Effect Of Dipyridamole Research Articles

Attenuation of HIV-Specific T Cell Responses Among People with HIV on art Following Dipyridamole Treatment.

Twelve weeks of dipyridamole increased extracellular adenosine levels and decreased T cell activation in people with HIV. In this analysis, we investigated the effect of dipyridamole on HIV-specific T cell responses. We compared changes in Gag- and Env-specific T cell responses using intracellular cytokine staining, following 12 weeks of dipyridamole treatment vs placebo. We evaluated whether frequencies of polyfunctional HIV-specific T cells were associated with purines in the adenosine pathway and with measures of HIV persistence and chronic inflammation. There was a significant decrease in CD4+ polyfunctional T cell responses to Gag (-62.6% vs -23.0%; p<0.001) and Env (-56.1% vs -6.0%; p<0.001) in the dipyridamole arm. In the dipyridamole group, lower frequencies of polyfunctional Env-specific CD4+ T cells were associated with higher plasma levels of adenosine (r= -0.85; p<0.01) and inosine (r= -0.70; p=0.04). Higher adenosine levels induced by dipyridamole treatment is associated with decreased HIV-specific CD4+ T cell polyfunctional responses in people with HIV on antiretroviral therapy.

The Therapeutic Target of IBD and the Mechanism of Dipyridamole in Treating IBD Explored by Geo Gene Chips, Network Pharmacology, and Molecular Docking.

Inflammatory Bowel Disease (IBD) is a refractory disease with repeated attacks, and there is no accurate treatment target at present. Dipyridamole, a phosphodiesterase (PDE) inhibitor, has been proven to be an effective treatment for IBD in a pilot study. This study explored the therapeutic target of IBD and the pharmacological mechanism of dipyridamole for the treatment of IBD. The candidate targets of dipyridamole were obtained by searching the pharmMapper online server and Swiss Target Prediction Database. The IBD-related targets were selected from four GEO chips and three databases, including Genecards, DisGeNET, and TTD database. A protein-protein interaction (PPI) network was constructed, and the core targets were identified according to the topological structure. KEGG and GO enrichment analysis and BioGPS location were performed. Finally, molecular docking was used to verify dipyridamole and the hub targets. We obtained 112 up-regulated genes and 157 down-regulated genes, as well as 105 composite targets of Dipyridamole-IBD. Through the PPI network analysis, we obtained the 7 hub targets, including SRC, EGFR, MAPK1, MAPK14, MAPK8, PTPN11, and LCK. The BioGPS showed that these genes were highly expressed in the immune system, digestive system, and endocrine system. In addition, the 7 hub targets had good intermolecular interactions with dipyridamole. The therapeutic effect of dipyridamole on IBD may involve immune system activation and regulation of inflammatory reactions involved in the regulation of extracellular matrix, perinuclear region of cytoplasm, protein kinase binding, and positive regulation of programmed cell death through cancer pathway (proteoglycans in cancer), lipid metabolism, Ras signaling pathway, MAPK signaling pathway, PI3K-AKT signaling pathway, Th17 cell differentiation, and other cellular and innate immune signaling pathways. This study predicted the therapeutic target of IBD and the molecular mechanism of dipyridamole in treating IBD, providing a new direction for the treatment of IBD and a theoretical basis for further research.

Targeting the adenosinergic system in restless legs syndrome: A pilot, "proof-of-concept" placebo-controlled TMS-based protocol.

Restless Legs Syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs that is responsive to movement (particularly during rest), periodic leg movements during sleep, and hyperarousal. Recent evidence suggests that the involvement of the adenosine system may establish a connection between dopamine and glutamate dysfunction in RLS. Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique widely applied to explore brain electrophysiology and neurochemistry under different experimental conditions. In this pilot study protocol, we aim to investigate the effects of dipyridamole (a well-known enhancer of adenosinergic transmission) and caffeine (an adenosine receptor antagonist) on measures of cortical excitation and inhibition in response to TMS in patients with primary RLS. Initially, we will assess cortical excitability using both single- and paired-pulse TMS in patients with RLS. Then, based on the measures obtained, we will explore the effects of dipyridamole and caffeine, in comparison to placebo, on various TMS parameters related to cortical excitation and inhibition. Finally, we will evaluate the psycho-cognitive performance of RLS patients to screen them for cognitive impairment and/or mood-behavioral dysfunction, thus aiming to correlate psycho-cognitive findings with TMS data. Overall, this study protocol will be the first to shed lights on the neurophysiological mechanisms of RLS involving the modulation of the adenosine system, thus potentially providing a foundation for innovative "pharmaco-TMS"-based treatments. The distinctive TMS profile observed in RLS holds indeed the potential utility for both diagnosis and treatment, as well as for patient monitoring. As such, it can be considered a target for both novel pharmacological (i.e., drug) and non-pharmacological (e.g., neuromodulatory), "TMS-guided", interventions.

