Phosphodiesterase 4 Inhibitor Research Articles

1130 Clinically relevant differences in the chemical and structural mechanism of action of dermatological phosphodiesterase-4 inhibitors

1130 Clinically relevant differences in the chemical and structural mechanism of action of dermatological phosphodiesterase-4 inhibitors

Pharmacological Profile of Difamilast, a Novel Selective Phosphodiesterase 4 Inhibitor, for Topical Treatment of Atopic Dermatitis.

PDE4 inhibitors are expected to be anti-inflammatory agents based on their mechanism of action, but the application of this drug class is limited by a narrow therapeutic window due to adverse effects associated with gastrointestinal function. Difamilast, a novel selective phosphodiesterase 4 (PDE4) inhibitor, demonstrated significant efficacy without adverse reactions such as nausea and diarrhea in patients with atopic dermatitis (AD) and was recently approved in Japan. In this study, we investigated the pharmacological and pharmacokinetic properties of difamilast to provide nonclinical data to help understand the clinical effects. Difamilast selectively inhibited recombinant human PDE4 activity in assays. The IC50 of difamilast against PDE4B, a PDE4 subtype that plays an important role in the inflammatory response, was 0.0112 μM, representing a 6.6-fold decrease compared with the IC50 against PDE4D (0.0738 μM), a subtype that can trigger emesis. Difamilast inhibited TNF-α production in human (IC50 = 0.0109 μM) and mouse (IC50 = 0.0035 μM) peripheral blood mononuclear cells and improved skin inflammation in a mouse model of chronic allergic contact dermatitis. These effects of difamilast on TNF-α production and dermatitis were superior to those of other topical PDE4 inhibitors: CP-80633, cipamfylline, and crisaborole. In pharmacokinetic studies using miniature pigs and rats, the concentrations of difamilast in the blood and brain after topical application were not sufficient to support pharmacological activity. This nonclinical study contributes to explain the efficacy and safety of difamilast with a sufficient therapeutic window in the clinical trials. SIGNIFICANCE STATEMENT: This is the first report on the nonclinical pharmacological profile of difamilast ointment, a novel topical PDE4 inhibitor that demonstrated utility in clinical trials in patients with atopic dermatitis. Difamilast, which has high PDE4 selectivity (especially for the PDE4B subtype), ameliorated chronic allergic contact dermatitis in mice after topical application, with a pharmacokinetic profile in animals that suggests few systemic side effects; thus, difamilast is a promising new therapeutic treatment for atopic dermatitis.

Crisaborole reverses dysregulation of the mild to moderate atopic dermatitis proteome toward nonlesional and normal skin

Safe and effective long-term topical treatments for atopic dermatitis (AD) remain limited. In this phase 2a, single-center, intrapatient, and vehicle-controlled study, we examine the mechanism of action of crisaborole 2% ointment, a topical nonsteroidal PDE4 (phosphodiesterase-4) inhibitor, in a proteomic analysis of 40 adults with mild to moderate AD and 20 healthy subjects. Within the AD cohort, 2 target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14days. Punch biopsy specimens were collected for biomarker analysis at baseline from all participants, then from AD patients only at day 8 (optional) and day 15. Compared to the vehicle, crisaborole significantly reversed dysregulation of the overall lesional proteome and of key markers and pathways (eg, Th2, Th17/Th22, and T-cell activation) associated with AD pathogenesis toward both nonlesional and normal skin. Significant clinical correlations were observed with markers associated with nociception and Th2, Th17, and neutrophilic activation. Study limitations include predominance of white patients in the cohort, relatively short treatment time, and regimented administration of crisaborole. Our results demonstrate crisaborole-induced normalization of the AD proteome toward a nonlesional molecular phenotype and further support topical PDE4 inhibition in the treatment of mild to moderate AD.

Rolipram suppresses migration and invasion of human choriocarcinoma cells by inhibiting phosphodiesterase 4-mediated epithelial-mesenchymal transition.

