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.

The Impact of Dipyridamole on Disease-Associated Microglia Phenotypic Transformation in White Matter Lesions Induced by Chronic Cerebral Hypoperfusion.

White matter lesions (WMLs) resulting from chronic cerebral hypoperfusion (CCH) are the leading cause of vascular dementia (VaD). This study aimed to investigate whether dipyridamole could alleviate WMLs by regulating the phenotype of disease-associated microglia (DAM) through equilibrative nucleoside transporter 2 (ENT2) and adenosine A2A receptor (Adora2a) and to clarify the underlying molecular mechanisms. CCH rat models were constructed to mimic VaD. Morris water maze and Luxol Fast Blue staining were employed to assess cognitive function and quantify the severity of WMLs, respectively. Immunofluorescent staining was performed to analyze the activation of glial cells and the phenotypic transformation of DAM. Additionally, levels of ENT2, proteins in the NF-κB and ERK1/2 pathways and inflammatory cytokines were detected. The results indicated that dipyridamole diminished the activation and proliferation of microglia and astrocytes, increased the expression of myelin basic protein and ameliorated WMLs and cognitive decline in CCH rats. Further study revealed that dipyridamole decreased the expression of ENT2 and inhibited the activation of ERK1/2 and NF-κB signaling pathways, which ultimately converted DAM to anti-inflammatory phenotype and suppressed the levels of TNF-α, IL-1ß, IL-6 in WMLs. However, Adora2a inhibitor (SCH58261) attenuated above effects. Our study demonstrates that dipyridamole facilitates the conversion of DAM to the anti-inflammatory phenotype through ENT2/Adora2a pathway and inhibits the activation of ERK1/2 and NF-κB signaling pathways, thereby alleviating neuroinflammation in WMLs. The current findings establish the basis for using dipyridamole to treat VaD.

Comparative evaluation of single and combined efficacy of dipyridamole, ketotifen and quercetin on cyclosporine induced hepatorenal toxicity.

Cyclosporine is an immunosuppressive drug that is used to prevent tissue rejection in organ transplants and to treat autoimmune diseases such as psoriasis and rheumatoid arthritis. It has important toxic effects in many organs such as the liver and kidney. The aim of this study was to determine and compare the effectiveness of the single and combined treatment of dipyridamole, which is a vasodilator and has an antioxidant effect, ketotifen which is toll-like receptor-4 inhibitory and has an antioxidant effect, quercetin which is an antioxidant and has an anti-inflammatory effect in cyclosporine-induced hepatorenal toxicity. Forty-eight Wistar Albino rats were divided into 7 groups. The research period was 21 days. The cyclosporine increased serum ALT and AST levels, in contrast to their increased levels prevented by all the treatments. The serum creatinine level decreased significantly with ketotifen and combined treatment, while cyclosporine partially increased serum creatinine and urea levels. The urine microalbumin and protein levels were increased significantly by cyclosporine, whereas they decreased with dipyridamole treatment. The protein levels decreased by quercetin and combined treatments. The kidney injury molecule- 1 and retinol-binding protein levels were increased by the cyclosporine, while ketotifen treatment partially decreased them. In conclusion, ketotifen and dipyridamole can prevent cyclosporine- induced hepatorenal toxicity and quercetin can increase the effectiveness of this treatment.

Bleeding with intensive versus guideline antiplatelet therapy in acute cerebral ischaemia.

