Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice.

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.

Role of Roflumilast Combined with ESHAP Chemotherapy in Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma.

PURPOSE: There are unmet needs associated with the current treatment strategies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) due to the poor treatment outcomes of these strategies. Roflumilast, a selective phosphodiesterase-4 inhibitor used for treating chronic obstructive pulmonary disease, is effective against B-cell malignancy via phosphoinositide 3-kinase (PI3K)-activity suppression. We analyzed the effects of roflumilast combined with ESHAP (etoposide, cisplatin, methylprednisolone, and cytarabine) chemotherapy in experimental and clinical settings. MATERIALS AND METHODS: An in vitro study using lymphoma cell lines and a pilot study on relapsed/refractory DLBCL patients were conducted to investigate the effects and mechanism of the combination of roflumilast and chemotherapy. The complete response (CR), overall response rate (ORR), and 1-year progression-free survival (PFS) were analyzed. RESULTS: We found that roflumilast is efficient when combined with other chemotherapy drugs, especially cytarabine. Synergistic effects between these two drugs influence the translation of mammalian target of rapamycin and myeloid cell leukemia 1, resulting in apoptosis and inhibition of B-cell lymphoma proliferation. In clinical setting, the roflumilast group showed better rates of CR (46.2% vs. 34.6%), ORR (76.9% vs. 53.8%), and 1-year PFS (50.0% vs. 25.9%) compared with the control group, though not statistically significant. The roflumilast group showed a higher incidence of asthenia and gastrointestinal adverse events. However, grade 3 or 4 adverse events were similar in both groups. CONCLUSION: We found that roflumilast, when combined with ESHAP chemotherapy, for relapsed/refractory DLBCL was clinically active and well tolerated. This combined treatment was able to suppress PI3K activity, which is correlated with the degree of clinical response.

Inhaled Phosphodiesterase Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease.

Phosphodiesterase (PDE) 4 inhibitors prevent the metabolism of cyclic adenosine monophosphate, thereby reducing inflammation. Inhaled PDE4 inhibitors aim to restrict systemic drug exposure to enhance the potential for clinical benefits (in the lungs) versus adverse events (systemically). The orally administered PDE4 inhibitor roflumilast reduces exacerbation rates in the subgroup of chronic obstructive pulmonary disease patients with a history of exacerbations and the presence of chronic bronchitis, but can cause PDE4 related adverse effects due to systemic exposure. CHF6001 is an inhaled PDE4 inhibitor, while inhaled ensifentrine is an inhibitor of both PDE3 and PDE4; antagonism of PDE3 facilitates smooth muscle relaxation and hence bronchodilation. These inhaled PDE inhibitors have both reported positive findings from early phase clinical trials, and have been well tolerated. Longer term trials are needed to firmly establish the clinical benefits of these drugs.

The anti-depressant effects of a novel PDE4 inhibitor derived from resveratrol.

CONTEXT: Resveratrol has shown anti-stress and anti-depressant-like abilities involved in inhibiting phosphodiesterase-4 (PDE4) enzyme. However, its application is limited due to its low efficacy, bioavailability and selectivity. OBJECTIVE: This study synthesized a new resveratrol derivative RES003 and evaluated its PDE4 inhibitory and anti-depressant-like activities in vitro and in vivo, respectively. MATERIALS AND METHODS: PDEs inhibitory activities were evaluated by radioactive tracer method. Anti-depressant-like activities of novel resveratrol analogue (RES003) at doses of 2.5, 5.0 and 10 mg/kg was investigated by sugar water consumption and forced swimming tests using male ICR mice under chronic unpredictable stress procedure for 10 days. A total of 84 mice were randomly distributed into seven groups (n = 12). Drugs and vehicle were administered (intra-gastric or intra-peritoneal) once a day from the first to the last day. The molecular mechanisms were identified by western blot. RESULTS: RES003 showed more potent PDE4 inhibitory activity (half maximal inhibitory concentration (IC50), 0.87 µM) and better selectivity than resveratrol (IC50, 18.8 µM). RES003 could significantly increase the consumption of sugar water (p < 0.01) and immobility time (p < 0.01) compared to vehicle-treated stressed groups at doses of 5 and 10 mg/kg. Furthermore, RES003 could significantly increase the levels of cyclic adenosine monophosphate response element binding protein phosphorylation (10 mg/kg, p < 0.05) and brain-derived neurotrophic factor (BDNF) expression (5 and 10 mg/kg, p < 0.05 and 0.01) in mouse brain. DISCUSSION AND CONCLUSIONS: RES003 could ameliorate chronic stress induced depression-like behaviours through inhibition of PDE4 and activation of cAMP-triggered phosphorylation of cAMP response element binding protein/BDNF signalling pathway. Consequently, RES003 is a promising lead compound for the treatment of depression.

