Pharmacokinetics of two modified release system of dipyridamole in beagle dogs

A novel floating osmotic pump controlled release system （FOP） and traditional matrix sustained release tablets （MT） of dipyridamole （DIP） were characterized in terms of pharmacokinetics, drug release, and in vitro-in vivo correlation. In vivo study was performed by a three-crossover study in six beagle dogs relative to the conventional tablet （CT）. A HPLC method for the determination of DIP in the plasma was developed. Cumulative percent of absorption fraction was compared to that of in vitro cumulative release. Both FOP and MT displayed obvious extended release characteristic in vivo while FOP showed a better extended release behavior. The bioavailability of FOP was higher than that of MT and a zero-order release linear correlation of DIP between fraction absorbed in vivo and fraction dissolved in vitro was established for FOP while not for MT. The results indicated the existence of an absorption window in upper part of the GI track of DIP, which meant that floating system could be excellent for the drug delivery. In addition, the in vitro model was a good choice for depicting in vivo absorption and for optimization of the formulation of FOP if it is needed to be bio-equivalent to MT.

Dipyridamole enhances inhibitory effect of adenosine on neutrophils in human peripheral blood

Objective： It was known that neutrophils play an important role in ischemic-reperfusion injury. In this study we tested the effect and its mechanism of dipyfidamole on neutrophils. Methods：Hydrogen peroxide（H2O2） production by neutrophils was determined using luminol amplified chemiluminescence and the percentage of activity was calculated by observing the uninhibited peak height. Results： Dipyfidamole per se produced a concentration-dependent inhibition of H2O2 by formyl-MetleuPhe（fMLP）-stimulated neutrophils. Dipyridamole at a low concentration（0.3 μ mol · L^-1） that per se affected neutrophils only slightly, enhanced markedly the effects of adenosine on neutrophils. On the other hand, dipyfidamole did not alter the inhibitory effect of NECA（5＇ -N-ethylcarboxamidoadenosine） on neutrophils. However, propentofylline, a known inhibitor of adenosine uptake, also gotten the same result. Conclusion：Dipyfidamole inhibited the production of H2O2 by fMLP-sfimulated neutrophils. Dipyfidamole at a low concentration enhanced the inhibitory effect of adenosine on neutrophils. The mechanism involved is probably due to the effect of dipyfidamole on adenosine uptake.

INDEPENDENT AND SYNERGIC INHIBITION OF DIPYRIDAMOLE AND RADIATION ON K562-AND K562/ADM CELL LINES IN VITRO

It is first demonstrated that dipyridamole (DP) and radiation were capable of significantly inhibiting, independently and synerglcally, clonogenlc growth in the two kinds of K562 cell lines, adriamycin (ADM) -sensitive and ADM- resistant. DP or radiation alone Increased clonogenlc Inhibition rate (CIR) in the two kinds of cell lines in a dose- dependent fashion. DP potentiated radiosensitivity and radiation increased inhibition of DP in the two kinds of cell lines. K562/ ADM cell lines were higher sensitive to DP. radiation and combination of them than K562 cell lines (P<0. 01). There was stronger synergic inhibition of clonogenlc growth in the two kinds of cell lines when pretreated with DP than when posttreated with DP (P<0. 01).

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can cause acute respiratory distress syndrome,hypercoagulability,hypertension,and multiorgan dysfunction.Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis.In an analysis of a randomly collected cohort of 124 patients with COVID-19,we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity.By virtual screening of a U.S.FDA approved drug library,we identified an anticoagulation agent dipyridamole(DIP)in silico,which suppressed SARS-CoV-2 replication in vitro.In a proof-of-concept trial involving 31 patients with COVID-19,DIP supplementation was associated with significantly decreased concentrations of D-dimers(P<0.05),increased lymphocyte and platelet recovery in the circulation,and markedly improved clinical outcomes in comparison to the control patients.In particular,all 8 of the DIP-treated severely ill patients showed remarkable improvement:7 patients(87.5%)achieved clinical cure and were discharged from the hospitals while the remaining 1 patient(12.5%)was in clinical remission.

Ginkgo Leaf Extract and Dipyridamole Injection as Adjuvant Treatment for Angina Pectoris:A Meta-Analysis of 41 Randomized Controlled Trials