Intensive antiplatelet therapy did not reduce recurrent stroke/transient ischaemic attack (TIA) events as compared with guideline treatment in the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial, but did increase the frequency and severity of bleeding. In this pre-specified analysis, we investigated predictors of bleeding and the association of bleeding with outcome. TARDIS was an international prospective randomised open-label blinded-endpoint trial in participants with ischaemic stroke or TIA within 48 h of onset. Participants were randomised to 30 days of intensive antiplatelet therapy (aspirin, clopidogrel, dipyridamole) or guideline-based therapy (either clopidogrel alone or combined aspirin and dipyridamole). Bleeding was defined using the International Society on Thrombosis and Haemostasis five-level ordered categorical scale: fatal, major, moderate, minor, none. Of 3,096 participants, bleeding severity was: fatal 0.4%, major 1.5%, moderate 1.2%, minor 11.4%, none 85.5%. Major/fatal bleeding was increased with intensive as compared with guideline therapy: 39 vs. 17 participants, adjusted hazard ratio 2.21, 95% CI 1.24-3.93, p = 0.007. Bleeding events diverged between treatment groups in the 8-35 day period but not in the 0-7 or 36-90 day epochs. In multivariate analysis more, and more severe, bleeding events were seen with increasing age, female sex, pre-morbid dependency, increased time to randomisation, prior major bleed, prior antiplatelet therapy and in those randomised to triple vs guideline antiplatelet therapy. More severe bleeding was associated with worse clinical outcomes across multiple physical, emotional and quality of life domains.Trial registration ISRCTN47823388 .

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

PURPOSE: 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. METHODS: 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, an Apcmin/+ 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. RESULTS: 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. CONCLUSIONS: 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.

Antiplatelet drugs and breast cancer risk in a large nationwide Danish case-control study.

Low-dose aspirin has been hypothesized to prevent cancer risk by inhibiting platelet aggregation. However, the anti-cancer effect of low-dose aspirin has recently been questioned and its effect on breast cancer development remains unclear. The impact of other antiplatelet drugs on breast cancer risk has rarely been evaluated. Thus, this study aimed to investigate the associations between breast cancer risk and antiplatelet drug use in a nationwide nested case-control study. From the Danish healthcare registries, we identified as cases all women with invasive breast cancer diagnosis between 2001 and 2018 (n = 68 852). The date of diagnosis corresponded to the index date. We matched cases to 10 population controls on age and calendar time, using risk set sampling. Controls were assigned the same index date as their matched case. We used the prescription registry to identify exposure to low-dose aspirin, clopidogrel and dipyridamole. We defined ever use of antiplatelet drugs as at least two prescriptions filled up to 1 year before the index date. We applied conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for breast cancer associated with the use of antiplatelet drugs, overall, by breast cancer subtype and by cumulative dose. Twelve percent of women had ever been exposed to low-dose aspirin, 2% to clopidogrel and 2% to dipyridamole. In multivariable models, breast cancer risk was not associated with ever use of low-dose aspirin (OR = 1.00 [0.97-1.03]), clopidogrel (OR = 0.93 [0.87-1.00]), and dipyridamole (OR = 1.02 [0.94-1.10]), compared with never use, and there was no evidence of a dose-response relation. However, we found an inverse association between dipyridamole use and breast cancer risk among women aged <55 years old, with suggestion of a dose-response relationship (OR per 1000 Defined Daily Doses = 0.72 [0.54-0.95]). Associations did not differ by breast cancer histological type, estrogen receptor status or clinical stage at diagnosis. Overall, the findings from this study do not support the use of antiplatelet drugs for breast cancer prevention.

Antiplatelet agents aspirin and dipyridamole, and the risk of different carcinoma in patients with type 2 diabetes mellitus: A Taiwan retrospective cohort study.