Monovalent antibody-conjugated lipid-polymer nanohybrids for active targeting to desmoglein 3 of keratinocytes to attenuate psoriasiform inflammation.

To improve the treatment of psoriasiform inflammation, we developed actively targeted nanocarriers loaded with the phosphodiesterase 4 inhibitor AN2728. Methods: Phospholipid-poly(lactic-co-glycolic acid) nanohybrids were prepared and conjugated with monovalent anti-desmoglein 3 antibody to bind keratinocytes. Results: The actively targeted nanohybrids were 229 nm in mean size with a nearly neutral surface charge. Flow cytometry and confocal microscopy showed a 9-fold increase in keratinocyte uptake of targeted nanohybrids relative to non-targeted nanoparticles. The nanoparticles localized mainly in lysosomes after internalization. AN2728-loaded antibody-conjugated nanocarriers inhibited cytokine/chemokine overexpression in activated keratinocytes without affecting cell viability. The targeted nanohybrids also suppressed neutrophil migration by reducing CXCL1 and CXCL2 release from keratinocytes. Following subcutaneous administration in mice, the nanohybrids distributed to the epidermis and hair follicles. In a psoriasis-like skin mouse model, the actively targeted nanoparticles were superior to free drug and non-targeted nanoparticles in mitigating skin inflammation. Intervention with the targeted nanosystem reduced the epidermal thickness of the psoriasiform lesion from 191 to 42 µm, decreased the Psoriasis Area Severity Index by 74%, restored barrier function, and returned chemokine levels to baseline. Conclusions: Our developed nanosystem was safe and demonstrated efficient targeting properties for the treatment of cutaneous inflammation.

Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies.

PURPOSE: To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. METHODS: Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement. RESULTS: Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7-33-fold higher than the dISF concentrations. CONCLUSIONS: Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

Apremilast and its role in psoriatic arthritis.

Psoriatic arthritis (PsA) is a seronegative inflammatory arthritis often observed in patients with skin psoriasis. Treatment of PsA, especially peripheral PsA, has typically relied on disease-modifying anti-rheumatic agents (DMARDs); however, these agents have limited efficacy and considerable associated toxicity. More recently, monoclonal antibodies (biologic agents) have revolutionized management of immune-mediated diseases; however, these therapies carry a high cost and require parenteral administration. Apremilast, a novel oral DMARD, was approved by the European Union for psoriatic arthritis in 2015. Apremilast inhibits the function of phosphodiesterase-4, a regulator of cyclic adenosine monophosphate, leading to a broad inhibition of proinflammatory mediators and subsequent reduction in tumour necrosis factor-alpha (TNF-α) response. The PALACE and ACTIVE trials, phase III randomized controlled trials for apremilast, showed that apremilast is effective at improving various clinical and patient-reported outcome measures for psoriatic arthritis in both DMARD-naïve and DMARD-experienced PsA patients. Efficacy was limited in patients with previous biologic DMARD failure and the overall efficacy of apremilast appears to be less than biologics agents, though no head-to-head trials exist comparing apremilast to biologic DMARDs. Apremilast is generally well tolerated, with short-lived gastrointestinal side effects being the most commonly reported adverse events. Guidelines suggest a trial of apremilast in patients who have failed traditional oral DMARDs and for whom, biologics are contraindicated. More studies directly comparing apremilast to conventional DMARDs and biologic DMARDs are needed and will be crucial in informing clinical and economic decisions about apremilast role in management of PsA.

Apremilast regulates acute effects of ethanol and other GABAergic drugs via protein kinase A-dependent signaling.

