Advances in clinical and safety studies of phosphodiesterase 4 inhibitors / 药学学报

Phosphodiesterase 4 (PDE4) is an important member of the phosphodiesterase enzyme family that specifically catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP), activates the downstream phosphorylation cascade pathway by altering cAMP concentration, and is strongly associated with multiple diseases. Inhibition of PDE4 is clinically investigated as a therapeutic strategy in a broad range of disease areas, including respiratory system diseases, autoimmune disorders, central nervous system diseases, and dermatological conditions. However, the incidence of adverse reactions such as nausea and vomiting is relatively high in the marketed PDE4 inhibitors, which has stalled their clinical development. In this review, we provide an overview of the clinical progression and safety issues of the marketed PDE4 inhibitors. We also review the main causes underlying PDE4-mediated adverse effects by combining the structural analysis of the PDE4 protein, the mechanism of action of PDE4 inhibitors, and the related side effect mechanism research, aiming to provide a reference for the development of safe and effective PDE4 inhibitors.

The possibility of phosphodiesterase 4 inhibitors as drug therapy for idiopathic pulmonary fibrosis / 中国临床药理学与治疗学

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and typical chronic fibrotic lung disease. In recent years, significant progress has been made in the pathophysiology, clinical diagnosis and treatment of IPF. However, to date, there is still no cure for IPF. The second messenger cyclic adenosine monophosphate (cAMP) inhibits fibroblast proliferation or differentiation into myofibroblasts during the development of IPF. Phosphodiesterase 4 (PDE4) is a major camp-degrading enzyme in lung fibroblasts, which is up-regulated during the progression of fibrosis. PDE4 inhibitors have anti-fibrosis effects in vivo and in vitro in IPF models. In addition, PDE4 is widely involved in inflammatory processes, which are also active in the pathogenesis of IPF. Thus, PDE4 inhibition is a potential therapeutic approach for IPF. This article reviews the pathogenesis of IPF and the physiological function of PDE subtype 4 inhibitors in the treatment of IPF.

PDE4 inhibition protects against rotenone-induced neurotoxicity through activation of the AMPK/Sirt1 pathway / 中国药理学与毒理学杂志

OBJECTIVE We have previously shown that inhibition of phosphodiesterase-4(PDE4)protects against neuronal damage in models of Parkinson's dis-ease(PD).However,the mechanisms have not yet been completely revealed.Here we aimed to elucidate the pharmacological effects and mechanisms of action of rof-lupram(ROF),an novel PDE4 inhibitor,in experimen-tal models of PD.METHODS The survival rate,apopto-sis rate and toxicity level of SH-SY5Y cells were deter-mined by MTT,flow cytometry and lactate dehydroge-nase detection kit.At the same time,LYT staining was used to detect the changes of lysosome fluorescence intensity:Western blotting was used to detect the changes of lysosome associated proteins,Sirtuin1 and α-Syn;NAD/NADH assay kit was used to determine the change of NAD content.To explore whether SIRT1 inhibitor(EX527)and lysosomal inhibitor could block the effect of ROF.In addition,ROT was used to stimulate C57BL/6J mice to construct a mouse model of PD to verify the effect and mechanism of ROF.The changes of motor function were evaluated by behavioral experiments(pole climb-ing,bar rotating and balance beam experiments).Super-oxide dismutase kit and Western blotting were used to detect the changes of SOD activity and expression of related proteins in substantia nigra.RESULTS We showed that pretreatment with ROF significantly attenu-ated cell apoptosis in ROT-treated SH-SY5Y cells.Fur-thermore,ROF significantly enhanced the lysosomal function,as evidenced by the increased levels of mature cathepsin D(CTSD)and lysosomal-associated mem-brane protein 1(LAMP1)through increasing NAD+/NADH and the expression of sirtuin 1(SIRT1).Pretreatment with an SIRT1 inhibitor selisistat(SELI,10 μ mol·L-1)attenuated the neuroprotection of ROF,and ROF-increased expression levels of LAMP1 and mature CTSD.Moreover,inhibition of CTSD by pepstatin A(20 μmol·L-1)attenuated the protective effects of ROF.In vivo study was conducted in mice exposed to ROT(10 mg·kg-1·d-1,ig)for six weeks;then,ROT-treated mice received ROF(0.5,1 and 2 mg·kg-1·d-1,ig)for four weeks.ROF significantly ameliorated motor deficits,which was accompanied by increased expression levels of tyro-sine hydroxylase,SIRT1,mature CTSD,and LAMP1 in the substantia nigra pars compacta.CONCLUSION Taken together,these results demonstrate that ROF exerts a neuroprotective action in PD models.The mech-anisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