Studies have shown aspirin decreases the risk of some cancers. However, the evidence reported the association between aspirin and cancer risk in the diabetic population. In this study, we investigate whether aspirin and dipyridamole decrease the risk of cancer in patients with type 2 diabetes. A total of 5308 patients with type 2 diabetes were identified by the National Health Insurance from 1998 to 2000 and followed up until 2013. The demographic characteristics among nondipyridamole nor aspirin, aspirin, and dipyridamole users were analyzed by using the χ(2) test. Cox proportional hazard regression models were used to determine the independent effects of no aspirin nor dipyridamole, aspirin, and dipyridamole users on the risk of different cancer. After adjustment with multiple covariates, both low and high doses of aspirin and dipyridamole decrease liver cancer with risk ratios of 0.56 (95% CI, 0.37-0.83), 0.14 (95% CI, 0.05-0.39), 0.61 (95% CI, 0.38-0.99), and 0.28 (95% CI, 0.12-0.66), respectively. Both low and high doses of aspirin decrease any types of cancer with risk ratios of 0.79 (95% CI, 0.64-0.98) and 0.49 (95% CI, 0.34-0.70), respectively. Therefore, we conclude aspirin may decrease any types of cancer and liver cancer, and dipyridamole may decrease the risk of liver cancer in patients with type 2 diabetes.

Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold: SAR of the Aryloxyaryl Moiety.

In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.

Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases.

Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.

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.

BACKGROUND: Data are limited on the ability of dipyridamole to additionally inhibit platelet function/reactivity in ischaemic cerebrovascular disease (CVD) patients on aspirin. AIMS: To assess inhibition of platelet function/reactivity and platelet activation with dipyridamole in CVD. METHODS: This 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. RESULTS: Dipyridamole-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. DISCUSSION: Additional 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.

Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis.

Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with the assistance of molecular docking. Among all the twenty-four synthesized compounds, compound (S)-4h showed outstanding metabolic stability (T1/2 = 67 min) in RLM, with an IC50 of 332 nM against PDE5. Furthermore, some interesting structure-activity relationships (SAR) were explained with the assistance of molecular docking.

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study.

Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC.

Use of dipyridamole is associated with lower risk of lymphoid neoplasms: a propensity score-matched cohort study.

The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.

Why Not Dipyridamole: a Review of Current Guidelines and Re-evaluation of Utility in the Modern Era.

Dipyridamole is an old anti-platelet and coronary vasodilator agent that inhibits platelet phosphodiesterase and increases interstitial adenosine levels. Its use in coronary artery disease (CAD) has fallen out of practice in the modern era with the advent of new anti-platelet agents, and most modern guidelines on the management of CAD either neglect to comment on its utility or outright recommend against it. The majority of the studies used in these guidelines are outdated and took place in an era when high doses of aspirin were used and statins were not widely utilized. There is growing evidence in rat models of dipyridamole's synergy with statins through adenosine modulation resulting in significant myocardial protection against ischemia-reperfusion injury and limitation of infract size. The data in human studies are limited but show a similar potential synergy between dipyridamole and statins. It would thus be prudent to reconsider the recommendations against the use of dipyridamole in CAD and to re-evaluate its possible role and potential benefits through well-designed randomized trials combining it with statins, low-dose aspirin, and/or other anti-platelet agents.

Balancing Benefits and Risks of Long-Term Antiplatelet Therapy in Noncardioembolic Transient Ischemic Attack or Stroke.

