Research progress of phosphodiesterase inhibitors in inflammatory bowel disease treatment / 浙江大学学报·医学版

Inflammatory bowel disease is a recurrent chronic intestinal inflammatory disease with unknown etiology and no effective treatment. Phosphodiesterase (PDE) regulates a variety of physiological and pathophysiological processes by mediating the hydrolysis of intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease.

A physiologically-based pharmacokinetic model adequately predicted the human pharmacokinetic profiles of ZSP1601, a novel pan-phosphodiesterase inhibitor / 药学学报

ZSP1601, a novel pan-phosphodiesterase inhibitor is in development for the treatment of nonalcoholic steatohepatitis. A physiologically-based pharmacokinetic (PBPK) model was developed to predict the pharmacokinetics of ZSP1601 in human. The PBPK model following intravenous and oral dose of ZSP1601 in rats and dogs was firstly built using preclinical in vitro and in vivo data. The PBPK model in human was then built based on models in animal. The in vitro-in vivo extrapolation (IVIVE) method and some allometric scaling methods were used to predict the clearance in human, respectively. The PBPK models using IVIVE and allometry of unbound CL plus the rule of exponents methods predicted the pharmacokinetics of ZSP1601 in healthy Chinese subjects successfully. The predicted parameters Cmax and AUC following single oral dose administration were within 0.5-2 folds of the observed data. The model was optimized and the final model was used to predict the pharmacokinetics of ZSP1601 in North European Caucasian, Geriatrics, Obese and Morbidly Obese, respectively. Animal studies were approved by the Animal Management and Use Committee of Suzhou AppTec Inc., and the approved No. is SZ20140916.

Advances in risk factors for non-arteritic anterior ischemic optic neuropathy / 国际眼科杂志(Guoji Yanke Zazhi)

@#Non-arteritic anterior ischemic optic neuropathy is an acute optic nerve disease that seriously impairs the visual function of middle-aged and elderly people. It is generally believed to be caused by ischemia of the short ciliary artery supplying the optic disc plate area and the posterior area of the sieve plate. The disease is associated with a variety of factors, such as diabetes that affects the systemic microcirculation, hypertension and respiratory sleep apnea syndrome that has been widely studied recently, and so on. Moreover, it was also found that genetic susceptibility, drugs, surgery and ocular diseases were all associated with the occurrence and development of the NAION. In this paper, the latest researches on these factors are reviewed.

Adequacy of phosphodiesterase inhibitor in prevention and treatment of LPS induced organ failure in BALB/c mice

Background: Even though with immense improvement and extensive understanding of pathophysiology of sepsis induced organ failure and affected population, it continues to put hundreds of people worldwide to eternal sleep due to lack of targeted therapy. Newer treatment modalities is the dire need of time. The present study was aimed to ascertain the adequacy of phosphodiesterases inhibitor - pentoxifylline (75mg/kg i.p) in endotoxin/LPS induced hepatotoxicity in BALB/c mice.Methods: The number of animals in each group was six. Endotoxin/lipopolysaccharides induced hepatotoxicity was reproduced in mice by giving lipopolysaccharide of serotype E. coli intraperitoneally. To ascertain the Preventive role, pentoxifylline was administered forehand LPS injection whereas therapeutic potential adjuged via post LPS delivering. The extent of liver damage was evaluated through serum alanine aminotransferases (ALT) and aspartate aminotransferase (AST) estimation along with histopathological examination of liver tissue.Results: Results set forth that serum ALT, AST levels and histological alteration abated considerably (p ?0.05) both in animals subjected to pentoxifylline pre and post-treatment.Conclusions: Pentoxifylline set up promising results in endotoxin induced hepatotoxicity and can be used therapeutic adjuncts to conventional treatment strategies in sepsis induced liver failure.