Rolipram is a selective phosphodiesterase-4 (PDE4) inhibitor. The effect of rolipram on the metastasis of choriocarcinoma is barely known. Here, we evaluated the role of rolipram in the migration and invasion of human choriocarcinoma cells in vitro.Human choriocarcinoma cells lines JEG3 and JAR were used in this study. The expression profile of PDE4 subfamily members in choriocarcinoma cells was evaluated using real-time PCR. The migration and invasion properties of choriocarcinoma cells before and after inhibition of PDE4 by rolipram or RNAi-directed knockdown were evaluated in vitro. Expression levels of MMP9, TIMP1, E-cadherin, vimentin, TGFβ1, SMAD1, and SMAD4 of choriocarcinoma cells were compared before and after rolipram treatment, RNAi-directed knockdown of PDE4D, and overexpression of PDE4D. We found PDE4D was the most commonly expressed isoform of PDE4 both in JEG3 and JAR cells. Rolipram and knockdown of PDE4D were efficient to inhibit the migration and invasion of choriocarcinoma cells in vitro, accompanied by decreased expression of MMP9 and TIMP1. Furthermore, rolipram and knockdown of PDE4D promoted the expression of E-cadherin but reduced the expression of vimentin in choriocarcinoma cells, and overexpression of PDE4D decreased the expression of E-cadherin but promoted the expression of vimentin. Rolipram suppressed migration and invasion of human choriocarcinoma cells in vitro, possibly by inhibiting epithelial-mesenchymal transition through PDE4 inhibition.

Apremilast Add-On Benefits Over Conventional Drugs (ABCD) in Unstable Non-segmental Vitiligo: A 12-Week Single-Center Randomized Controlled Trial.

Background Apremilast is an oral phosphodiesterase-4 enzyme inhibitor that modulates the immune system by increasing intracellular cyclic adenosine monophosphate levels and inhibiting inflammatory cytokines synthesis. We aimed to compare the efficacy and safety of add-on apremilast in combination therapy with standard treatment in patients with unstable, non-segmental vitiligo. Methods The study was a 12-week randomized, controlled, parallel-group, open-labeled trial.The control group received standard treatment (n=15), and the intervention group received 30 mg apremilasttwice daily in addition to standard treatment (n= 16). Time to the first sign of re-pigmentation, halt in progression, and change invitiligo area scoring index (VASI) score is the primary outcomes. Normality was assessed, and appropriate parametric and nonparametric tests were undertaken. Results Thirty-seven participants were randomized into two groups, and analysis was done on thirty-one participants. Over the treatment duration of 12 weeks, the median time to observe the first sign of re-pigmentation was four weeks in the add-on apremilast group compared to seven weeks in the control group (p=0.018). The halt in progression was observed more in the add-on Apremilast group (93.75%) compared to the control group (66.66%) (p=0.08). The VASI score decreased by 1.24 in the add-on apremilast group and 0.05 in the control group (p= 0.754). Parameters including body surface area, dermatology life quality index, and body mass index reduced significantly, while the visual analog scale increased significantly in the add-on apremilast group. However, results were comparable between groups. Conclusions Treatment with add-on apremilast accelerated clinical improvement. It also reduced disease progression and improved the disease index among participants. However, add-on apremilast had a lower tolerability profile than the control group.

Intermittent treatment with Apremilast, a phosphodiesterase-4 inhibitor, ameliorates Alzheimer's-like pathology and symptoms through multiple targeting actions in aged T2D rats.

Apremilast (Apre), a novel phosphodiesterase-4 (PDE4) inhibitor, has been shown to have anti-inflammatory, immunomodulator, neuroprotective and senolytic properties, therefore, Apre like other PDE4 inhibitors may be a promising candidate for treatment of Alzheimer's disease (AD). To evaluate the effectiveness of Apre on Alzheimer's like pathology and symptoms in an animal model. The effects of Apre and cilostazol, a reference drug, on the behavioral, biochemical, and pathological features of Alzheimer's disease induced by a high-fat/high-fructose diet combined with low-dose streptozotocin (HF/HFr/l-STZ) were investigated. Apre 5mg/kg IP/day for 3 consecutive days per week for 8weeks attenuated memory and learning deficits tested by novel object recognition, Morris water maze and passive avoidance tests. Apre treatment significantly decreased the number of degenerating cells, and abnormal suppression of gene expression of AMPA and NMDA receptor subunits in the cortex and hippocampus of the AD rat model compared to rats that received vehicle. A significant decrease in elevated levels of hippocampal amyloid beta, tau-positive cell count, cholinesterase activity, and hippocampal caspase-3, a biomarker of neurodegeneration, was also observed after treatment with Apre in AD rats compared to rats that received placebo. Furthermore, a significant decrease in pro-inflammatory cytokines, oxidative stress, insulin resistance and GSK-3 was demonstrated in AD aged rats treated by Apre. Our findings demonstrate that intermittent treatment with Apre can enhance cognitive function in HF/HFr/l-STZ rats which may be related to decreased pro-inflammatory cytokines, oxidative stress, insulin resistance and GSK-3β.