Background and Purpose: Lifelong treatment with antiplatelet drugs is recommended following a transient ischemic attack or ischemic stroke. Bleeding complications may offset the benefit of antiplatelet drugs in patients at increased risk of bleeding and low risk of recurrent ischemic events. We aimed to investigate the net benefit of antiplatelet treatment according to an individuals' bleeding risk. Methods: We pooled individual patient data from 6 randomized clinical trials (CAPRIE [Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events], ESPS-2 [European Stroke Prevention Study-2], MATCH [Management of Atherothrombosis With Clopidogrel in High-Risk Patients], CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance], ESPRIT [European/Australasian Stroke Prevention in Reversible Ischemia Trial], and PRoFESS [Prevention Regimen for Effectively Avoiding Second Strokes]) investigating antiplatelet therapy in the subacute or chronic phase after noncardioembolic transient ischemic attack or stroke. Patients were stratified into quintiles according to their predicted risk of major bleeding with the S2TOP-BLEED score. The annual risk of major bleeding and recurrent ischemic events was assessed per quintile for 4 scenarios: (1) aspirin monotherapy, (2) aspirin-clopidogrel versus aspirin or clopidogrel monotherapy, (3) aspirin-dipyridamole versus clopidogrel, and (4) aspirin versus clopidogrel. Net benefit was calculated for the second, third, and fourth scenario. Results: Thirty seven thousand eighty-seven patients were included in the analyses. Both risk of major bleeding and recurrent ischemic events increased over quintiles of predicted bleeding risk, but risk of ischemic events was consistently higher (eg, from 0.7%/y (bottom quintile) to 3.2%/y (top quintile) for major bleeding on aspirin and from 2.5%/y to 10.2%/y for risk of ischemic events on aspirin). Treatment with aspirin-clopidogrel led to more major bleedings (0.9%­1.7% per year), than reduction in ischemic events (ranging from 0.4% to 0.9/1.0% per year) across all quintiles. There was no clear preference for either aspirin-dipyridamole or clopidogrel according to baseline bleeding risk. Conclusions: Among patients with a transient ischemic attack or ischemic stroke included in clinical trials of antiplatelet therapy, the risk of recurrent ischemic events and of major bleeding increase in parallel. Antiplatelet treatment cannot be individualized solely based on bleeding risk assessment.

A Randomized, Placebo-Controlled Crossover Study with Dipyridamole for Restless Legs Syndrome.

BACKGROUND: New pharmacological targets are needed for restless legs syndrome. Preclinical data suggest that a hypoadenosinergic state plays an important pathogenetic role. OBJECTIVE: The objective of this study was to determine whether inhibitors of equilibrative nucleoside transporters, for example, dipyridamole, could provide effective symptomatic treatment. METHODS: A 2-week double-blind, placebo-controlled crossover study assessed the efficacy of dipyridamole (possible up-titration to 300 mg) in untreated patients with idiopathic restless legs syndrome. Multiple suggested immobilization tests and polysomnography were performed after each treatment phase. Severity was assessed weekly using the International Restless Legs Rating Scale, Clinical Global Impression, and the Medical Outcomes Study Sleep scale. The primary end point was therapeutic response. RESULTS: Twenty-eight of 29 patients recruited were included. International Restless Legs Rating Scale scores improved from a mean ± standard deviation of 24.1 ± 3.1 at baseline to 11.1 ± 2.3 at the end of week 2, versus 23.7 ± 3.4 to 18.7 ± 3.2 under placebo (P < 0.001). Clinical Global Impression, Medical Outcomes Study Sleep, and Multiple Suggested Immobilization Test scores all improved (P < 0.001). The mean effective dose of dipyridamole was 217.8 ± 33.1 mg/d. Sleep variables improved. The mean periodic leg movement index at the end of treatment with dipyridamole was 8.2 ± 3.5 versus. 28.1 ± 6.7 under placebo. Side effects (dipyridamole vs placebo) included abdominal distension (18% vs. 7%), dizziness (10.7% vs 7.1%), diarrhea, and asthenia (each 7.1% vs 3.6%). CONCLUSIONS: Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Combined therapy of hypertensive nephropathy with ginkgo leaf extract and dipyridamole injection and antihypertensive drugs: A systematic review and meta-analysis.