Effects of Dipyridamole on Histopathology of Tongue and Salivary Glands in Rabbits

Effects of Dipyridamole on Histopathology of Tongue and Salivary Glands in Rabbits

Antimanic-like effect of dipyridamole in the methylphenidate-induced hyperlocomotion.

Adenosinergic system has been implicated in the pathophysiology of bipolar disorder and drugs that affect adenosine neurotransmission have shown some efficacy as add-on therapy in manic patients. Thus, the aim of the present study was to screen adenosinergic drugs for antimanic-like effect in methylphenidate (MPH)-induced hyperlocomotion in mice. Male and female Swiss mice received a single allopurinol (50 and 200 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) administration before an acute MPH challenge (5mg/kg, sc). In experiments with repeated treatment, male mice received a daily administration of allopurinol (25 and 50 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) for 14 days. Finally, pretreatment with aminophylline (2mg/kg, sc), an unspecific adenosine receptor antagonist, was used to evaluate a putative adenosinergic mediation. Locomotor activity was measured in the automated activity chamber for 20 min. Acute and repeated dipyridamole reduced the increase in locomotor activity induced by MPH, while allopurinol and inosine had no effect. Aminophylline blocked the effect of dipyridamole in MPH-induced hyperlocomotion. The present results suggest that dipyridamole may have an antimanic-like effect through adenosine receptors and reinforce the proposal that the adenosine system may be an interesting target for new antimanic drugs.

Abstract TP317: The Neuroprotective Effect of Dipyridamole in Ischemia-Reperfusion Injury via Neuronal cGK1/2 Activation

Background and rationale: Smooth muscle cell-specific cGK1 knock-out mice (SMKO) due to impaired blood vessel motility is a leading cause of reduced blood flow in ischemic stroke. This study investigated relative cerebral blood flow (rCBF), neuronal cGK1/2, and vessels cGK1/2 activity in smooth muscle cGK1 littermate control (SMLC), and SMKO mice with and without PDE5 inhibitor, dipyridamole. Methods: Middle cerebral artery occlusion (MCAO)-reperfusion was performed in SMLC and SMKO. All mice were measured for the rCBF by laser Doppler flowmetry and investigated the behaviors after ischemic stroke. To confirm the time-kinetics of cGK1/2 changes, brain samples were divided ischemia-reperfusion period in SMLC and SMKO mice with and without dipyridamole (60 mg/kg, p.o.). Results: Infarction volumes were larger in SMKO compared to that of SMLC mice and neurological deficit score was worsening in SMKO compared to that of SMLC mice. The rCBF values during MCAO and at reperfusion were significantly decreased in the SMKO group. During the ischemia and reperfusion period, neuronal cGK1 was sustained without protein degradation. Not only SMLC but also SMKO were the same. However, neuronal cGK2 was decreased time-dependent manner. In contrast, infarction volume was decreased in SMKO by dipyridamole treatment and NDS was improved in SMKO with dipyridamole. The changes of cGK1 and cGK2 were reversed in the reperfusion period in the cerebral cortex and hippocampus with dipyridamole. Conclusion: We conclude that the neuroprotective effect of dipyridamole in ischemic stroke is not only dependent on smooth muscle cell-specific cGK1 function but also related to the neuronal cGK1/2 activation via PDE5 inhibition.

Comparison of Regadenoson and Dipyridamole Safety Profiles During Stress Myocardial Perfusion Imaging.