Formulation Development and Evaluation of Apremilast Nanoemulgel for Enhancing Permeability

Background: Oral apremilast, a selective phosphodiesterase-4 inhibitor, is effective in the treatment of moderate to severe plaque psoriasis and acute psoriatic arthritic disease. According to BCS categorization, it is a class IV medication, which denotes low solubility and lesser permeability through the skin. Objective: The objective of the research is to develop a nanoemulsion that will increase apremilast’s skin permeability. Utilizing a simplex lattice design, an optimised nanoemulsion has been developed, and then transformed into a gel form and created as a nanoemulgel. Method: The nanoemulsion was developed by selecting the oil, surfactant, co-surfactant, and cosolvent, in that order, based on the solubility study, and was then evaluated based on various criteria. Different grades and concentrations of carbopol polymer were used to make nanoemulgel, which was then tested for physicochemical parameters like pH, viscosity, spreadability, extrudability, percentage of drug content, percentage of drug diffusion, skin permeation, and skin retention. For skin irritancy tests, male Wistar albino rats weighing between 200 and 250 g were used to find out how likely it was that apremilast-loaded nanoemulgel would cause skin irritation. Result: The nanoemulsion formulation A5 containing 10% Captex 355 and 40% Smix in a 3:1 ratio of Cremophore RH 40: Labrafil showed the smallest particle size and greatest drug diffusion. In comparison to other formulations of emulgel, the 0.75 % concentration of carbopol 940 produced the best results. Conclusion: A stable nanoemulgel system with apremilast loaded was created, and a number of process factors were assessed. The optimised batch produced repeatable results when evaluated, exhibited no skin irritation, and was shown to be stable after three months at ambient conditions of temperature and humidity.

Phosphodiesterase (PDE) 4 inhibition boosts Schwann cell myelination in a 3D regeneration model

Phosphodiesterase 4 (PDE4) inhibitors have been extensively researched for their anti-inflammatory and neuroregenerative properties. Despite the known neuroplastic and myelin regenerative properties of nonselective PDE4 inhibitors on the central nervous system, the direct impact on peripheral remyelination and subsequent neuroregeneration has not yet been investigated. Therefore, to examine the possible therapeutic effect of PDE4 inhibition on peripheral glia, we assessed the differentiation of primary rat Schwann cells exposed in vitro to the PDE4 inhibitor roflumilast. To further investigate the differentiation promoting effects of roflumilast, we developed a 3D model of rat Schwann cell myelination that closely resembles the in vivo situation. Using these in vitro models, we demonstrated that pan-PDE4 inhibition using roflumilast significantly promoted differentiation of Schwann cells towards a myelinating phenotype, as indicated by the upregulation of myelin proteins, including MBP and MAG. Additionally, we created a unique regenerative model comprised of a 3D co-culture of rat Schwann cells and human iPSC-derived neurons. Schwann cells treated with roflumilast enhanced axonal outgrowth of iPSC-derived nociceptive neurons, which was accompanied by an accelerated myelination speed, thereby showing not only phenotypic but also functional changes of roflumilast-treated Schwann cells. Taken together, the PDE4 inhibitor roflumilast possesses a therapeutic benefit to stimulate Schwann cell differentiation and, subsequently myelination, as demonstrated in the biologically relevant in vitro platform used in this study. These results can aid in the development of novel PDE4 inhibition-based therapies in the advancement of peripheral regenerative medicine.

Blood-Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats.

Phosphodiesterase 4 inhibitors (PDE4-I), which selectively increase cyclic adenosine monophosphate (cAMP) levels, have shown neuroprotective effects after several neurological injuries inducing blood-brain barrier (BBB) damage including local/focal cerebral ischemia. The present investigated whether roflumilast confers BBB neuroprotection in the hippocampus after transient global cerebral ischemia (TGCI) in rats. TGCI resulted in whole BBB disruption as measured by the increase of Evans blue (EB) and IgG extravasation, neurodegeneration, and downregulation of claudin-5 and endothelial nitric oxide synthase (eNOS) levels in the CA1 hippocampal subfield of ischemic rats. Roflumilast attenuated BBB disruption and restored the levels of eNOS in the CA1 hippocampal area. Moreover, roflumilast increased the levels of B2 cell lymphoma (BcL-2) and neuron-glial antigen-2 (NG2) in the CA1 subfield after global ischemia in rats. The protective effects of roflumilast against TGCI-induced BBB breakdown might involve preservation of BBB integrity, vascularization and angiogenesis, and myelin repair.