Inhibition of phosphodiesterase 4 attenuates aquapo-rin 4 expression and astrocyte swelling following cerebral ischemia/reperfusion injury / 中国药理学与毒理学杂志

OBJECTIVE To investigate the role of PDE4 inhibition in astrocyte swelling caused by cerebral ischemic/reperfusion(I/R)injury and the molecular mech-anisms.METHODS SD rats were subjected to 2 h of focal cerebral ischemia induced by middle cerebral artery occlusion/reperfusion(MCAO/R).Roflumilast(Roflu)was intraperitoneally injected 2 h after MCAO.At 24 h after reperfusion,a high-resolution MRI was performed and using the wet-dry weighting method to measure the water content.The oxygen-glucose deprivation/reoxygenation(OGD/R)model was established in primary astrocytes for 2 h.After 24 h of reoxygenation,CellMask? plasma membrane stain was used to label the plasma membrane to calculate cell volume.The protein expressions insides astrocytes and penumbra were detected by Western blot-ting.To investigate the role of Akt/FoxO3a in mediating the effect of Roflu on the expression of AQP4.The astro-cytes were treated with an Akt inhibitor MK2206 before treatment with Roflu and the activation of Akt,the expres-sion of AQP4 and cell volume were determined as described above.In addition,an IL-1β-stimulated cell model was established in astrocytes,the expression of AQP4 and the activation of Akt/FoxO3a were detected by Western blotting.The change of AQP4 expression inside astrocytes and penumbra were visualized by immunofluo-rescence staining.RESULTS Roflu reduced MCAO/R-induced water contents,the expression of AQP4 and the phsophorylation of Akt and FoxO3a in the brains of MCAO/R rats.Inhibition of PDE4 decreased the cell volume and the expression of AQP4 in primary astro-cytes subjected to OGD/R.PDE4 inhibition activated Akt/FoxO3a,and inhibition of Akt by MK2206 blocked the protective effect of Roflu against OGD/R induced astro-cyte swelling.PDE4B knocking down reduced the expres-sion of AQP4,while PDE4B overexpression reversed the effect of PDE4B siRNA in astrocytes.Roflu exert-ed similar protective effect in IL-1β-cultured astrocytes,and importantly overexpression of FoxO3a remarkably increased the expression of AQP4 in IL-1β-stimulated astrocytes.CONCLUSION Our findings indicate that PDE4 inhibition limits I/R-induced brain edema and astro-cyte swelling via the Akt/FoxO3a/AQP4 pathway.PDE4 inhibition is a promising strategy for the treatment of brain edema after I/R injury.

Small-molecule targeted agents: new choices for the treatment of psoriasis / 中华皮肤科杂志

With the rapid development of immunology and molecular biology in recent years, great progress has been made in the research on psoriatic pathogenesis, as well as in therapeutic strategies targeting key molecules in the pathogenesis. In addition to biologics, small-molecule targeted agents for psoriasis have also received increasing attention, especially agents targeting phosphodiesterase 4, Janus kinase, and tyrosine kinase 2, etc. An increasing number of small-molecule drug candidates have shown favorable efficacy in clinical studies, and some of them have been approved for clinical application and play a unique role in the treatment of psoriasis.