Objective： To provide information about the effectiveness and safety of Ginkgo Leaf Extract and Dipyridamole Injection （GD） as one adjuvant therapy for treating angina pectoris （AP） and to evaluate the relevant randomized controlled trials （RCTs） with meta-analysis. Methods： RCTs concerning AP treated by GD were searched in China Biology Medicine Disc （SinoMed）, PubMed, the China National Knowledge Infrastructure Database （CNKI）, the Chinese Scientific Journals Database （VIP）, Wanfang Database, Embase, and the Cochrane Library, from inception to February, 2017. The Cochrane Risk Assessment Tool was adopted to assess the methodological quality of the RCTs. The Review Manager 5.3 software was utilized to conduct the meta-analysis. Results： A total of 41 RCTs involving 4,462 patients were included in the meta-analysis. The results indicated that the combined use of GD and Western medicine （WM） against AP was associated with a higher total effective rate [risk ratio （RR）=1.25, 95% confidence interval （CI）： 1.21-1.29, P〈0.01], total effective rate of electrocardiogram （RR=1.29, 95% CI： 1.21-1.36, P〈0.01）. Additional, GD combined with WM could decrease the level of plasma viscosity [mean difference （MD）=-0.56, 95% CI： -0,81 to -0.30, P〈0.01], flbrinogen [MD=-1.02, 95% CI： -1.50 to -0.54, P〈0.01], whole blood low shear viscosity [MD=-2.27, 95% CI： -3.04 to -1.49, P〈0.01], and whole blood high shear viscosity （MD=-0.90, 95% CI： 1.37 to -0.44, P〈0.01）. Conclusions： Comparing with receiving WM only, the combine use of GD and WM was associated with a better curative effect for patients with AP. Nevertheless, limited by the methodological quality of included RCTs more large-sample, multi-center RCTs were needed to confirm our findings and provide further evidence for the clinical utility of GD.

PLATELET ACTIVATION IN PATIENTS WITH CHRONIC PULMONARY HEART DISEASE EFFECT OF DIPYRIDAMOLE TREATMENT

Plasma levels of /f-thromboglobulin (/?-TG), platelet fac-tor 4(P and platelet aggregation rate (PAR) were measured in remission phase of 15 patients affected with chronic pulmonary heart disease (CPHD). 0-TG, /?-TG / PF4, PF4 and PAR were significantly higher in the patients than in controls (/3<0.01 and 0.05, respectively). After 10 days of treatment with Dipyridamole lOOtng tid, fi-TG, /?-TG / PF4 and PF4 decreased significantly compared with pretreatment values (/><0.01 and 0.05, respectively). The results suggest that in vivo platelet activation is indeed present in patients with CPHD and that dipyridamole can antagonize platelet activation in vivo.

THE ROLE OF DIPYRIDAMOLE IN PREVENTING ANGIOGENESIS IMPAIRMENT BY HOMOCYSTEINE AND ADENOSINE: A MODEL FOR SCREENING HERBAL BIOACTIVES

Herbal bioactives have been shown to influence the pathogenesis of homocysteine associated vascular complications.However,there are no simple cellular models to study their role in preventing angiogenesis impairment by homocysteine and adenosine.Using dipyridamole,an inhibitor for nucleoside transport,we examined its mechanism of action on impaired

Suppression of cell pyroptosis by omeprazole through PDE4-mediated autophagy in gastric epithelial cells

Helicobacter pylori is a risk factor for the development of peptic ulcers with autophagy dysfunction.Omeprazole was widely known as the first-line regimen for H.pylori-associated gastritis.Objectives:The objective of this work was to assess the role of omeprazole on cell pyroptosis and autophagy.Methods:The clinical samples were collected.Quantitative polymerase chain reaction,western blotting,enzyme linked immunosorbent assay,and immunofluorescence(IF)analysis were conducted to reveal the mechanism of omeprazole on cell pyroptosis and autophagy.Results:The results revealed that omeprazole could decrease cell pyroptosis,which was attributed to the downregulation of cleaved caspase-1 expression,resulting in the inhibition of gasdermin E and interleukin-18/1βmaturation and secretion as well as the resolution of inflammation.Mechanistically,omeprazole treatment led to drastic downregulation of mammalian target of rapamycin(mTOR)activity was observed in BGC823 cells,leading to enhanced autophagy characterized by increased LC3II expression,which further reduced cell pyroptosis.This omeprazole-mediated phenomenon was enhanced after phosphodiesterase-4(PDE4)inhibitor dipyridamole(DIP)treatment.In addition,activation of mTOR by MHY1485 could rescue the suppression of cell pyroptosis induced by omeprazole.Most importantly,IF analysis suggested that phosphorylation of mTOR and PDE4 activity and caspase-1 were enhanced in H.pylori-infected gastric mucosa.Conclusion:These findings indicate that omeprazole suppresses cell pyroptosis through PDE4-mediated autophagy in gastric epithelial cells,and DIP enhanced the omeprazole-mediated inhibition of cell pyroptosis,implying that DIP is an alternative combined therapy strategy in improving the treatment of patients with H.pylori infection.