Efficacy and Safety of Roflumilast Foam 0.3% in Patients With Seborrheic Dermatitis in a Phase 3 Trial

Introduction: Seborrheic dermatitis (SD) is a common, chronic, inflammatory dermatosis that affects patients of all ages with a global prevalence ≥5%. Treatments usually consist of topical therapies, including antifungals and low potency corticosteroids; however, current treatments have limitations such as side effects with long-term use and/or vehicles that can be difficult to use on both hair-bearing and non-hair-bearing areas. Roflumilast is a selective, nonsteroidal, highly potent phosphodiesterase-4 inhibitor once-daily foam under investigation for the treatment of SD. Efficacy, safety, and local tolerability of roflumilast foam 0.3% in patients with SD were demonstrated in a phase 2a and subsequent open-label trial (NCT04091646 and NCT04445987, respectively). Here, we present efficacy, safety, and local tolerability in a phase 3 trial of roflumilast foam 0.3% in patients with SD (NCT04973228). Methods: This phase 3 randomized, parallel group, double blind, vehicle-controlled trial was conducted in patients ≥9 years old with at least moderate SD affecting scalp and/or non-scalp areas. Patients were randomized 2:1 to apply once-daily roflumilast foam 0.3% (n=304) or vehicle (n=153) for 8 weeks. The primary efficacy endpoint was Investigator Global Assessment (IGA) Success (IGA of Clear or Almost Clear plus ≥2-grade improvement from baseline) at Week 8. Secondary efficacy endpoints included IGA score of Clear at Week 8, achievement of ≥4-point improvement from baseline in Worst Itch Numeric Rating Score (WI-NRS) among patients with baseline score ≥4 (WI-NRS Success), Overall Assessment of Erythema score of 0, and Overall Assessment of Scaling score of 0. Safety and local tolerability were also evaluated. Results: Overall, significantly more roflumilast-treated patients than vehicle-treated patients achieved the primary efficacy endpoint of IGA Success (79.5% vs. 58.0%; P<0.0001) and IGA status of Clear (50.6% vs. 27.7%; P<0.0001) at Week 8. Percentages of patients achieving IGA Success and IGA Clear at Weeks 2 and 4 were also greater with roflumilast. Significantly greater percentages of roflumilast- than vehicle-treated patients achieved secondary endpoints of WI-NRS success at Weeks 2, 4, and 8 (62.8% vs. 40.6%; P<0.0001); Overall Assessment of Erythema score of 0 (57.8% vs. 32.0%; P<0.0001) at Week 8; and Overall Assessment of Scaling score of 0 (58.1% vs. 36.5%; P<0.0001) at Week 8. Local tolerability was favorable, with ≥98.9% of patients having no evidence of irritation at Weeks 4 and 8 on investigator-rated assessments and ≥92.3% of patients reporting a score of 0 (no sensation) or 1 (slight warm, tingling sensation; not really bothersome) after application on patient-rated tolerability. Overall incidence of treatment-emergent adverse events (TEAE), serious adverse events, and TEAEs leading to discontinuation were low, with similar rates between roflumilast and vehicle. Conclusion: Once-daily roflumilast foam provided improvement across multiple efficacy endpoints vs vehicle while demonstrating favorable safety and tolerability in patients ≥9 years old with SD affecting scalp and/or non-scalp body areas. Sponsored by Arcutis Biotherapeutics, Inc.

Pathophysiology, Therapeutic Targets, and Future Therapeutic Alternatives in COPD: Focus on the Importance of the Cholinergic System

Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by airway limitation and changes in airway structure. It has a high global burden of mortality and morbidity. The etiology of COPD is complex, but exposure to tobacco smoke and other inhaled lung oxidants are major risk factors. Both pharmacological and non-pharmacological approaches are used to manage COPD, but there remains an urgent unmet need for drugs that can modify the course of the disease. This review focuses on the role of acetylcholine and other components of the pulmonary cholinergic system in the pathogenesis of COPD, and the inhaled pharmacological agents that target it. In addition to its role as a neurotransmitter, acetylcholine regulates diverse aspects of COPD pathogenesis including bronchoconstriction, airway remodeling, mucus secretion and inflammation. Inhaled antimuscarinic drugs are a key component of therapy for COPD, as monotherapy or in combination with inhaled β2 agonists or corticosteroids. We review the evidence supporting the use of current anticholinergic agents in COPD and preview novel drugs targeting the cholinergic system and agents from other classes in clinical development, such as phosphodiesterase-4 inhibitors and monoclonal antibodies targeting inflammatory mediators.

Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. A substantial proportion of patients with PCOS are either overweight or obese, and excess body weight aggravates the hormonal, reproductive and metabolic manifestations of PCOS. In recent years, several studies evaluated the role of various pharmacological agents in the management of obesity in this population. Most reports assessed glucagon-like peptide-1 receptor agonists and showed a substantial reduction in body weight. More limited data suggest that sodium-glucose cotransporter-2 inhibitors and phosphodiesterase-4 inhibitors might also be effective in the management of obesity in these patients. In the present review, we discuss the current evidence on the safety and efficacy of these agents in overweight and obese patients with PCOS.

Therapeutic treatment with phosphodiesterase-4 inhibitors alleviates kidney injury and renal fibrosis by increasing MMP-9 in a doxorubicin-induced nephrotoxicity mouse model

Nephrotic syndrome (NS) is associated with kidney dysfunction and is an important cause of morbidity and mortality in industrialized countries. Here, we evaluated the effects of the phosphodiesterase-4 (PDE-4) inhibitors rolipram and roflumilast on a doxorubicin-induced NS model. Early-stage rolipram treatment preserved glomerular filtration barrier function, as indicated by reduced serum protein and albumin loss and the prevention of hypercholesterolemia. These effects were associated with reduced glomerular and tubular lesions and abrogated renal cell apoptosis. In addition, rolipram treatment reduced inflammation, which was characterized by a decrease in macrophage accumulation and reduced levels of CCL2 and TNF in the kidneys. Rolipram also reduced renal fibrosis, which was associated with decreased α-smooth muscle actin (α-SMA) area and increased metalloproteinase 9 (MMP9) activity in renal tissue. Late-stage rolipram or roflumilast treatment preserved glomerular filtration barrier function, as characterized by reduced serum albumin loss, decreased proteinuria, and the prevention of hypercholesterolemia. Importantly, only roflumilast treatment was associated with a reduction in glomerular and tubular lesions at this time point. In addition, both rolipram and roflumilast reduced renal tissue fibrosis and MMP9 activity in renal tissue.

Topical roflumilast (Zoryve) for plaque psoriasis.

The FDA has approved a 0.3% cream formulation of the phosphodiesterase-4 (PDE4) inhibitor roflumilast (Zoryve – Arcutis) for topical treatment of plaque psoriasis in patients ≥12 years old.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment. The objective of this study was to examine the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo. The PDE1-11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone-induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed. Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T-helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMC. In vivo, 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (p < 0.0001, respectively). Orismilast displayed selective and potent PDE4 inhibition and broad-spectrum anti-inflammatory activity in several pre-clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.

Guidelines of care for the management of atopic dermatitis in adults with topical therapies

New evidence has emerged since the 2014 guidelines that further informs the management of atopic dermatitis (AD) with topical therapies. These guidelines update the 2014 recommendations for management of AD with topical therapies. To provide evidence-based recommendations related to management of AD in adults using topical treatments. A multidisciplinary workgroup conducted a systematic review and applied the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach for assessing the certainty of evidence and formulating and grading recommendations. The workgroup developed 12 recommendations on the management of AD in adults with topical therapies, including nonprescription agents and prescription topical corticosteroids (TCS), calcineurin inhibitors (TCIs), Janus kinase (JAK) inhibitors, phosphodiesterase-4 inhibitors (PDE-4), antimicrobials, and antihistamines. The pragmatic decision to limit the literature review to English-language randomized trials may have excluded data published in other languages and relevant long-term follow-up data. Strong recommendations are made for the use of moisturizers, TCIs, TCS, and topical PDE-4 and JAK inhibitors. Conditional recommendations are made for the use of bathing and wet wrap therapy and against the use of topical antimicrobials, antiseptics, and antihistamines.