Improved synthetic process of apremilast / 中国药科大学学报

@#To optimize the process of hydrogenation reduction in the synthesis of apremilast (APST), 3-nitrophthalic anhydride (4) and (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethanamine-(S)-2-acetamido-4-methylpentanoate (7) were used as starting materials to synthesize (S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4-nitroisoindoline-1,3-dione (8) by amination.Then compound 8 was reduced to (S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl) isoindoline-1,3-dione (9) with ammonium formate as hydrogen source and palladium hydroxide as catalyst.Finally, apremilast was obtained by the acetylation reaction with acetic anhydride.The structure of the products were verified by optical rotation, 1H NMR, 13C NMR, MS and elemental analysis.And the total yield of three steps was increased to 67.0%.The improved reduction process can avoid the special reaction of hydrogenation and pressurization, and reduce the safety risk and production costs with high commercial value.

Effect of a novel phosphodiesterase 4 inhibitor ZL-n-91 on proliferation, cell cycle and apoptosis of human glioma U87 cells / 中国药理学通报

Aim: To investigate the effect of ZL-n-91, a novel phosphodiesterase 4 (PDE4) inhibitor, on proliferation, cell cycle and apoptosis of human glioma U87 cells. Methods In vitro the different concentrations of ZL-n-91 were set up to evaluate the proliferation of U87 cells by CCK-8 assay. The cell apoptosis and cell cycle distribution were examined by flow cytometry. The expression of CDK2, CDK4, cyclin Dl and apoptosis-related protein Bax and Bcl-2 proteins were detected by Western blot. A subcutaneous transplanted tumor model of U87 in nude mice was established for the in vivo experiment using a dosage of 5 mg · kg

Advances in studies of cognition enhancement by phosphodiesterase-4 inhibitor roflumilast / 中国药理学与毒理学杂志

Roflumilast, one of the second generation of phosphodiesterase-4 inhibitors, has been approved for the treatment of severe chronic obstructive pulmonary disease by the United States Food and Drug Administration since 2011. It has shown a variety of beneficial effects, including anti-inflammatory, anti-tumor, anti-alcoholic, and anti-diabetic profiles. Recent studies have demonstrated that roflumilast, like other PDE4 inhibitors, has neuroprotective and precognitive properties. It also has been shown to produce promising cognitive improvement in animals and humans. Therefore, roflumilast can be a potential drug for treatment of various degenerative diseases of the central nervous system, including Alzheimer disease and Parkinson disease. The major mechanism is the activation of cyclic AMP signaling and its downstream targeting molecules. All these are discussed and summarized in the current review.

Relationship between PDE4C gene methylation in peripheral blood leukocytes, interaction of environmental factors and pathogenesis of breast cancer / 实用肿瘤学杂志

Objective The objective of this study was to investigate the relationship between the methylation of phosphodies-terase 4C(PDE4C)gene in peripheral blood leukocytes,and its interaction with environmental factors and the pathogenesis of breast cancer. Methods A case-control study was conducted to select 402 cases of breast cancer and 470 cancer-free controls from Octo-ber 2010 to December 2014. The specific DNA methylation-modified quantitative PCR method was used to detect the methylation of PDE4C gene. The use of crossover analysis and multivariate logistic regression was used to analyze the relationship between the level of gene methylation and its interaction with environmental factors and the pathogenesis of breast cancer. Results PDE4C methylation was not found to be significantly associated with the onset of breast cancer. High-frequency/high-intake of whole grains,vegetables, onion-based plants,poultry,milk,and regular exercise could reduce the risk of breast cancer;high-frequency/high-intake of pork, irregular menstrual cycle,and a high psychological stress index could increase the risk of breast cancer. PDE4C hypermethylation had a significant combining effect with edible onion-producing plants greater than 3 times/week,with an OR of 0. 373(95% CI:0. 208~0. 668,P=0. 001). Conclusion Hypermethylation of PDE4C is not an independent risk factor for breast cancer,and its combination with environmental factors affects the risk of breast cancer.