Phosphodiesterase type 4 (PDE4) inhibitors prevent hydrolysis of cyclic adenosine monophosphate and increase protein kinase A (PKA)-mediated phosphorylation. PDE4 inhibitors also regulate responses to ethanol and GABAergic drugs. We investigated mechanisms by which the PDE4 inhibitor, apremilast, regulates acute effects of ethanol and GABAergic drugs in male and female mice. Apremilast prolonged the sedative-hypnotic effects of gaboxadol, zolpidem, and propofol but did not alter etomidate effects, and unexpectedly shortened the sedative-hypnotic effects of diazepam. Apremilast prolonged rotarod ataxia induced by zolpidem, propofol, and loreclezole, shortened recovery from diazepam, but had no effect on ataxia induced by gaboxadol or etomidate. The PKA inhibitor H-89 blocked apremilast's ability to prolong the sedative-hypnotic effects of ethanol, gaboxadol, and propofol and to prolong ethanol- and propofol-induced ataxia. H-89 also blocked apremilast's ability to shorten the sedative-hypnotic and ataxic effects of diazepam. The ß1-specific antagonist, salicylidene salicylhydrazide (SCS), produced faster recovery from ethanol- and diazepam-induced ataxia, but did not alter propofol- or etomidate-induced ataxia. SCS shortened the sedative-hypnotic effects of ethanol and diazepam but not of propofol. In Xenopus oocytes, a phosphomimetic (aspartate) mutation at the PKA phosphorylation site in ß1 subunits decreased the maximal GABA current in receptors containing α1 or α3, but not α2 subunits. In contrast, phosphomimetic mutations at PKA sites in ß3 subunits increased the maximal GABA current in receptors containing α1 or α2, but not α3 subunits. The GABA potency and allosteric modulation by ethanol, propofol, etomidate, zolpidem, flunitrazepam, or diazepam were not altered by these mutations. We propose a model whereby apremilast increases PKA-mediated phosphorylation of ß1-and ß3-containing GABAA receptors and selectively alters acute tolerance to ethanol and GABAergic drugs.

The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer's Disease: A Preclinical Study in APP/PS1 Transgenic Mice.

BACKGROUND: Depression is highly related to Alzheimer's disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis. METHODS: Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays. RESULTS: In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin-eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice. CONCLUSIONS: Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.

Roflumilast attenuates cognitive deficits in estrogen insufficient rats.

Estrogen replacement therapy including specific estrogen receptor alpha (ERα) agonist, 4,4',4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) trisphenol (PPT), improves cognitive function in the females with estrogen insufficiency condition. It is well suggested that the cyclic nucleotides are considered as one of the downstream mediators to ERα receptor activity and they can be hypothesized as a potential target in the management of estrogen insufficiency condition. Roflumilast, a phosphodiesterase-4 inhibitor, increases the level of cyclic adenosine monophosphate (cAMP) in most of the tissues including the brain, and is reported to have procognitive activity in the experimental animals. Hence, the present study evaluated the therapeutic effect of roflumilast with or without PPT in rats with experimentally-induced estrogen insufficiency. Estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Roflumilast (0.3 and 1.0 mg/kg; p.o.) and PPT (333µg/kg; i.p.) attenuated ovariectomy-induced cognitive deficits in the rodents during behavioral tests. Roflumilast and PPT increased the cholinergic function and cAMP level in the rat hippocampus and prefrontal cortex. Further, ovariectomy-induced decrease in the extent of phosphorylation of ERα in both the brain regions was attenuated with the monotherapy of either roflumilast or PPT. Interestingly, the combination of 1.0 mg/kg roflumilast and PPT exhibited better therapeutic effectiveness than their monotherapy. In addition, roflumilast facilitated PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in both the rat brain regions. Hence, it can be assumed that the combination of roflumilast and PPT could be a therapeutic option in the management of estrogen insufficiency-induced disorders.

Apremilast for psoriasis treatment.

Apremilast is a small-molecule inhibitor of phosphodiesterase 4 with an intracellular mechanism of action that increases levels of cyclic adenosine monophosphate (cAMP) indicated for the oral treatment of moderate to severe plaque psoriasis and for the treatment of psoriatic arthritis. Efficacy of apremilast in moderate-to-severe psoriasis has been demonstrated in the pivotal trials, with a 30% PASI-75 response rate at week 16, an efficacy that was maintained through week 52. Apremilast also achieved significant responses in disease involving specific sites, such as palmoplantar, nail and scalp psoriasis, improved patient quality of life, and achieved rapid improvements in pruritus. The findings of some of the real world series indicate that the PASI-75 response may be higher in patients with a lower baseline PASI than that observed in the pivotal trials, enhancing the importance of using the absolute PASI score as a marker of therapeutic success rather than a relative PASI index in this setting. Apremilast has demonstrated good safety and tolerability in both clinical trials and clinical practice series. The most frequent adverse effects were diarrhea (17.3%), nausea (15.7%), upper respiratory tract infections (15.5%), nasopharyngitis (14.4%), tension headache (9.0%) and headache (6.3%). The rate of adverse events recorded in the clinical practice series has been lower compared to the clinical trials.

