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.

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 Scientifific 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% confifidence 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], fifibrinogen [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 confifirm our fifindings and provide further evidence for the clinical utility of GD.

Antiplatelet Therapy and Adverse Hematologic Events During Heart Mate II Support.

BACKGROUND: Hematologic adverse events are common during continuous flow left ventricular assist device support; yet, their relation to antiplatelet therapy, including aspirin (ASA) dosing, is uncertain. METHODS AND RESULTS: A single-center retrospective review of all patients supported by a continuous flow left ventricular assist device (Heart Mate II) from June 2006 to November 2014 was conducted. Patients were categorized into 3 groups: (1) ASA 81 mg+dipyridamole 75 mg daily (n = 26) with a target international normalized ratio (INR) of 2 to 3 from June 2006 to August 2009; (2) ASA 81 mg daily (n = 18) from September 2009 to August 2011 with a target INR of 1.5 to 2; and (3) ASA 325 mg daily from September 2011 to November 2014 with a target INR of 2 to 3 (n = 70). Hemorrhagic and thrombotic outcomes were retrieved ≤ 365 days after implantation. Cumulative survival free from adverse events was calculated using Kaplan-Meier curves and Cox proportional hazard ratios were generated. Hemorrhagic events occurred in 6 patients on ASA 81 mg+dipyridamole (26%; 0.42 events per patient year; mean INR at event, 2.2), 4 patients on ASA 81 mg (22%; 0.38 events per patient year; mean INR at event, 2.0), and in 38 patients on ASA 325 mg (54%; 1.4 events per patient year; mean INR at event, 2.2); P = 0.004. Patients on ASA 325 mg had a higher adjusted hazard ratio of 2.9 (95% confidence interval, 1.2-7.0 versus ASA 81 mg+dipyridamole; P = 0.02) and 3.4 (95% confidence interval, 1.2-9.5 versus ASA 81 mg; P = 0.02) for hemorrhagic events. Thrombotic events rates were not different between groups. CONCLUSIONS: High-dose ASA in Heart Mate II patients treated concomitantly with warfarin is associated with an increased hazard of bleeding but does not reduce thrombotic events.

Effect of diallyl trisulfide on the pharmacokinetics of dipyridamole in rats.

This study was aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic used to inhibit platelet thromboxane formation, on the pharmacokinetics of dipyridamole. Pharmacokinetic parameters of dipyridamole were determined in rats following intragastric (80 mg/kg suspension or 40 mg/kg solution) or intravenous (3 mg/kg) administration of dipyridamole with coadministration (20 mg/kg) and long-term pretreatment of DATS (10 or 20 mg/kg/day for 15 consecutive days). In addition, everted gut sac models were used to assess transepithelial transport of dipyridamole and the effect of DATS on the intestinal absorption of dipyridamole. After coadministration and long-term pretreatment of DATS, significantly lower Cmax and AUC(0-24 h) were observed for intragastric administration of dipyridamole, whereas little change was noted after intravenous dipyridamole administration. After adding DATS (10 and 50 µg/mL) in the everted gut sacs, absorption of dipyridamole was remarkably decreased in the ileum and jejunum (p < 0.01). In conclusion, DATS reduced the oral exposure of dipyridamole in rats likely by the modification of the dissolution rate and intestinal absorption of dipyridamole, indicating that combined use of DATS or DATS-containing supplements with dipyridamole may require caution as low plasma concentrations of dipyridamole may lead to a subtherapeutic effect of this agent.

Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset.

BACKGROUND AND PURPOSE: Antiplatelets (APs) may increase the risk of symptomatic intracerebral hemorrhage (ICH) following intravenous thrombolysis after ischemic stroke. METHODS: We assessed the safety of thrombolysis under APs in 11,865 patients compliant with the European license criteria and recorded between 2002 and 2007 in the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register (SITS-ISTR). Outcome measures of univariable and multivariable analyses included symptomatic ICH (SICH) per SITS Monitoring Study (SITS-MOST [deterioration in National Institutes of Health Stroke Scale >or=4 plus ICH type 2 within 24 hours]), per European Cooperative Acute Stroke Study II (ECASS II [deterioration in National Institutes of Health Stroke Scale >or=4 plus any ICH]), functional outcome at 3 months and mortality. RESULTS: A total of 3782 (31.9%) patients had received 1 or 2 AP drugs at baseline: 3016 (25.4%) acetylsalicylic acid (ASA), 243 (2.0%) clopidogrel, 175 (1.5%) ASA and dipyridamole, 151 (1.3%) ASA and clopidogrel, and 197 (1.7%) others. Patients receiving APs were 5 years older and had more risk factors than AP naïve patients. Incidences of SICH per SITS-MOST (ECASS II respectively) were as follows: 1.1% (4.1%) AP naïve, 2.5% (6.2%) any AP, 2.5% (5.9%) ASA, 1.7% (4.2%) clopidogrel, 2.3% (5.9%) ASA and dipyridamole, and 4.1% (13.4%) ASA and clopidogrel. In multivariable analyses, the combination of ASA and clopidogrel was associated with increased risk for SICH per ECASS II (odds ratio, 2.11; 95% CI, 1.29 to 3.45; P=0.003). However, we found no significant increase in the risk for mortality or poor functional outcome, irrespective of the AP subgroup or SICH definition. CONCLUSIONS: The absolute excess of SICH of 1.4% (2.1%) in the pooled AP group is small compared with the benefit of thrombolysis seen in randomized trials. Although caution is warranted in patients receiving the combination of ASA and clopidogrel, AP treatment should not be considered a contraindication to thrombolysis.

Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke.

Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TIA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.

Enhanced antiplatelet effects of clopidogrel plus acetylsalicylic acid compared with acetylsalicylic acid alone or combined with extended-release dipyridamole in healthy volunteers.

BACKGROUND: Previous studies have shown the potential benefit of using antiplatelet agents with complementary modes of action. METHODS: Using a crossover design, the ex vivo antiplatelet effects of 10 days' treatment with clopidogrel 75 mg + acetylsalicylic acid (ASA) 75 mg daily, ASA 75 mg/day, or extended-release dipyridamole 200 mg/low-dose ASA 25 mg twice daily were compared, using various platelet agonists. RESULTS: Clopidogrel + ASA was significantly more effective than dipyridamole + ASA in inhibiting collagen-induced platelet aggregation in whole blood (mean 44.9 +/- 5.6% inhibition vs. 16.5 +/- 6.7%; p = 0.0009). Clopidogrel + ASA was significantly more effective than ASA or dipyridamole + ASA in inhibiting ADP-induced platelet aggregation in whole blood (p < or = 0.0001) and platelet-rich plasma (PRP) (p < or = 0.0001), and in inhibiting collagen-induced aggregation in PRP (p < or = 0.0001). ASA alone and clopidogrel + ASA were significantly more effective than dipyridamole + ASA in inhibiting arachidonic acid-induced platelet aggregation in whole blood (p < or = 0.0001). CONCLUSIONS: Based on ex vivo platelet aggregometry, clopidogrel + ASA is a more potent antiplatelet regimen than either ASA alone or the marketed combination of dipyridamole + ASA. However, the clinical significance of this finding remains to be confirmed.

Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: acceptable toxicity and suggestion of improved 1-year disease-free survival.

PURPOSE: (1) To determine the toxicity of an intensified postoperative adjuvant regimen for periampullary adenocarcinoma (pancreatic and nonpancreatic) utilizing concurrent 5-fluorouracil (5-FU), leucovorin (LV), dipyridamole (DPM), and mitomycin-C (MMC) combined with split-course locoregional external beam radiotherapy (EBRT) to 50 Gy. This was followed by 4 cycles of the same chemotherapy as adjuvant therapy. (2) To determine preliminary estimates of the overall and disease-free survival associated with the use of this regimen. (3) To compare the toxicities and early survival results of patients treated with the current regimen to those of patients who completed our prior trial of concurrent chemoradiation infusion with 5-FU/LV chemotherapy and regional nodal and prophylactic hepatic irradiation. METHODS: Postpancreaticoduodenectomy, patients received every 4 weeks bolus administration of 5-FU, (400 mg/m(2)), and LV, (20 mg/m(2), Days l-3), DPM (75 mg p.o., 4 times per day, Days 0-3, and every 8 weeks), MMC, (10 mg/m(2); maximum of 20 mg, Day l during EBRT). This was followed by 4 months of the same chemotherapy, beginning 1 month following the completion of EBRT. EBRT consisted of split-course 5000 cGy/20 fractions with a 2-week planned rest after the first 10 fractions (2500 cGy). RESULTS: From 4/96 to 6/99, 45 patients were enrolled and treated. Their experience constitutes the basis of this analysis. There were 29 patients with pancreatic cancer and 16 with nonpancreatic periampullary cancer. Seventeen patients had tumors of 3 cm or more, and 39 patients had at least 1 histologically involved lymph node. Thirteen patients had a histologically positive margin of resection. The mean time to start of treatment was 63 days following surgery. During chemoradiation therapy there were no Grade 3 or worse nonhematologic toxicities and 47% Grade 3 or Grade 4 hematologic toxicities of short duration. Following chemoradiation, during chemotherapy treatment only, there was one Grade 3 hepatic and one Grade 3 pulmonary toxicity which was nondebilitating (2% each case) and 42% Grade 3 or 4 hematologic toxicity. There were 2 episodes of neutropenic fever requiring admission and no treatment-related mortalities. One patient developed a mild case of HUS, which responded to standard management. One patient developed persistent shortness of breath (nondebilitating), and another patient had occasional dyspnea on exertion, both occurring after all therapy. The majority of patients complained of increased fatigue (Grade 1-2), greatest during the combined therapy and improving post all treatment. As of 6/23/99, 20 of 45 patients have relapsed, 13 in the liver. Twelve patients have died. Median follow-up for surviving patients is 14.3 months. Disease-free survival at 12 months following surgery is 66% (as compared to 25% in our prior study), and the median disease-free survival is 17 months (as compared to 8. 3 months in our prior study). Median survival has not yet been reached, but will be greater than 17 months. CONCLUSION: With a 14.3-month median follow-up, acute toxicity has been acceptable and manageable. Observed relapses were seen 9-13 months following surgical resection. Early survival analysis suggests a trend toward increased median disease-free survival (8.3 vs. 17 months), especially for patients with nonpancreatic periampullary adenocarcinoma.