Effect of Ro20-1724 on ketamine-induced apoptosis in hippocampal neurons of neonatal rats / 中华麻醉学杂志

Objective To valuate the effect of Ro20-1724 on ketamine-induced apoptosis in hippocampal neurons of neonatal rats.Methods Hippocampal neurons from newborn Sprague-Dawley rats were obtained and cultured in vitro.The primary hippocampal neurons were randomly divided into 4 groups (n =24 each) using a random number table:control group (group C),ketamine group (group K),solvent control group (group E),and Ro20-1724 group (R group).The neurons were incubated for 72 h in the normal culture medium in group C.The neurons were incubated for 72 h in the culture medium containing ketamine 150 μmol/L in group K.In E and R groups,after the neurons were incubated for 30 min in the culture medium containing ketamine 150 μmol/L,the culture medium was then replaced,0.01％ ethanol (final concentration) and 1 × 10-3 μmol/L Ro20-1724 (final concentration) were added to the culture medium,respectively,and the neurons were then incubated for 72 h.After 72 h incubation,the cell viability was detected by MTT assay,the cell apoptosis was detected by flow cytometry,the expression of Bcl-2 mRNA and Bax mRNA was determined by RT-PCR,and synaptophysin Ⅰ expression was detected by Western blot.The apoptosis rate was calculated.Results Compared with group C,the survival rate was significantly decreased,the apoptosis rate was increased,the expression of Bcl-2 mRNA and synaptophysin Ⅰ was down-regnlated,and Bax mRNA expression was up-regulated in K and E groups (P ＜ 0.05 or 0.01).Compared with group K,the survival rate was significantly increased,the apoptosis rate was decreased,the expression of Bcl-2 mRNA and synaptophysin Ⅰ was up-regulated,and Bax mRNA expression was downregulated in R group (P ＜ 0.05 or 0.01).Conclusion Ro20-1724 can inhibit ketamine-induced apoptosis in hippocampal neurons of neonatal rats and correction of Bcl-2/Bax imbalance is involved in the mechanism.

Successful Opening of Ductus Arteriosus with Milrinone in a Newborn with Tetralogy of Fallot and Pulmonary Atresia

Tetralogy of Fallot (TOF) assumes its' most severe form when accompanied by pulmonary atresia (PA). Preserving the patent ductus arteriosus to maintain pulmonary blood flow is life-saving for patients with this congenital heart disease. Milrinone, a selective phosphodiesterase III inhibitor, is a potent vasodilator. Here, we report the successful use of milrinone for a newborn infant with TOF and PA for keeping the ductus arteriosus open and thereby maintaining pulmonary circulation. Milrinone is a useful drug because of its inotropic, lusitropic, and pulmonary vasodilating effects, in addition to its ability to keep the ductus arteriosus open and its relatively mild side-effects. Case series and comparative studies will be needed in the future to verify the effectiveness of this drug.

Oxidative stress and Alzheimer's disease / 中国药理学通报

Alzheimer's disease(AD)is a progressive neurodegenerative disease characterized by cognition impairment and behavioral abnormalities.While the mechanisms involved in AD remain unclear,various hypotheses have been proposed regarding pathogenesis of AD,among which the oxidative stress hypothesis has attracted more and more attention.In the present article,the relationship between oxidative stress and AD is reviewed,including sources of neuronal oxygen radical generation,the link of oxidative stress to pathogenesis of AD,preclinical and clinical studies of AD,therapeutic effects of antioxidants and phosphodiesterase inhibitors on AD.

The Efficacy of a Combination of Phosphodiesterase Type 5 Inhibitor and Testosterone Replacement Therapy in Nonresponders to Phosphodiesterase Type 5 Inhibitor Mono-therapy / 대한남성과학회지