Roflumilast, a phosphodiesterase-4 inhibitor, improves hyperoxia-induced lung injury via anti-inflammation.

Roflumilast is an inhibitor of phosphodiesterase-4 (PDE4) and can suppress the hydrolysis of cAMP in inflammatory cells, conferring anti-inflammatory effects. This study aimed to investigate the protective effects of roflumilast on hyperoxia-induced acute lung injury (HALI) in a rat model. Male Sprague-Dawley rats were randomly assigned into: control group; HALI group; 2.5 mg/kg roflumilast group; and 5 mg/kg roflumilast group. Rats were pressurized to 250 kPa with pure oxygen to induce lung injury. In the roflumilast groups, rats were orally administered with roflumilast at 2.5 or 5 mg/kg once before hyperoxia exposure and once daily for two days after exposure. Rats were sacrificed 72 hours after hyperoxia exposure. The lung tissues were collected for the detection of lung water content, inflammatory cytokines and NF-κB/p-NF-κB protein expression, and the bronchoalveolar lavage fluid was harvested for the measurement of protein concentration and lactate dehydrogenase activity. Results showed roflumilast at different doses could significantly reduce lung edema, improve lung pathology and reduce the expression of inflammatory cytokines in the lung. The protective effects seemed to be related to the dose of roflumilast. Our study indicates roflumilast has the potential as a medication for the treatment of HALI.

Persistence of the extinction of fear memory requires late-phase cAMP/PKA signaling in the infralimbic cortex.

Fear extinction is a form of new learning that inhibits expression of the original fear memory without erasing the conditioned stimulus-unconditioned stimulus association. Much is known about the mechanisms that underlie the acquisition of extinction, but the way in which fear extinction is maintained has been scarcely explored. Evidence suggests that protein kinase A (PKA) in the frontal cortex might be related to the persistence of extinction. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP). The present study evaluated the effect of the selective PDE4 inhibitor roflumilast (ROF; 0.01, 0.03, and 0.1 mg/kg given i.p.) on acquisition and consolidation of the extinction of fear memory in male Wistar rats in a contextual fear conditioning paradigm. When administered before acquisition, 0.1 mg/kg ROF disrupted short-term (1 day) extinction recall. In contrast, 0.03 mg/kg ROF administration in the late consolidation phase (3 h after extinction learning) but not in the early phase immediately after learning improved long-term extinction recall at 11 days, suggesting potentiation of the persistence of extinction. This effect of ROF requires the first (day 1) exposure to the context. A similar effect was observed when 9 ng ROF or 30 µM 8-bromoadenosine 3',5'-cAMP (PKA activator) was directly infused in the infralimbic cortex (IL), a brain region necessary for memory extinction. The PKA activity-dependent ROF-induced effect in the IL was correlated with an increase in its brain-derived neurotrophic factor (BDNF) protein expression, while blockade of PKA with 10 µM H89 in the IL abolished the ROF-induced increase in BDNF expression and prevented the effect of ROF on extinction recall. These effects were not associated with changes in anxiety-like behavior or general exploratory behavior. Altogether, these findings suggest that cAMP-PKA activity in the IL during the late consolidation phase after extinction learning underlies the persistence of extinction.

Phosphodiesterase-4 inhibitors for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea, and a reduction in lung function, quality of life, and life expectancy. Apart from smoking cessation, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020. OBJECTIVES: To evaluate the efficacy and safety of oral PDE4 inhibitors for management of stable COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at web-based clinical trials registers. SELECTION CRITERIA: We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations). MAIN RESULTS: We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years. We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials. Lung function Treatment with a PDE4 inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV1) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence). Quality of life Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence). Incidence of exacerbations Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found. Adverse events More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE4 inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms. Participants treated with PDE4 inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups. Mortality No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials. AUTHORS' CONCLUSIONS: For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review. PDE4 inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg. The findings of this review provide cautious support for the use of PDE4 inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation, or mortality in COPD.