The pharmacological stress test with vasodilator agents is an alternative cardiological diagnostic tool for patients with contraindications to the classical stress test provided by physical activity during single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The study compared the frequency of the side effects of regadenoson and dipyridamole during a SPECT MPI. This retrospective study included data of 283 consecutive patients who underwent pharmacological stress tests in years 2015-2020. The study group consisted of 240 patients who had received dipyridamole and 43 patients who had received regadenoson. The collected data included the patients' characteristics, the occurrence of side effects (divided into mild: headache, vertigo, nausea, vomiting, dyspnea, chest discomfort, hot flushes, general weakness and severe: bradycardia, hypotension, loss of consciousness), and blood pressure values/measurements. Overall, complications occurred relatively often (regadenoson: 23.2%, dipirydamol: 26.7%, p=0.639). Procedure discontinuation was necessary in 0.7% of examinations, whereas pharmacological support was necessary in 4.7%. There was no difference in the prevalence of mild (regadenoson: 16.2%, dipirydamol: 18.3%, p=0.747) and severe complications (regadenoson: 11.6%, dipyridamole: 15.0%, p=0.563). However, regadenoson has been found to cause a significantly smaller mean decrease of systolic blood pressure (SBP) (regadenoson: -2.6±10.0 mmHg, dipyridamole: -8.7±9.6 mmHg, p=0.002), diastolic blood pressure (DBP) (regadenoson: -0.9±5.4 mmHg, dipyridamole: -3.6±6.2 mmHg, p=0.032), as well as mean arterial pressure (MAP) (regadenoson: -1.5±5.6 mmHg, dipyridamole: -5.4±6.5 mmHg, p=0.001). Regadenoson and dipyridamole presented a similar safety profile during SPECT MPI. However, regadenoson has been found to cause significantly smaller decreases in SBP, DBP, and MAP.

Employing Indirect Adenosine 2A Receptors (A2AR) to Enhance Osseointegration of Titanium Devices: A Pre-Clinical Study.

The present study aimed to evaluate the effect of dipyridamole, an indirect adenosine 2A receptors (A2AR), on the osseointegration of titanium implants in a large, translational pre-clinical model. Sixty tapered, acid-etched titanium implants, treated with four different coatings ((i) Type I Bovine Collagen (control), (ii) 10 μM dipyridamole (DIPY), (iii) 100 μM DIPY, and (iv) 1000 μM DIPY), were inserted in the vertebral bodies of 15 female sheep (weight ~65 kg). Qualitative and quantitative analysis were performed after 3, 6, and 12 weeks in vivo to assess histological features, and percentages of bone-to-implant contact (%BIC) and bone area fraction occupancy (%BAFO). Data was analyzed using a general linear mixed model analysis with time in vivo and coating as fixed factors. Histomorphometric analysis after 3 weeks in vivo revealed higher BIC for DIPY coated implant groups (10 μM (30.42% ± 10.62), 100 μM (36.41% ± 10.62), and 1000 μM (32.46% ± 10.62)) in comparison to the control group (17.99% ± 5.82). Further, significantly higher BAFO was observed for implants augmented with 1000 μM of DIPY (43.84% ± 9.97) compared to the control group (31.89% ± 5.46). At 6 and 12 weeks, no significant differences were observed among groups. Histological analysis evidenced similar osseointegration features and an intramembranous-type healing pattern for all groups. Qualitative observation corroborated the increased presence of woven bone formation in intimate contact with the surface of the implant and within the threads at 3 weeks with increased concentrations of DIPY. Coating the implant surface with dipyridamole yielded a favorable effect with regard to BIC and BAFO at 3 weeks in vivo. These findings suggest a positive effect of DIPY on the early stages of osseointegration.

Dipyridamole enhances the anti-cancer ability of aspirin against colorectal cancer by inducing apoptosis in an unfolded protein response-dependent manner.

Available evidence indicates that dipyridamole enhances the anti-thrombotic effects of aspirin for the prevention of secondary strokes. Aspirin is a well-known non-steroid anti-inflammatory drug. This anti-inflammatory property has turned aspirin into a potential drug for inflammation-related cancers such as colorectal cancer (CRC). Here, we aimed to explore whether the anti-cancer effect of aspirin against CRC could be improved by combined administration with dipyridamole. Population-based clinical data analysis was conducted to assess a possible therapeutic effect of combined dipyridamole and aspirin treatment in inhibiting CRC compared with either monotherapy. This therapeutic effect was further verified in different CRC mouse models, i.e. an orthotopic xenograft mouse model, an AOM/DSS mouse model, anApcmin/+ mouse model and a patient derived xenograft (PDX) mouse model. The in vitro effects of the drugs on CRC cells were tested using CCK8 and flow cytometry assays. RNA-Seq, Western blotting, qRT-PCR and flow cytometry were used to identify the underlying molecular mechanisms. We found that dipyridamole combined with aspirin had a better inhibitory effect on CRC than either monotherapy alone. The enhanced anti-cancer effect of the combined use of dipyridamole with aspirin was found to rely on the induction of an overwhelmed endoplasmic reticulum (ER) stress and subsequent pro-apoptotic unfolded protein response (UPR), which was different from the anti-platelet effect. Our data indicate that the anti-cancer effect of aspirin against CRC may be enhanced by combined administration with dipyridamole. In case further clinical studies confirm our findings, these may be repurposed as adjuvant agents.