2005～2008年我院银杏叶注射液使用情况分析

银杏（Ginkgo biloba）属我国特产植物资源,在全球的天然药物中,银杏制剂是用量最大的品种之一。银杏叶注射液原研厂家为德国施瓦伯公司。银杏叶提取物注射液（Ginkgo Biloba Leaf Extract Injection,EGb761）主要活性成分有银杏黄酮，银杏内酯A、B、C，白果内脂（BB）。银杏达莫（Ginkgo Leaf Extract and Dipyridamole Injection）是由银杏黄酮和双嘧达莫组成的复方制剂。EGb761具有扩张血管、改善微循环、

Psoas Hematoma Following Lumbar Sympathetic Block in a Patient with Renal and Liver Diseases and Recent Use of Aggrenox

Lumbar sympathetic block is an analgesic procedure frequently performed in chronic pain clinics for ischemic lower limb pain from peripheral arterial disease. Although the lumbar sympathetic ganglia are anatomically near major vascular and neural structures, complications such as severe hemorrhage is rarely reported. Aspirin/extended release dipyridamole (Aggrenox) is indicated for secondary stroke prevention. Stroke is frequently a co-morbid condition in patients with peripheral vascular disease. Interventional pain physicians frequently face the difficulty of deciding whether to continue or stop antithrombotic medications in the periprocedural period because of the devastating consequences of both hemorrhagic and thrombotic complications. Due to a paucity of data, no guidelines have been specifically written for interventional procedures for chronic pain. To aid future decision making, we present a case report of psoas hematoma developed after lumbar sympathetic block in a patient with end stage renal failure and hepatic dysfunction who had limb-threatening ischemia. The patient was treated with Aggrenox until three days before the procedure.

Reduced Heart Rate Response during Drug-Induced Stress Is Related to the Severity of Perfusion Defect

Introduction: During the pharmacological stress test with dipyridamole, a normal hemodynamic response is slightly reduced blood pressure and raised heart rate (HR). However, sometimes the HR response is reduced. This study investigated the relationship between the HR response during the dipyridamole stress test and the severity of the perfusion defects using Thallium 201 myocardial perfusion imaging. Methods: We enrolled 50 patients undergoing dipyridamole stress at the nuclear cardiology Lab, Main University Hospital of Alexandria. Standard dipyridamole protocol (infusion over 4 min) and standard thallium 201 protocol (2 min after dipyridamole infusion) were followed. If the heart rate (HR) ratio (peak HR/rest HR) was 1.20 or less, it was considered a reduced response. Total perfusion defect (TPD), summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) for myocardial perfusion were calculated. Patients with reduced HR response and normal HR responses were compared and independent predictors of reduced HR response were determined. Results: About 56% of patients had reduced HR response;which included a high number of patients with a history of dyslipidemia and diabetes mellitus. The reduced HR response group showed lower SSS, SRS. The analysis showed that the independent predictors of reduced HR response were rest HR, SSS, and diabetes mellitus. Conclusions: Reduction in the HR response during the dipyridamole-induced stress test is related to the severity of perfusion defect, diabetes mellitus, and Dyslipidemia.

A new echocardiographic system for assessment of epicardial and intramyocardial coronary flow in a swine model

OBJECTIVE: To visualize epicardial and intramyocardial coronary blood flow by using a noninvasive echocardiography system. METHODS: In five juvenile swines, coronary flow imaging was used to visualize the different segments of epicardial coronary and intramyocardial arteries. Pulsed-Doppler spectrums were recorded and analyzed. The left anterior descending artery (LAD) and intramyocardial coronary blood flow signals were recorded at baseline and during dipyridamole administration. RESULTS: Epicardial and intramyocardial coronary arteries could be visualized by coronary flow imaging. The systolic component of coronary flow in the right coronary artery (RCA) was greater than in the LAD. The intramyocardial blood flow was characterized by persistent retrograde blood flow velocity during systole. Vasodilation with dipyridamole produced exaggerated differences in the phasic pattern of coronary blood flow in epicardial and intramyocardial vessels. CONCLUSION: Color Doppler coronary flow imaging provides a noninvasive method to study the coronary blood flow.

Microspheres Sensor Based on Molecularly Imprinted Polymer Synthesized by Precipitation Polymerization

A new biomimetic bulk acoustic wave sensor based on molecularly imprinted microspheres (MUM) technique was described. The sensing materials were synthesized by precipitation polymerization. By using the Scatchard analysis, the equilibrium dissociation constant K-D and the apparent maximum number Q(max) of the binding sites were calculated to be 3.70 mmol (.) L-1 and 9.11 mumol (.) g(-1), respectively. The sensor exhibited a sensitive response to the template compound (dipyridamole) in liquid phase with a detection Unfit of 2 x 10(-9) mol (.) L-1. The recoveries of the sensor were 95.1%-105.4%. Studies presented in this paper show that the stability of this sensor is excellent. The sensor has been applied successfully to the determination of dipyridamole in human urine.

了解PROFESS研究进行卒中二级预防

有效避免二次卒中预防方案（Prevention Regimen for Effectively Avoiding Second Strokes，PROFESS）试验是迄今规模最大的一项卒中二级预防研究，它对缓释型双嘧达莫＋阿司匹林（extended-release dipyridamole plusaspirin，eDYP-ASA）与氯吡格雷以及替米沙坦与除血管紧张素受体拮抗药（angiotensin receptor blocker，ARB）以外的抗高血压治疗方案进行了比较。