The use of combination biological or small molecule therapy in inflammatory bowel disease: A retrospective cohort study.

OBJECTIVE: There are limited data on using more than one biologic or small molecule drug combined to treat patients with inflammatory bowel disease. The aim of our study was to determine the effectiveness and safety of combination biologic use in inflammatory bowel disease. METHODS: We identified patients with Crohn's disease or ulcerative colitis who received treatment with a combination of two biologics or a biologic and a small molecule drug from 2015 to 2019 for persistent disease activity or concomitant rheumatological or dermatological disease. The primary end-point was effectiveness, based on improvements in inflammatory markers, clinical, and endoscopic remission. The secondary end-point was safety. RESULTS: Of the 50 patients treated with combination therapy there were significantly more patients in clinical and endoscopic remission at follow-up compared to baseline (50% vs 14%, P = 0.0018, delta 36%, 95% confidence interval [CI] 0.13-0.53; and 34% vs 6%, P = 0.0039, delta 28%, 95% CI 0.09-0.47), respectively. Median erythrocyte sedimentation rate (17 mm/h vs 13 mm/h, P = 0.002) and C-reactive protein (5.00 mg/dL vs 2.35 mg/dL, P = 0.002) also decreased posttreatment. There were eight serious adverse events and no deaths CONCLUSIONS: Combination biologic therapy appears to be an effective option for patients with refractory inflammatory bowel disease or concomitant autoimmune disease that is inadequately controlled by biologic monotherapy. There was an increased risk of serious infection compared with biologic monotherapy; however, this risk might be minimized by discontinuing immunomodulators prior to initiating combination therapy. Large prospective studies are needed to confirm these findings.

Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis.

BACKGROUND: Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. METHODS: Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 µg and placebo twice daily (BID) in a randomised crossover study. RESULTS: CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 µg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. CONCLUSIONS: Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. TRIAL REGISTRATION: ClinicalTrial.gov, EudraCT, 2015-005550-35. Registered 15 July 2016.

A Mechanistic Rationale for PDE-4 Inhibitors to Treat Residual Cognitive Deficits in Acquired Brain Injury.

Patients with acquired brain injury (ABI) suffer from cognitive deficits that interfere significantly with their daily lives. These deficits are long-lasting and no treatment options are available. A better understanding of the mechanistic basis for these cognitive deficits is needed to develop novel treatments. Intracellular cyclic adenosine monophosphate (cAMP) levels are decreased in ABI. Herein, we focus on augmentation of cAMP by PDE4 inhibitors and the potentially synergistic mechanisms in traumatic brain injury. A major acute pathophysiological event in ABI is the breakdown of the blood-brain-barrier (BBB). Intracellular cAMP pathways are involved in the subsequent emergence of edema, inflammation and hyperexcitability. We propose that PDE4 inhibitors such as roflumilast can improve cognition by modulation of the activity in the cAMPPhosphokinase A-Ras-related C3 botulinum toxin substrate (RAC1) inflammation pathway. In addition, PDE4 inhibitors can also directly enhance network plasticity and attenuate degenerative processes and cognitive dysfunction by increasing activity of the canonical cAMP/phosphokinase- A/cAMP Responsive Element Binding protein (cAMP/PKA/CREB) plasticity pathway. Doublecourtin and microtubule-associated protein 2 are generated following activation of the cAMP/PKA/CREB pathway and are decreased or even absent after injury. Both proteins are involved in neuronal plasticity and may consist of viable markers to track these processes. It is concluded that PDE4 inhibitors may consist of a novel class of drugs for the treatment of residual symptoms in ABI attenuating the pathophysiological consequences of a BBB breakdown by their anti-inflammatory actions via the cAMP/PKA/RAC1 pathway and by increasing synaptic plasticity via the cAMP/PKA/CREB pathway. Roflumilast improves cognition in young and elderly humans and would be an excellent candidate for a proof of concept study in ABI patients.

Detrimental Effects of an Inhaled Phosphodiesterase-4 Inhibitor on Lung Inflammation in Ventilated Preterm Lambs Exposed to Chorioamnionitis Are Dose Dependent.

Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 µg/kg) or low dose (1 µg/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.