PURPOSE: The aim of this study was to evaluate the efficacy of a combination therapy with PDE5 inhibitor and testosterone replacement therapy in erectile dysfunction patients with testosterone deficiency syndrome (TDS) after failure of PDE5 inhibitor mono-therapy. MATERIALS AND METHODS: From March 2004 to July 2008, we evaluated 38 men (aged 38 to 69 years) who showed no response to PDE5 inhibitor therapy at the maximal recommended dose and they had testosterone levels less than 350ng/dL. Testosterone replacement therapy (TRT) was subsequently started with injectable testosterone undecanoate (NEBIDO(R)) or transdermal testosterone (Testogel(R)) in those patients. They received TRT during an 18-week period. After 14 weeks of TRT alone, PDE5 inhibitor was added to the TRT for an additional 4 weeks. After treatment, we evaluated the patients' sexual function, which was primarily based on the International Index of Erectile Function (IIEF), and the serum testosterone levels. RESULTS: All patients showed elevated serum testosterone levels after TRT (range: 212 to 662ng/dl, mean level: 362.19 ng/dl). At week 18, almost all of the men reported improved potency with combination therapy. After treatment, the mean total IIEF score and each sub-domain score were increased significantly compared to the baseline score. CONCLUSIONS: Testosterone replacement therapy combined with PDE5 inhibitor may be beneficial in improving the erectile function in testosterone deficiency syndrome patients with erectile dysfunction and who are unresponsive to PDE5 inhibitor alone.

Effects of Chronic Treatment with a Type 5 Phosphodiesterase Inhibitor on Erectile Function in Diabetic Rats / 대한남성과학회지

PURPOSE: We investigated whether chronic treatment with a type 5 phosphodiesterase inhibitor (PDE5I) could suppress corporal apoptosis and improve erectile function in diabetic erectile dysfunction. MATERIALS AND METHODS: Sprague-Dawley rats (12 weeks old) were assigned into 1) normal control 2) diabetes, and 3) diabetes with PDE5I treatment groups (n=12 per group). After inducing diabetes with intraperitoneal injection of streptozotocin, the diabetic and PDE5I-treatment groups were treated with vehicle or PDE5I (mirodenafil, 10 mg/kg) for 4 weeks. To examine the effect on erectile response, 6 rats in each group underwent cavernosometry under cavernous nerve electrostimulation (2 V, 0.2 msec, 50 sec, 2.5~20 Hz). The penile tissues from the remaining 6 rats were used for immunohistochemical evaluation of apoptosis. RESULTS: The diabetic group showed markedly lower mean intracavernosal pressure/mean arterial pressure (ICP/MAP) and area under the curve of cavernosometry than normal controls, whereas the diabetes with PDE5I treatment group showed normal results. Despite persistent hyperglycemia, PDE5I treatment significantly reduced the mean apoptotic index (39.6+/-4.6 vs 21.8+/-5.1, p<0.05). CONCLUSIONS: Chronic administration of PDE5I suppressed apoptosis of corporal smooth muscle and improved erectile function in a rat model of diabetic erectile dysfunction.

Phosphodiesterase 3 inhibitor attenuates cough response in a sensitized guinea pig model / 中国病理生理杂志

AIM: To investigate the effects of selective phosphodiesterase 3 inhibitor olprinone on cough response in guinea pigs sensitized and challenged with ovalbumin. METHODS: Forty sensitized guinea pigs were randomly divided into control ( n = 10), challenged ( n = 10), olprinone ( n = 10) and aminophylline group ( n = 10 ). Two hours after challenged with the aerosol of 1% ovalbumin or saline, animals were intraperitoneally injected either with saline,25 mg/kg of olprinone or 25 mg/kg aminophylline. At 24 h, the injection was repeated with 2. 5 mg/kg and 25 mg/kg olprinone or 2. 5 mg/kg and 25 mg/kg aminophylline respectively in olprinone and aminophylline group, cough response to inhaled capsaicin and airway responsiveness to methacholine (PC150) were measured. Then, total cell number and differential counts were analyzed in bronchoalveolar lavage fluid. RESULTS: The cough frequency was (5 ± 2) times/3 min in control group and (24 ± 3 ) times/3 min in challenged group ( P ＜ 0. 05 ), while PC150 was (659 + 57 ) mg/L in control group and (238 + 67 ) mg/L inchallenged group ( P ＜ 0. 05 ). 25 mg/kg olprinone significantly inhibited the augmented cough response and airway hyperresponsiveness, the cough frequency and PC150 were (15 ±2) times/3 min and (580 ±45) mg/L (P ＜ 0. 05 ), which differed significantly from (18 ± 2) times/3 min and (438± 52) mg/L in aminophilline group (P ＜ 0. 05). However, olprinone failed to reverse the elevated total cell number and percentage of eosinophils in bronchoalveolar lavage fluid from guinea pigs challenged with ovalbumin (P ＞ 0. 05 ). CONCLUSION: Phosphodiesterase 3 inhibitor attenuates cough response associated with eosinophilic airway inflammation by bronchodilatory effect.