BACKGROUND: In recent years, the incidence rate of hypertensive nephropathy has been increasing quickly, which has been a major threat to people's health. Renin-angiotensin-aldosterone system blockers have certain curative effects. However, there are some patients having serious adverse reactions, and the benefit population is limited, so the treatment of hypertensive renal damage is necessary to have beneficial supplement. More and more clinical studies have shown that ginkgo leaf extract and dipyridamole injection (GDI) combined with antihypertensive drugs has achieved good results in the treatment of hypertensive renal damage. It is supposed to be a supplementary treatment in hypertensive nephropathy. OBJECTIVES: To systematically assess the efficacy and safety of GDI combined with antihypertensive drugs on hypertensive renal injury. METHODS: Seven databases including PubMed, Cochrane Library, Embase, Wanfang database, China biomedical literature service system (Sino Med), VIP Chinese Sci-tech journal database (VIP), and China national knowledge internet (CNKI) were retrieved to collect randomized controlled trials (RCTs) in the experimental group containing combined therapy of hypertensive nephropathy with GDI and antihypertensive drugs. The retrieval time was from the establishment of database to July 8, 2020. Two researchers independently selected literature, extracted data, and evaluated the risk of bias in the study. The methodological quality was evaluated with Cochrane handbook and meta-analysis was performed with Stata 14.0 software. RESULTS: Eight studies were included in this study which involved 556 patients. The meta-analyses indicated that, compared with using antihypertensive drugs alone, combined treatment of GDI with antihypertensive drugs can decrease 24-hour urinary total protein (weighted mean difference [WMD] -0.61, 95% confidence interval [CI]: -0.82, -0.39; k = 6, P ≤ .001), blood urea nitrogen (WMD -1.27, 95% CI: -2.45, -0.10; k = 6, P = .033, serum creatinine (WMD -29.50, 95% CI: -56.44, -2.56; number of estimates [k] = 6, P = .032). CONCLUSIONS: Our meta-analyses showed that GDI combined with antihypertensive drugs can improve the renal function of hypertensive patients with renal injury.

Interventions for preventing thrombosis in solid organ transplant recipients.

BACKGROUND: Graft thrombosis is a well-recognised complication of solid organ transplantation and is one of the leading causes of graft failure. Currently there are no standardised protocols for thromboprophylaxis. Many transplant units use unfractionated heparin (UFH) and fractionated heparins (low molecular weight heparin; LMWH) as prophylaxis for thrombosis. Antiplatelet agents such as aspirin are routinely used as prophylaxis of other thrombotic conditions and may have a role in preventing graft thrombosis. However, any pharmacological thromboprophylaxis comes with the theoretical risk of increasing the risk of major blood loss following transplant. This review looks at benefits and harms of thromboprophylaxis in patients undergoing solid organ transplantation. OBJECTIVES: To assess the benefits and harms of instituting thromboprophylaxis to patients undergoing solid organ transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 November 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) and quasi-RCTs designed to examine interventions to prevent thrombosis in solid organ transplant recipients. All donor types were included (donor after circulatory (DCD) and brainstem death (DBD) and live transplantation). There was no upper age limit for recipients in our search. DATA COLLECTION AND ANALYSIS: The results of the literature search were screened and data collected by two independent authors. Dichotomous outcome results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Random effects models were used for data analysis. Risk of bias was independently assessed by two authors using the risk of bias assessment tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified nine studies (712 participants). Seven studies (544 participants) included kidney transplant recipients, and studies included liver transplant recipients. We did not identify any study enrolling heart, lung, pancreas, bowel, or any other solid organ transplant recipient. Selection bias was high or unclear in eight of the nine studies; five studies were at high risk of bias for performance and/or detection bias; while attrition and reporting biases were in general low or unclear. Three studies (180 participants) primarily investigated heparinisation in kidney transplantation. Only two studies reported on graft vessel thrombosis in kidney transplantation (144 participants). These small studies were at high risk of bias in several domains and reported only two graft thromboses between them; it therefore remains unclear whether heparin decreases the risk of early graft thrombosis or non-graft thrombosis (very low certainty). UFH may make little or no difference versus placebo to the rate of major bleeding events in kidney transplantation (3 studies, 155 participants: RR 2.92, 95% CI 0.89 to 9.56; I² = 0%; low certainty evidence). Sensitivity analysis using a fixed-effect model suggested that UFH may increase the risk of haemorrhagic events compared to placebo (RR 3.33, 95% CI 1.04 to 10.67, P = 0.04). Compared to control, any heparin (including LMWH) may make little or no difference to the number of major bleeding events (3 studies, 180 participants: RR 2.70, 95% CI 0.89 to 8.19; I² = 0%; low certainty evidence) and had an unclear effect on risk of readmission to intensive care (3 studies, 180 participants: RR 0.68, 95% CI 0.12 to 3.90, I² = 45%; very low certainty evidence). The effect of heparin on our other outcomes (including death, patient and graft survival, transfusion requirements) remains unclear (very low certainty evidence). Three studies (144 participants) investigated antiplatelet interventions in kidney transplantation: aspirin versus dipyridamole (1), and Lipo-PGE1 plus low-dose heparin to "control" in patients who had a diagnosis of acute rejection (2). None of these reported on early graft thromboses. The effect of aspirin, dipyridamole and Lipo PGE1 plus low-dose heparin on any outcomes is unclear (very low certainty evidence). Two studies (168 participants) assessed interventions in liver transplants. One compared warfarin versus aspirin in patients with pre-existing portal vein thrombosis and the other investigated plasmapheresis plus anticoagulation. Both studies were abstract-only publications, had high risk of bias in several domains, and no outcomes could be meta-analysed. Overall, the effect of any of these interventions on any of our outcomes remains unclear with no evidence to guide anti-thrombotic therapy in standard liver transplant recipients (very low certainty evidence). AUTHORS' CONCLUSIONS: Overall, there is a paucity of research in the field of graft thrombosis prevention. Due to a lack of high quality evidence, it remains unclear whether any therapy is able to reduce the rate of early graft thrombosis in any type of solid organ transplant. UFH may increase the risk of major bleeding in kidney transplant recipients, however this is based on low certainty evidence. There is no evidence from RCTs to guide anti-thrombotic strategies in liver, heart, lung, or other solid organ transplants. Further studies are required in comparing anticoagulants, antiplatelets to placebo in solid organ transplantation. These should focus on outcomes such as early graft thrombosis, major haemorrhagic complications, return to theatre, and patient/graft survival.