Effect of Oral Drug Apremilast on Histopathological Changes in Patients of Plaque Psoriasis: A Prospective Observational Study

Introduction: Psoriasis is a chronic non infectious recurrent papulosquamous inflammatory disorder characterised by vascular alterations such as angiogenesis, dilatation, increased endothelial venule generation, epidermal keratinocyte hyperproliferation, and aberrant differentiation, and lymphocytic invasion of T-cells. The aetiopathogenesis of disease is influenced by both hereditary and environmental factors. Pathogenesis is significantly influenced by immune dysregulation, which affects both innate and acquired immunity. A relatively recent medication for the management of moderate to severe plaque psoriasis is apremilast, an oral phosphodiesterase-4 inhibitor. Compared to other immune-suppressing drugs used in psoriasis apremilast causes no reactivation of tuberculosis or opportunistic infections, does not need dose adjustment in elderly or patients with hepatic impairment, and is not contraindicated in diabetes, ischaemic heart disease, or congestive cardiac failure. Due to its advantage of the absence of the need for laboratory monitoring, the patients on long-term methotrexate can also be switched to apremilast. Aim: To evaluate the histopathological changes in the skin of all plaque psoriatic patients treated with oral drug apremilast. Materials and Methods: This hospital-based prospective study was done in the Department of Pathology at the Rajasthan University of Health Sciences (RUHS), Jaipur, India for a period of one year from February 2020 to January 2021 comparing the efficacy of Apremilast clinically by evaluating plaque psoriasis patients’ by Psoriasis Area and Severity Index (PASI) scores. Patients of all age groups with a clinical diagnosis of psoriasis were subjected to a punch biopsy from an active lesion by a dermatologist. For histopathological examination, biopsy was taken from the lesion before starting treatment with apremilast and after four weeks of apremilast therapy. The subsequent changes in the form of histopathological score and PASI score were analysed and compared with the previous score to study the effect of oral drug apremilast. Results: Total of 100 patients enrolled in the study with the mean age 39.14 years including 59% males and 41% females. Main site of lesion was back, hand and leg. The PASI score at the first visit was 11.28 and at the second visit were 7.27 with the improvement 35.54% which was statistically significant from first visit (p-value&lt;0.001). The histopathological score at the first visit was 15.98 and at the second visit were 10.06 with the improvement 37.1%. Conclusion: Apremilast was found to be a safe and effective treatment for psoriasis patients, and this impact was unaffected by confounding variables.

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.

Recovering object-location memories after sleep deprivation-induced amnesia

It is well established that sleep deprivation after learning impairs hippocampal memory processes and can cause amnesia. It is unknown, however, whether sleep deprivation leads to the loss of information or merely the suboptimal storage of information that is difficult to retrieve. Here, we show that hippocampal object-location memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training, using optogenetic dentate gyrus (DG) memory engram activation or treatment with the clinically approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, the combination of optogenetic DG memory engram activation and roflumilast treatment, 2days following training and sleep deprivation, made the memory more persistently accessible for retrieval even several days later (i.e., without further optogenetic or pharmacological manipulation). Altogether, our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss but instead leads to the suboptimal storage of information that cannot be retrieved without drug treatment or optogenetic stimulation. Furthermore, our findings suggest that object-location memories, consolidated under sleep deprivation conditions and thought to be lost, can be made accessible again several days after the learning and sleep deprivation episode, using the clinically approved PDE4 inhibitor roflumilast.

Crisaborole efficacy in murine models of skin inflammation and Staphylococcus aureus infection.

Phosphodiesterase 4 (PDE4) is highly expressed in keratinocytes and immune cells and promotes pro-inflammatory responses upon activation. The activity of PDE4 has been attributed to various inflammatory conditions, leading to the development and approval of PDE4 inhibitors as host-directed therapeutics in humans. For example, the topical PDE4 inhibitor, crisaborole, is approved for the treatment of mild-to-moderate atopic dermatitis and has shown efficacy in patients with psoriasis. However, the role of crisaborole in regulating the immunopathogenesis of inflammatory skin diseases and infection is not entirely known. Therefore, we evaluated the effects of crisaborole in multiple mouse models, including psoriasis-like dermatitis, AD-like skin inflammation with and without filaggrin mutations, and Staphylococcus aureus skin infection. We discovered that crisaborole dampens myeloid cells and itch in the skin during psoriasis-like dermatitis. Furthermore, crisaborole was effective in reducing skin inflammation in the context of filaggrin deficiency. Importantly, crisaborole reduced S. aureus skin colonization during AD-like skin inflammation. However, crisaborole was not efficacious in treating S. aureus skin infections, even as adjunctive therapy to antibiotics. Taken together, we found that crisaborole reduced itch during psoriasis-like dermatitis and decreased S. aureus skin colonization upon AD-like skin inflammation, which act as additional mechanisms by which crisaborole dampens the immunopathogenesis in mouse models of inflammatory skin diseases. Further examination is warranted to translate these preclinical findings to human disease.