Medeical Therapy For Pulmonary Arterial Hypertention / 결핵및호흡기질환

Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. We tried to provide evidence?based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.

The Combined Effect of Desflurane and Milrinone on the Function of the Isolated Rat Heart / 대한마취과학회지

BACKGROUND: Desflurane depresses the contractile function of the myocardium. It also causes direct coronary vasodilation. Milrinone, a phosphodiesterase III inhibitor, usually increases myocardial contractility and also has vasodilatory activity. Some inhalation anesthetic agents, such as isoflurane, are safely combined with phosphodiesterase III inhibitors clinically, but milrinone sometimes causes significant hypotension by reducing systemic vascular resistance. The purpose of this study was to evaluate the effect of the combined use of desflurane and milrinone on the function of the isolated rat heart. METHOD: Thirty isolated rat hearts were divided into two groups. [Group 1 (n = 15): desflurane, Group 2 (n = 15): desflurane and milrinone] They were perfused continuously with modified Krebs' solution in a Langendorff retrograde perfusion apparatus. After measuring the control values of the hemodynamic and oxygenation parameters in each group, we administered 6.6 vol% of desflurane to both groups and added sequential perfusion of modified Krebs' solution containing 0.5, 1.0, and 1.5mug/ml of milrinone in Group 2 and then measured the parameters and analyzed them statistically. RESULTS: Baseline measurements in both groups were not statistically different. In Group 1, desflurane significantly decreased LVP (55+/-5 mmHg), dp/dt (557+/-65 mmHg/sec) and MVO2 (71.2+/-16.3 ml/g/min) after 15 minutes. CF (13.9+/-3.1 ml/g/min) and DO2 (176.7+/-43.4 ml/g/min) were increased after 15 minutes. There was no further change after this. In Group 2, desflurane decreased LVP (53+/-18 mmHg), dp/dt (558 90 mmHg/sec) and MVO2 (72.0+/-11.0 ml/g/min) and increased CF (14.2+/-1.9 ml/g/min) and DO2 (175.3+/-29.1 ml/g/min). But, there was no significant difference in the effects of desflurane between the two groups. Milrinone restored LVP, dp/dt and MVO2 to the baseline level, but not with dose-dependency. Desflurane-induced elevated CF and DO2 did not show further changes. CONCLUSIONS: These findings suggest that milrinone increased myocardial contractility and restored the desflurane-induced myocardial depression of the isolated rat heart without further increase of oxygen consumption from the baseline control value. In addition, no additive effects was observed on coronary blood flow when these two agents were used in combination.

The Effects of Sildenafil Citrate as an Intracavernosal Agent / 대한남성과학회지

PURPOSE: Treatment of impotence has advanced considerably by an orally active, effective and well-tolerated drug, sildenafil citrate. However, Sildenafil citrate is not so effective for the treatment of severe organic impotence patients. Intracavernosal injection of vasoactive substance is still the most effective therapy for those patients but side effects, e.g. pain, priapism, require a more comfortable therapy. We performed this study to assess the feasibility of sildenafil citrate as a new intracavernosal agent. MATERIALS AND METHODS: In New Zealand white male rabbits (n=11), relaxations of precontracted cavernosal smooth muscle strips were studied after administration of sildenafil citrate, acetylcholine and sodium nitroprusside (SNP), respectively. In separate in vivo experiment, changes of intracavernosal pressure (ICP), duration of increased ICP and changes of systemic arterial blood pressure after retrograde selective internal pudendal arterial administration of four separate doses (0.1 mg, n=5; 0.3 mg, n=6; 0.5 mg, n=7; 1.0 mg, n=7) of sildenafil citrate were monitored in adult male cats (n=25). RESULTS: Acetylcholine, SNP and sildenafil citrate effectively relaxed the precontracted strips in a dose-dependent manner (3x10 8-3x10 3 M), respectively. Maximal relaxation of strips to acetylcholine, SNP and sildenafil citrate were 50.11%, 98.65%, and 68.32%, respectively. The order of potency was acetylcholine