Research progress in phosphodiesterase 4 inhibitors in treatment of inflammatory bowel diseases / 中国药理学与毒理学杂志

Inflammatory bowel disease (IBD) is a chronic idiopathic intestinal inflammatory disease that affects all parts of the intestine. Phosphodiesterase 4 (PDE4) is a key enzyme that mediates inflammation, and its inhibitor is useful in many inflammatory diseases. In this review, we summarize the research progress in PDE 4 inhibitors in the treatment of IBD in preclinical studies, such as rolipram, mesopram, roflumilast, tetomilast and apremilast, as well as PDE4 inhibitors in clinical studies, such as apremilast and tetomilast. All PDE4 inhibitors have shown therapeutic effect on IBD, and the mechanisms involve the inhibition of cytokine release, such as tumor necrosis factor-α, lnterleukin-8, suppression thr inflammation in colon, enhancement of the barrier of the intensine, and reduction of the collagen deposition. As a novel drug for IBD therapy, PDE4 inhibitor apremilast might have therapeutic benefit in IBD, and roflumilast, which is yet to enter clinical trial, may have a good therapeutic prospect.

Pharmacotherapy for chronic obstructive pulmonary disease

The goals of management of stable chronic obstructive pulmonary disease (COPD) are to reduce both current symptoms and future risks with minimal side effects from treatment. Identification and reduction of exposure to risk factors are important in the treatment and prevention of COPD. Appropriate pharmacologic therapy can reduce symptoms and exacerbations, and improve health status and exercise tolerance. To date, none of the existing medications for COPD has been shown to modify disease progression or reduce mortality. The classes of medication are bronchodilators including beta2-agonist, anticholinergics and anti-inflammatory drug including inhaled corticosteroid and phosphodiesterase-4 inhibitor such as roflumilast. Each treatment regimen needs to be individualized as the relationship between severity of symptoms, airflow limitation and severity of exacerbation can differ between patients.

Inhibition of the crude extract of Eriobotryae Folium collected from different districts towards phosphodiesterase-4 / 药物评价研究

Objective To investigate the inhibition of Eriobotryae Folium from twenty different districts towards phosphodiesterase 4(PDF4) in vitro.Methods The Eriobotryae Folium were extracted with 95％ ethanol reflux and the inhibition rates against PDE4D2 were carried out by liquid scintillation counting method.Results All the samples exhibited inhibitory activities towards PDE4 at 5 mg/L.Among them,nine samples were of the inhibition rate less than 80％,eleven samples were of more than 80％ inhibition and eight samples were of more than 90％ inhibition.Conclusion The Eriobotryae Folium shows significantly different inhibitory activities towards PED4.

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K⁺-induced tonic, and Ca²⁺-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-1β, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced TNFα and IL-1β uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.

Effect of Electroacupuncture on Expression of Phosphodiesterase 4 and Subtypes in Hippocampus in Rats with Chronic Stress Depression / 中国康复理论与实践

@#Objective To explore the biological mechanisms of electroacupuncture (EA) for depression. Methods Forty male adult Sprague-Dawley rats were randomly divided into control group (n=8), model group (n=8), EA group (n=8) and fluoxetine group (n=8). Depressive models were established with lonely raising and chronic unpredictable mild stress. They were tested with Open-field Test, and the expression of phosphodiesterase 4 (PDE4)A and PDE4D in hippocampus was detected with RT-PCR. Results The cross and rear scores were significantly lower in the model group than in the control group (P<0.001), while it increased in the EA group and the fluoxetine group (P<0.001). Compared with the model group, the expression of PDE4A and PDE4D decreased in the EA group (P<0.001). Conclusion Electroacupuncture may relieve depression through inhibiting the expression of PDE4A and PDE4D.