High Grade AV Block Associated with Dipyridamole Infusion

The use of dipyridamole for thallium imaging has proved very successful in demonstrating coronary arterial disease [1]. Dipyridamole causes coronary arteriolar vasodilation by increasing interstitial adenosine levels by inhibition of both adenosine deaminase and facilitated cellular adenosine uptake. Differential flow changes occur in coronary arteries if a significant luminal stenosis exists [2]. Intravenous infusion of dipyridamole is safe although transient noncardiac side effects are common. These side effects are mostly mild and not need to treat although can be treated with aminophylline [5]. High-grade AV block after dipyridamole has been described in few case reports and mostly was associated with transient myocardial ischemia [2-4]. We describe a case of long-lasting high grade AV block following dipyridamole infusion. In context of near normal baseline ECG. In our case the AV block occurred without evidence of ischemia in myocardial perfusion imaging and we think it can be an unexpected adverse effect of dipyridamole and clinicians should be aware of AV block as a possible adverse effect of dipyridamole.

Effects of adenosine and dipyridamole on serum levels of some biochemical markers in rabbits: Running title: Biochemical effects of adenosine and dipyridamole

Adenosine is a nucleoside which occurs naturally in a diverse forms in all cells of the body and in most biological fluids. Under basal conditions, the extracellular adenosine concentration is maintained within certain limits. Dipyridamol inhibits adenosine reuptake by erythrocytes, endothelial cells and platelet increasing plasma levels of adenosine Aims: study the effects of adenosine and dipyridamole on serum levels of serum urea, creatinine, alkaline phosphatase(ALP), lactate dehydrogenase (LDH), Aspartate Aminotransferase (GOT), and Alanine Aminotransferase (GPT). Material and methods: Thirty-five male rabbits were included in the study. The animals were divided into 3 groups: Group one(5 animals): injected intraperitoneal (i.p) with 2 ml of distilled water/day (control group). Group two (15 animals): were treated by i.p injection of adenosine, they were divided into 3 sub groups (5 animals) according to adenosine dose:1 mg/kg, 2mg/kg and 4 mg/kg.Group 3 (15 animals): were treated by dipyridamole orally, they were divided into 3 sub-groups (5 animals) according to dipyridamole dose:4 mg/kg, 8 mg/kg and 12 mg/kg. Result: Significant differences among 3 groups were found in blood urea, LDH, GOT levels, and in GPT levels. While statistical analysis of serum levels of S. creatinine and ALP showed no significant differences among 3 study groups. Conclusion: both adenosine, dipyridamole cause Significant differences among 3 groups were found in blood urea, LDH, GOT levels, and in GPT levels in rabbit

Effect of Dipyridamole on Membrane Energization and Energy Transfer in Chromatophores of Rba. sphaeroides.

Effect of dipyridamole (DIP) at concentrations up to 1 mM on fluorescent characteristics of light-harvesting complexes LH2 and LH1, as well as on conditions of photosynthetic electron transport chain in the bacterial chromatophores of Rba. sphaeroides was investigated. DIP was found to affect efficiency of energy transfer from the light-harvesting complex LH2 to the LH1–reaction center core complex and to produce the long-wavelength (“red”) shift of the absorption band of light-harvesting bacteriochlorophyll molecules in the IR spectral region at 840-900 nm. This shift is associated with the membrane transition to the energized state. It was shown that DIP is able to reduce the photooxidized bacteriochlorophyll of the reaction center, which accelerated electron flow along the electron transport chain, thereby stimulating generation of the transmembrane potential on the chromatophore membrane. The results are important for clarifying possible mechanisms of DIP influence on the activity of membrane-bound functional proteins. In particular, they might be significant for interpreting numerous therapeutic effects of DIP.