The Effect of Local Delivery of IBMX on the Neointimal Proliferation in Rat Carotid Balloon Injury Model

BACKGROUND: Hyperplastic neointima is one of the major mechanisms of restenosis following balloon angioplasty in selected patients with symptomatic angina pectoris. Elevation of cellular cyclic nucleotide levels such as cAMP and cGMP are known to inhibit the proliferation of vascular smooth muscle cells. 3-isobutyl-1-methylxanthine (IBMX) increases intracellular cAMP and cGMP by nonselective inhibition of phosphodiesterases (PDEs). We conducted this study under the hypothesis that local delivery of IBMX could inhibit neointimal hyperplasia after balloon injury of the rat carotid artery. METHODS: Left common carotid artery of 10 week old male Sprague-Dawley rats were subjected to arterial injury by 2F Fogarty balloon catheter. After injury, animals were allocated to the control groups (control 1: injury control and control 2: pluronic gel plus DMSO control) and IBMX group, which received pluronic polymer gel, DMSO and IBMX mixture periadventitially. After 3 weeks, the rats were killed by overdose of ketamine, and the injured left arteries were pressure-fixed with 10% formalin and subjected to histomorphological analysis. RESULTS: Mean body weight of rats was not statistically different among study groups. The mean area of neointima (control group 1:0.28+/-0.05 mm2,Control group 2:0.27+/-0.08 mm2 , IBMX group:0.18+/-0.08 mm2 : p<0.05) and the mean ratio of neointima to medial area[versus (control group 1:1.89+/-0.37, control group 2:1.95+/-0.41, IBMX group: 1.41+/-0.47: p<0.05)] were significantly less in IBMX group. The mean area of external elastic lamina was significantly larger in control group 1 than IBMX group (0.57+/-0.07 mm2 versus 0.47+/-0.10 mm2 ) and mean luminal area showed no significant difference among groups (control group1:0.14+/-0.07 mm2 , control group 2: 0.10+/-0.05 mm2 , control group 3: 0.16+/-0.06 mm2). CONCLUSION: Peri-adventitial single administration of IBMX showed its effectiveness in reducing the neointimal proliferation in rat carotid balloon injury model. Furthermore we observed the positive correlation between intimal area and EELA suggesting vascular remodeling depending on the intima volume.

The Effect of Local Delivery of IBMX on the Neointimal Proliferation in Rat Carotid Balloon Injury Model