Pentoxifylline Alleviates Perinatal Hypoxic-Ischemia-Induced Short-term Memory Impairment by Suppressing Apoptosis in the Hippocampus of Rat Pups / 대한배뇨장애요실금학회지

PURPOSE: Perinatal hypoxic-ischemic brain damage is a major cause of acute mortality and chronic neurologic morbidity in infants and children. We investigated the effects of pentoxifylline, a methylxanthine derivative and type-4 phosphodiesterase inhibitor, on short-term memory and apoptotic neuronal cell death in the hippocampus following perinatal hypoxic-ischemia in newborn rats. METHODS: We used a step-down avoidance task to evaluate short-term memory and 3ʹ-5ʹ-cyclic adenosine monophosphate (cAMP) assay to detect cAMP levels. We evaluated apoptosis using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for evidence of DNA fragmentation, immunohistochemistry for caspase-3 levels, and western blot for Bcl-2 and Bax. RESULTS: Perinatal hypoxic-ischemic injury increased apoptotic cell death in the hippocampus, resulting in impaired short-term memory with decreased cAMP levels. Pentoxifylline treatment improved short-term memory by suppressing apoptotic cell death in the hippocampus with elevated cAMP levels. CONCLUSIONS: Pentoxifylline ameliorated perinatal hypoxic-ischemia in rat pups. This alleviating effect could be ascribed to the inhibition apoptosis due to increased cAMP production by pentoxifylline.

Roflumilast therapy in COPD − Update and Trials

Chronic Obstructive Pulmonary Disease (COPD) represents an important public health challenge that is both preventable and treatable. Pharmacological treatment regimen for COPD needs to be patient specific. Hence  management of  COPD    should  be  based  on  strategy  considering  both  disease  impact  and  future  risk  of  disease  progression ( especially of  exacerbation ). Risk of exacerbations significantly increases in GOLD 3 and GOLD 4 COPD. Exacerbations  increase  the   decline in  lung function , deteorriation  in  health  status  and  risk   of  death. Roflumilast   is   a   phosphodiesterase-4 (PDE4) inhibitor. It reduces   risk of moderate to severe   exacerbations in patients   of   GOLD 3   & GOLD 4   COPD. It  has  no  direct  bronchodilator  activity, although it  has  been  shown  to  improve  FEV1  in  patients treated  with   inhaled  long-acting  bronchodilator. Adverse  effects  may occur  early during the  treatment  but  these  are  reversible  and  diminish  overtime  with  continued  treatment .

Novel phosphodiesterase 4 inhibitor chlorbipram enhanced memory deficits in AD rats and its mechanisms involved / 中国药学杂志

OBJECTIVE: To investigate the effect and mechanism of novel phosphodiesterase 4 inhibitor chlorbipram on learning and memory disorders in Alzheimer's disease animal model. METHODS: The rat model of learning and memory deficits with AD was used by bilateral microinjection of Aβ25-35 into the CA1 region of the hippocampus. Then the rats were randomly divided into six groups; sham-operated group, Aβ25-35 microinjected (model group), chlorbipram treatment(0.05 and 0.15 mg · kg-1) group, rolipram-treated (0.05 mg · kg-1) and donepezil (1.0 mg · kg-1) group. The effect of chlorbipram on memory behavioral performance were evaluated with Morris water maze and step-through passive avoidance test, and the open field test was performed to determine the animal locomotor activity. After the last behavioral performance test, the hippocampus were dissected for further molecular analysis. The protein level of BDNF and the phosphorylation of PKA and CREB were analyzed by Western blotting; the mRNA level of BDNF in the hippocampus was detected by real-time PCR. RESULTS: Microinfusion with Aβ25-35 produced impairment of spatial memory in behavioral tests, which was reversed by either PDE4 inhibitor or donepezil administration. Chlorbipram, rolipram and donepezil increased the number of crossing and percent of time in the target quadrant in the Morris water maze probe trial. In the step-through passive avoidance test, the 24 h latency was significantly decreased in rats treated with either chlorbipram or positive control drugs, while no significant difference were shown in total locomotor activity among the groups. Western blot analyses showed that Aβ25-35-microinjection decreased the phosphorylation of PKA and CREB and inhibited the protein expression of BDNF in the hippocampus. Chlorbipram, rolipram and donepezil reversed the reduction of the phosphorylated PKA and CREB induced by Aβ25-35. Moreover, these drugs also enhanced both the mRNA and protein levels of BDNF. CONCLUSION: Chlorbipram produces a significant improvement of learning and memory in AD animal, and this effect is due to the mediation of cAMP/PKA/CREB/BDNF signal pathway.