Effects of adenosine and dipyridamole on serum levels of IL-6, TNF - , and some antioxidants in rabbits

Nearly 30 years of research findings stated that adenosine adjust ischemia. Although, adenosine use for treatment has not been accepted clinically in wide manner, also there have no many clinical trials. Aims: study the effects of adenosine and dipyridamole on total Antioxidant Capacity (TAC), Adenosine Deaminase (ADA), GSH (Glutathione), TNF - a (tumor necrosis factor Alpha) and IL-6 (Interleukin 6) in rabbits. Material and methods: Thirty five male rabbits were included in the study. The animals were divided into 3 groups: Group one(5 animals): injected (i.p) with 2 ml of distilled water/day (control group). Group two (15 animals): were treated by intraperitoneal injection of adenosine, they were divided into 3 sub groups (5 animals) according to adenosine dose:1 mg/kg, 2mg/kg and 4 mg/kg.Group 3 (15 animals): were treated by dipyridamole orally, they were divided into 3 sub groups (5 animals) according to dipyridamole dose:4 mg/kg, 8 mg/kg and 12 mg/kg. Total Antioxidant Capacity Assay kit, Adenosine Deaminase (ADA) colorimetric Assay kit, Rabbit IL-6 (Interleukin 6) ELIISA kit, Rabbit TNF - a (tumor necrosis factor Alpha), GSH (Glutathione) ELISA kits were used. Results: ANOVA Test and Duncan’s Multiple Range Test were applied between study groups. In comparison among adenosine, dipyridamole and control groups, highly significant differences were found among them in TAC,ADA and GSH levels while no significant differences were found in TNF -a and IL-6 levels among all groups. Conclusion: both adenosine, dipyridamole cause reduction in total Antioxidant Capacity together with increase in glutathione levels and Adenosine Deaminase.

Dipyridamole ameliorates doxorubicin-induced cardiotoxicity.

Dipyridamole is a platelet inhibitor with antithrombotic properties that can help prevent stroke recurrence. Twenty-eight male rats were divided randomly into four groups (7 rats in each group). Control group: rats received a natural diet and water. Normal saline group: rats received 0.9% normal saline for two weeks. Doxorubicin group (induced group): rats received 2.5 mg/kg three times a week for two weeks. Dipyridamole group (dipyridamole treated group): received dipyridamole (6 mg/kg/daily) orally for two weeks. Doxorubicin caused cardiotoxicity as indicated by a significant increase in tumor necrosis factor-α, interleukin-6, malondialdehyde, and caspase-3 level (P<0.05), while total antioxidant capacity and Bcl-2 levels were significantly reduced in cardiac tissues of rats in the doxorubicin group compared to the normal saline control group (P<0.05). Dipyridamole significantly ameliorates doxorubicin-induced cardiotoxicity, as suggested by a significant decrease in inflammatory markers (tumor necrosis factor-α and interleukin-6) (P<0.05). Moreover, the cardiac tissue level of oxidative marker malondialdehyde was significantly decreased (P<0.05), and total antioxidant capacity significantly increased in the dipyridamole group in comparison to the doxorubicin-only group (P<0.05). Dipyridamole exerted a significant heart-protective effect against doxorubicin-induced cardiotoxicity in rats, probably via interfering with oxidative stress, inflammatory response, and apoptotic pathway. The goal of this study was to investigate the potential protective effect of dipyridamole against doxorubicin-induced cardiotoxicity via interfering with pro-inflammatory, oxidative, and apoptotic pathways.

Assessment of on-treatment platelet reactivity at high and low shear stress and platelet activation status after the addition of dipyridamole to aspirin in the early and late phases after TIA and ischaemic stroke