BACKGROUND: Hyperplastic neointima is one of the major mechanisms of restenosis following balloon angioplasty in selected patients with symptomatic angina pectoris. Elevation of cellular cyclic nucleotide levels such as cAMP and cGMP are known to inhibit the proliferation of vascular smooth muscle cells. 3-isobutyl-1-methylxanthine (IBMX) increases intracellular cAMP and cGMP by nonselective inhibition of phosphodiesterases (PDEs). We conducted this study under the hypothesis that local delivery of IBMX could inhibit neointimal hyperplasia after balloon injury of the rat carotid artery. METHODS: Left common carotid artery of 10 week old male Sprague-Dawley rats were subjected to arterial injury by 2F Fogarty balloon catheter. After injury, animals were allocated to the control groups (control 1: injury control and control 2: pluronic gel plus DMSO control) and IBMX group, which received pluronic polymer gel, DMSO and IBMX mixture periadventitially. After 3 weeks, the rats were killed by overdose of ketamine, and the injured left arteries were pressure-fixed with 10% formalin and subjected to histomorphological analysis. RESULTS: Mean body weight of rats was not statistically different among study groups. The mean area of neointima (control group 1:0.28+/-0.05 mm2,Control group 2:0.27+/-0.08 mm2 , IBMX group:0.18+/-0.08 mm2 : p<0.05) and the mean ratio of neointima to medial area[versus (control group 1:1.89+/-0.37, control group 2:1.95+/-0.41, IBMX group: 1.41+/-0.47: p<0.05)] were significantly less in IBMX group. The mean area of external elastic lamina was significantly larger in control group 1 than IBMX group (0.57+/-0.07 mm2 versus 0.47+/-0.10 mm2 ) and mean luminal area showed no significant difference among groups (control group1:0.14+/-0.07 mm2 , control group 2: 0.10+/-0.05 mm2 , control group 3: 0.16+/-0.06 mm2). CONCLUSION: Peri-adventitial single administration of IBMX showed its effectiveness in reducing the neointimal proliferation in rat carotid balloon injury model. Furthermore we observed the positive correlation between intimal area and EELA suggesting vascular remodeling depending on the intima volume.

The in vitro effect of theophylline on 17α 20ß-dihydroxy-4-pregnen-3-one-induced germinal vesicle breakdown in the catfish, Clarias batrachus.

The effects of theophylline (a phosphodiesterase inhibitor) and cAMP on 17α, 20ß-dihydroxy-4-pregnen-3-one-induced germinal vesicle breakdown was investigated in vitro in catfish (Clarias batrachus) oocytes. Folliculated oocytes incubated with 17α, 20ß-dihydroxy-4-pregnen-3-one at the concentration of 1 μg/ml induced 93·2 ± 2·23% germinal vesicle breakdown. When the oocytes were prestimulated with 17α,20ß-dihydroxy- 4-pregnen-3-one for 6 h and then treated with different concentrations of theophylline, there was a significant drop in the frequency of germinal vesicle breakdown at the concentrations 2·0, 1·5 and 1·0 mM. However, theophylline was found to be incapable of inhibiting germinal vesicle breakdown at its lowest concentration (0·5 inM). In the time course study, significant inhibition of germinal vesicle breakdown was recorded when 1 mM theophylline was added up to 30 h of 17α,20ß-dihydroxy-4-pregnen-3-one Stimulation but the inhibitory effect of theophylline gradually (time dependent manner) declined if the stimulatory time of 17α,20ß-dihydroxy-4-pregnen-3-one was increased. A similar inhibition of germinal vesicle breakdown was also recorded with various concentrations of cAMP. Except 0·5 mM, all the higher concentrations of cAMP significantly inhibited 17α,20ß-dihydroxy- 4-pregnen-3-one induced germinal vesicle breakdown.

Effects of MS23 on KCl~-,?-adrenoceptor agonists-and U46619-induced contractions of arteries isolated from rat different organs / 中国药理学通报

Aim To study the vasodilation of MS23,a brand new phosphodiesteras inhibitor,on contractions induced by various stimuli in rings of arteries isolated from rat different organs.Method Tension of aortic and microvessel rings were recorded isometrically by PowerLab and DMT system respectively.Results MS23 concentration-dependently shifted the noradrenaline(NA)-induced concentration-contraction curves rightward in a non-parallel manner with the maximal contraction depressed by 74.7%.MS23 and aminophylline(Ami) produced concentration-dependent relaxation on KCl or NA-induced precontraction.Endothelium deprivation and NO synthesis inhibition induced by L-NAME failed to affect the relaxation.MS23 and Ami relaxed KCl-induced precontraction of rat coronary,middle cerebral,renal and mesenteric arterial rings in a concentration-dependent manner,and showed no organ preference in this respect.Conclusion MS23 antagonizes and relaxes contractions induced by various stimuli in the rings of arteries isolated from different organs of rat without marked preference among the organ origin of artery and stimuli.The vasorelaxation induced by MS23 is related neither to endothelium nor to nitric oxide synthesis.