Specific Expression of Aplysia Phosphodiesterase 4 in Bag Cells Revealed by in situ Hybridization Analysis

Phosphodiesterases (PDEs) play a key role in the regulation of cyclic adenosine monophosphate (cAMP), which in turn mediates various cellular functions including learning and memory. We previously cloned and characterized three PDE4 isoforms (ApPDE4) from Aplysia kurodai. Using reverse transcription polymerase chain reaction (RT-PCR), we found that ApPDE4 isoforms are primarily expressed in the central nervous system. However, the detailed distribution of ApPDE4 mRNA in Aplysia individual ganglions was not evident. In this study, to determine the distribution of ApPDE4 mRNAs in Aplysia ganglions, we performed in situ hybridization (ISH) using a probe targeting ApPDE4, including the PDE catalytic domain. Interestingly, we found the strongest ISH-positive signals in the symmetrical bag cell clusters of the abdominal ganglion. The R2, R14, L7, L2 and L11 neurons in the abdominal ganglion, LP1 neuron in pleural ganglion, and metacerebral (MCC) neurons were ISH-positive. Mechanosensory neurons of the sensory cluster were also stained on the ventral aspect of the right and left pleural ganglia. Taken together, we found the detailed distribution of ApPDE4 mRNA in Aplysia ganglion and support their roles in serotonin (5-HT)-induced synaptic facilitation of Aplysia mechanosensory neurons.

Effect of a Dose-Escalation Regimen for Improving Adherence to Roflumilast in Patients with Chronic Obstructive Pulmonary Disease / 결핵및호흡기질환

BACKGROUND: The adverse effects of the phosphodiesterase-4 inhibitor roflumilast, appear to be more frequent in clinical practice than what was observed in chronic obstructive pulmonary disease (COPD) clinical trials. Thus, we designed this study to determine whether adverse effects could be reduced by starting roflumilast at half the dose, and then increasing a few weeks later to 500 microg daily. METHODS: We retrospectively investigated 85 patients with COPD who had taken either 500 microg roflumilast, or a starting dose of 250 microg and then increased to 500 microg. We analyzed all adverse events and assessed differences between patients who continued taking the drug after dose escalation and those who had stopped. RESULTS: Adverse events were reported by 22 of the 85 patients (25.9%). The most common adverse event was diarrhea (10.6%). Of the 52 patients who had increased from a starting dose of 250 microg roflumilast to 500 microg, 43 (82.7%) successfully maintained the 500 microg roflumilast dose. No difference in factors likely to affect the risk of adverse effects, was detected between the dose-escalated and the discontinued groups. Of the 26 patients who started with the 500 microg roflumilast regimen, seven (26.9%) discontinued because of adverse effects. There was no statistically significant difference in discontinuation rate between the dose-escalated and the control groups (p=0.22). CONCLUSION: Escalating the roflumilast dose may reduce treatment-related adverse effects and improve tolerance to the full dose. This study suggests that the dose-escalated regimen reduced the rate of discontinuation. However, longer-term and larger-scale studies are needed to support the full benefit of a dose escalation strategy.

A potential novel antidepressant target based on phosphodiesterase 4: Research advances / 国际药学研究杂志

Depression is a prevalent and life-threatening mental disorder. Its mechanisms remain unclear. It was found that depressive disorders are closely related to monoamine neurotransmitters absence, down-regulation of hypothalamic-pituitary-adrenal (HPA) axis and neurotrophic factors and dendritic complexity in brain. Phosphodiesterase 4 (PDE4) inhibitor rolipram produce antidepressant and memory-enhancing effects via intracellular cAMP signaling. However, its clinical utility is limited by the major side effect of emesis, which appears to be PDE isoform-specific. Therefore, this research is to investigate whether long-form PDED variants mediate antidepressant and cognition-enhancing effects, without causing emesis. This review summaries the PDE molecular structure, distribution and its antidepressant function, so as to illustrate the advantage of selective subtype inhibitor in the treatment of depression.