Revisiting the Evidence for Dipyridamole in Reducing Restenosis: A Systematic Review and Meta-analysis.

ABSTRACT: Atherosclerosis remains a leading cause of morbidity and mortality, with revascularization remaining a cornerstone of management. Conventional revascularization modalities remain challenged by target vessel reocclusion-an event driven by mechanical, thrombotic, and proliferative processes. Despite considerable advancements, restenosis remains the focus of ongoing research. Adjunctive agents, including dipyridamole, offer a multitude of effects that may improve vascular homeostasis. We sought to quantify the potential therapeutic impact of dipyridamole on vascular occlusion. We performed a literature search (EMBASE and MEDLINE) examining studies that encompassed 3 areas: (1) one of the designated medical therapies applied in (2) the setting of a vascular intervention with (3) an outcome including vascular occlusion rates and/or quantification of neointimal proliferation/restenosis. The primary outcome was vascular occlusion rates. The secondary outcome was the degree of restenosis by neointimal quantification. Both human and animal studies were included in this translational analysis. There were 6,839 articles screened, from which 73 studies were included, encompassing 16,146 vessels followed up for a mean of 327.3 days (range 7-3650 days). Preclinical studies demonstrate that dipyridamole results in reduced vascular occlusion rates {24.9% vs. 48.8%, risk ratio 0.53 [95% confidence interval (CI) 0.40-0.70], I2 = 39%, P < 0.00001}, owing to diminished neointimal proliferation [standardized mean differences -1.13 (95% CI -1.74 to -0.53), I2 = 91%, P = 0.0002]. Clinical studies similarly demonstrated reduced occlusion rates with dipyridamole therapy [23.5% vs. 31.0%, risk ratio 0.77 (95% CI 0.67-0.88), I2 = 84%, P < 0.0001]. Dipyridamole may improve post-intervention vascular patency and mitigate restenosis. Dedicated studies are warranted to delineate its role as an adjunctive agent after revascularization.