BackgroundData are limited on the ability of dipyridamole to additionally inhibit platelet function/reactivity in ischaemic cerebrovascular disease (CVD) patients on aspirin. AimsTo assess inhibition of platelet function/reactivity and platelet activation with dipyridamole in CVD. MethodsThis prospective, observational study assessed TIA/ischaemic stroke patients before (baseline; N = 60), at 14 ±7 days (14d, N = 39) and ≥ 90 days (90d, N = 31) after adding dipyridamole to aspirin. Platelet function/reactivity at high shear stress (PFA-100® C-ADP) and low shear stress (VerifyNow® P2Y12 and Multiplate® ADP assays), and platelet activation status (% expression of CD62P, CD63 and leucocyte-platelet complexes on whole blood flow cytometry) were quantified. ‘Dipyridamole-high on-treatment platelet reactivity (HTPR)’ was defined as failure to inhibit ADP-induced platelet aggregation +/- adhesion compared with the patient's baseline on aspirin monotherapy by more than twice the coefficient-of-variation of the assay after adding dipyridamole to aspirin. ResultsDipyridamole-HTPR was identified in 71.4–75% of patients on PFA-100 C-ADP, 83.9–86.8% of patients on VerifyNow P2Y12, and 81.5–83.3% of patients on Multiplate ADP assays. There were no changes in CD62P/CD63 expression (P ≥ 0.18), or consistent changes in leucocyte-platelet complexes in CVD patients overall at 14d or 90d vs. baseline after commencing dipyridamole. Monocyte-platelet complexes increased in the patient subgroup with dipyridamole-HTPR at 14d and 90d on PFA-100, and at 14d on VerifyNow (P ≤ 0.04), but not in those without dipyridamole-HTPR. DiscussionAdditional antiplatelet effects of dipyridamole are detectable under high and low shear stress conditions with user-friendly platelet function/reactivity tests ex vivo. Increasing circulating monocyte-platelet complexes over time are associated with dipyridamole-HTPR.

Lactobacillus plantarum HFY05 Attenuates Carrageenan-Induced Thrombosis in Mice by Regulating NF-κB Pathway-Associated Inflammatory Responses.

In this study, a carrageenan-induced thrombus model was established in mice to observe the ability of Lactobacillus plantarum KFY05 (LP-KFY05) to inhibit thrombosis through an NF-κB-associated pathway. Biochemical analysis, microscopical observations, quantitative polymerase chain reactions (qPCR) and western blot analysis were used to examine relevant serum and tissue indexes, and the composition of intestinal microorganisms was determined by examining the abundance of microorganisms in feces. The results showed that LP-KFY05 could markedly reduce the degree of black tail in thrombotic mice; increase the activated partial thromboplastin time (APTT); and decrease the thrombin time (TT), fibrinogen (FIB) level, and prothrombin time (PT). LP-KFY05 could also reduce tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) levels in sera and renal tissues of thrombotic mice. Hematoxylin and eosin staining showed that LP-KFY05 could alleviate renal tissue lesions and tail vein thrombosis. qPCR results showed that LP-KFY05 could down-regulate nuclear factor kappa-B (NF-κB) p65, IL-6, TNF-α, and interferon γ (IFN-γ) mRNA expression in renal tissues, as well as NF-κB p65, intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin mRNA expression in tail vein vascular tissues of thrombotic mice. Western blot analysis showed that LP-KFY05 also down-regulated NF-κB protein expression in renal and tail vein vascular tissues of thrombotic mice. Lastly, LP-KFY05 increased the abundances of Bacteroidetes, Lactobacillus, and Bifidobacterium, as well as decreased the abundance of Firmicutes. These results show that LP-KFY05 can reduce inflammation and inhibit thrombosis in thrombotic mice, and the effects of high concentrations of LP-KFY05 were most pronounced, which were similar to the effects of dipyridamole.

Effects of dipyridamole and its use in neurology

Dipyridamole has been on the pharmaceutical market since 1959 and, as a pyrimidyl-pyrimidine compound, has a variety of mechanisms of action. The very first action of dipyridamole was its antianginal effect. In subsequent years, attention was drawn to the antiplatelet properties of dipyridamole, which are related to inhibition of platelet phosphodiesterase as well as to blocking adenosine transport. Another important property of dipyridamole is its effect on the deformability of red blood cells, thereby improving microcirculation. Dipyridamole affects changes in the dynamics of platelet activity and vascular reactivity and causes improvement of cerebral perfusion. Due to its pronounced antiplatelet properties, the drug has been widely studied for the prevention of ischemic strokes and transient ischemic attacks, both as monotherapy and in combination with other drugs. Unlike other platelet antiaggregants, dipyridamole does not have a damaging effect on mucous membranes. Its antiplatelet effect is not accompanied with inhibition of cyclooxygenase activity and reduction of prostacyclin synthesis. In the treatment of cerebral circulation disorders, dipyridamole can be used to control the antithrombotic effect by selecting the optimal dose of the drug. Dipyridamole has antioxidant properties, enhances NO-mediated pathways, has indirect anti-inflammatory effects via adenosine and prostaglandin-2 as well as direct anti-inflammatory effects and several other effects. Dipyridamole is considered a safe drug based on decades of clinical experience. Its side effects are usually limited and transient. Given the diverse effects of dipyridamole, it can be used for a wide range of pathologies other than thrombosis prevention. Data on the efficacy and safety of dipyridamole in various diseases of the neurological spectrum are presented.

