decreasing trend from 8.47 at baseline to 4.73 at the end of the study. Six patients withdrew from the study due to exacerbation of symptoms, possibly burning at the site of application. Conclusion: Although crisaborole reduced symptoms, it did not provide any instant relief to symptoms of AD, leading to discontinuation in a few patients, making it a viable drug for maintenance rather than a first-line therapy.

An In-depth Review of the Off-label Use of Apremilast in Dermatology

Background Apremilast is a phosphodiesterase-4 (PDE-4) inhibitor approved by the US-Food and Drug Administration (US-FDA) for the management of adult patients with plaque psoriasis (who are candidates for phototherapy/systemic therapy), moderate-to-severely active psoriatic arthritis and Behcet’s disease associated with oral ulcers. Purpose This review aims to summarize the current evidence for the off-label use of apremilast in various dermatological disorders. Methods A comprehensive search of relevant literature was conducted using databases like PubMed, MEDLINE and Embase. Studies investigating the use of apremilast for dermatological conditions beyond its approved indications were included. Results The use of apremilast has been outlined in a number of reports for inflammatory dermatoses. Randomized controlled trials showed promise for atopic dermatitis, hidradenitis suppurativa and vitiligo. Open-label trials suggested potential benefit in cutaneous sarcoidosis, discoid lupus erythematosus, rosacea and lichen planus. Conclusion Apremilast can be considered a valid therapeutic option for a range of inflammatory dermatological conditions beyond its approved uses. Further, owing to lack of immunosuppression, apremilast delineates an added advantage when compared to the usual immunosuppressive drugs used by dermatologists. However, stronger evidence from well-designed clinical trials is needed to establish its role in these aforementioned disorders.

The phosphodiesterase-4 inhibitor Zl-n-91 suppresses glioblastoma growth via EGR1/PTEN/AKT pathway.

Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor, which presents significant challenges for treatment in clinical settings. Phosphodiesterase 4 (PDE4) inhibitors can prevent the degradation of cAMP and have been used as a potential targeted therapeutic approach for different cancer types. However, its clinical use is restricted by the side effects such as nausea and vomiting. Herein, we investigated the efficacy and therapeutic mechanisms of a specific PDE4 inhibitor, Zl-n-91, on GBM cells. The results demonstrated that Zl-n-91 exhibited more effectiveness than the well-known PDE4 inhibitor Rolipram in treating GBM. It can notably suppress the proliferation of GBM cells by inducing G0/G1 phase arrest and apoptosis. Additionally, Zl-n-91 significantly inhibited the growth of subcutaneous glioma xenografts. Mechanistically, Zl-n-91 treatment increased the expression and nuclear transcription of Early growth response (EGR1), while knockdown EGR1 could decrease PTEN levels and increase p-AKT levels, restoring the inhibition of cell proliferation induced by Zl-n-91. Collectively, we revealed for the first time that PDE4 inhibitor Zl-n-91 could inhibit the growth of GBM cells through the EGR1/PTEN/AKT signaling pathway. Zl-n-91, a specific PDE4 inhibitor, may be a promising therapeutic candidate for GBM.

Topical Application of Dipyridamole and Roflumilast Combination Nanoparticles Loaded Nanoemulgel for the Treatment of Psoriasis in Rats.

Phosphodiesterase-4 is an enzyme that regulates immune responses and contributes to the development of psoriasis. Dipyridamole and roflumilast function as phosphodiesterase-4 inhibitors, reducing pro-inflammatory cytokine expression. The aim was to evaluate the anti-psoriatic effect of the topical administration of dipyridamole and roflumilast nanoemulgel combination on imiquimod-induced psoriasiform skin inflammation in rats. Dipyridamole and roflumilast were formulated into nanoemulgel to enhance skin penetration and retention. The production of nanoemulgels involves a two-part process. A nanoemulsion is created (the aqueous phase titration method was employed to create nanoemulsions‎), which is then incorporated into the gelling agent during the second phase. The new formula was then tested in rats. The rats were divided into seven groups; all animals were treated for 16 days. Induction was achieved by 120 mg of 5% imiquimod cream, which was applied daily for 8 days. After induction, groups received one of the following: 0.05% clobetasol ointment, 1% dipyridamole nanoemulgel (D-NEG), 0.3% roflumilast nanoemulgel (R-NEG), 1% dipyridamole and 0.3% roflumilast gel combination (DR-gel), and 1% dipyridamole and 0.3% roflumilast nanoemulgel combination (DR-NEG). At the end of the experiment, all animals were euthanized, and their blood and skin tissue samples were obtained. Inflammatory markers, immunohistochemistry, and histopathology were measured. The DR-NEG group showed significantly lower levels of IL17, IL23, and TNF-α, while TGF-β showed higher levels than the clobetasol group. The expression of CK16 was significantly lower compared to the clobetasol group. DR-NEG showed a significantly lower PASI and Baker score than the clobetasol group. The new DR-NEG's topical combination administration showed better anti-inflammatory, tissue healing, and anti-psoriatic activity than each drug alone or topical clobetasol administration; this could be attributed to the possible synergic effects of both drugs and the enhanced skin penetration offered by the nanoemulgel formulation.

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.

Apremilast: First Pediatric Approval.

Apremilast (Otezla®) is an inhibitor of phosphodiesterase-4 (PDE-4) being developed by Amgen. It is approved in multiple countries worldwide, including the USA and those of the EU, for the treatment of adults with psoriatic arthritis, plaque psoriasis, or oral ulcers associated with Behçet's disease. In April 2024, based on clinical data in patients aged 6-17years, apremilast received its first pediatric approval in the USA for the treatment of pediatric patients aged ≥ 6years and weighing ≥ 20kg with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Apremilast was also approved in the EU in October 2024 for the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6years and weighing ≥ 20kg who are candidates for systemic therapy. This article summarizes the milestones in the development of apremilast leading to the first pediatric approval for plaque psoriasis.

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.

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