Fluorouracil, high-dose folinic acid, low-dose alpha-2b interferon and dipyridamole in the treatment of advanced colorectal cancer. A pilot study.

Twenty-six patients with advanced colorectal cancer were treated with a combination based on multimodal biochemical modulation of 5-fluorouracil by means of high dose folinic acid, low-dose alpha-2b interferon and dipyridamole. The overall response rate was 42% (95% confidence intervals = 23%. 61%) with four complete remissions (15%). The median duration of response was 9 months and the median survival for responders was 15 months (all patients = 12 months). Toxic side effects included oral mucositis (grade III-IV = 38%) and a generally mild flu-like syndrome. This regimen seems active and safe enough to be compared with the combination of fluorouracil and high-dose folinic acid.

Dipyridamole combination chemotherapy can be used safely in treating gastric cancer patients.

The feasibility of a combined chemotherapy using dipyridamole (DP) with adriamycin (ADM) and 5-fluorouracil (5-FU) was investigated. First, the chemosensitivity of gastric cancer tissues was determined by the succinate dehydrogenase inhibition test, which showed sensitivity to ADM and 5-FU is increased by DP. Next, a clinical trial of combined therapy of DP, ADM and 5-FU, as a post-operative adjuvant chemotherapy for gastric cancer patients, was performed. DP (50 mg) was given as a 1-h i.v. infusion, and ADM (20 mg) was given as a single i.v. injection. This treatment was started on post-operative day 10, and was repeated every 2 weeks. Simultaneously with these treatments, DP (300 mg) and 5-FU (150 mg) were administered post-operatively daily. A total of 63 courses of therapy in nine patients were performed. The adverse effects related to the DP infusion were flushing, headache, nausea and upper abdominal discomfort, all of a low grade. DP did not appear to alter the toxicity of ADM and 5-FU, and no severe adverse effect was noted for this combination therapy. The pharmacokinetics of DP were also investigated in five patients. The mean plasma concentration of DP increased 4.41 micrograms/ml and remained above 0.25 microgram/ml for over 6 h. This combination chemotherapy appears to be safe and may be useful clinically in treating cancer.

Phase I trial of dipyridamole with 5-fluorouracil and folinic acid.

We have performed two Phase I trials of the combination of dipyridamole, 5-fluorouracil (5-FU), and folinic acid in patients with advanced refractory malignancy, based upon in vitro evidence that dipyridamole can modulate the cytotoxicity of 5-FU. In the first trial, patients were treated every 4 wk with dipyridamole (50 mg/m2) p.o. every 6 h on Days 0 to 6, beginning 24 h prior to the i.v. administration of folinic acid (200 mg/m2) and escalating doses of i.v. 5-FU on Days 1 to 5. The maximum tolerated daily dose of 5-FU that could be given with this combination was 375 mg/m2. Because dipyridamole is extensively bound to plasma proteins, it was hypothesized that the concentrations of free dipyridamole achieved with a dose of 50 mg/m2 were inadequate to modulate the cytotoxicity of 5-FU and folinic acid. Therefore, a second Phase I trial of escalating dose of p.o. dipyridamole was performed. Folinic acid (200 mg/m2) and 5-FU (375 mg/m2) were given i.v. on Days 1 to 5 every 4 wk, beginning 24 h after the start of therapy with dipyridamole; dipyridamole was administered p.o. on Days 0 to 6 at doses of 75, 100, 125, 150, 175, or 200 mg/m2/dose to successive cohorts of patients. Dose-limiting neutropenia, mucositis, and nausea were produced at a dose of 200 mg/m2/dose; the recommended dose of dipyridamole for use in Phase II studies is 175 mg/m2 p.o. every 6 h, or 700 mg/m2/day. At this dose, a mean peak plasma concentration of total dipyridamole of 16.32 mumol and a mean peak plasma concentration of free dipyridamole of 38.30 nmol were observed. Trough concentrations of free dipyridamole averaged 60% of the peak concentrations. Objective antitumor responses were seen in a number of tumor types; five of 13 patients with breast cancer treated with high-dose p.o. dipyridamole, 5-FU, and folinic acid responded. High-dose p.o. dipyridamole can produce plasma concentrations of free dipyridamole within the range shown to modulate the cytotoxicity of 5-FU and other agents. Phase II trials of this combination are justified.