Cytotoxic and genotoxic evaluation of dipyridamole and its alternative therapeutic potential in cancer therapy: an in vitro and in vivo approach.

The molecular mechanism behind the anti-cancer potential of dipyridamole, an antiplatelet drug was investigated by examining the interaction of dipyridamole with DNA as well as the genotoxicity and cytotoxicity associated with dipyridamole . Interaction of dipyridamole with calf thymus DNA (Ct-DNA) was determined in order to ascertain the strength and mode of binding as well as the thermodynamic parameters involved. Dipyridamole interacts with Ct-DNA through a groove binding mechanism. Furthermore, a preliminary assessment of the genotoxic effect of dipyridamole was performed in vitro using the plasmid nicking assay and comet assay. Genotoxicity was also confirmed through DAPI nuclear staining of HeLa and HCT-116 cells. Cytotoxicity was assessed in vitro on HeLa, HCT-116 as well as HEK293 cells using the MTT assay as well as through inverted microscopy. Dipyridamole was selectively more toxic towards cancer cells. Dipyridamole demonstrated induction of micronucleus and chromosomal aberrations only at high concentrations in bone marrow cells of male Wistar rats, suggesting its safe usage at clinically relevant concentrations. These results indicated the existence of an intrinsic genotoxic potential of dipyridamole which may be contributing to its anti-cancer properties.

Interventions for preventing thrombosis in solid organ transplant recipients.

Interventions for preventing thrombosis in solid organ transplant recipients.

Exosomal HMGB1 Promoted Cancer Malignancy.

Simple SummaryIn addition to their role in hemostasis and thrombosis, platelets have been implicated in cancer malignancy and thrombocytosis in cancer patients and have been associated with an adverse prognosis. These phenomena indicate that antiplatelet drugs may be useful as an anticancer therapy. Using K562-differentiated megakaryocytes and murine platelets, conditioned medium and exosomes obtained from megakaryocytes and platelets contained high-mobility group box 1 (HMGB1) and promoted cancer cell survival, as well as protected cancer cells from doxorubicin cytotoxicity. Data of tumor-bearing mice established by Lewis lung carcinoma (LLC) cells and C57BL/6 mice revealed that antiplatelet drug dipyridamole and exosome release inhibitor GW4869 mitigated tumor growth and ameliorated concurrent alterations in blood circulation and tumor tissues, as well as platelet infiltration in tumor tissues. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.Reciprocal crosstalk between platelets and malignancies underscores the potential of antiplatelet therapy in cancer treatment. In this study, we found that human chronic myeloid leukemia K562 cell-differentiated megakaryocytes and murine platelets produced bioactive substances and these are released into the extracellular space, partly in their exosomal form. High-mobility group box 1 (HMGB1) is a type of exosomal cargo, and the antiplatelet drugs aspirin and dipyridamole interfered with its incorporation into the exosomes. Those released substances and exosomes, along with exogenous HMGB1, promoted cancer cell survival and protected cells from doxorubicin cytotoxicity. In a tumor-bearing model established using murine Lewis lung carcinoma (LLC) cells and C57BL/6 mice, the tumor suppressive effect of dipyridamole correlated well with decreased circulating white blood cells, soluble P-selectin, TGF-β1 (Transforming Growth Factor-β1), exosomes, and exosomal HMGB1, as well as tumor platelet infiltration. Exosome release inhibitor GW4869 exhibited suppressive effects as well. The suppressive effect of dipyridamole on cancer cell survival was paralleled by a reduction of HMGB1/receptor for advanced glycation end-products axis, and proliferation- and migration-related β-catenin, Yes-associated protein 1, Runt-related transcription factor 2, and TGF- β1/Smad signals. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.