Combination antiplatelet agents for secondary prevention of ischemic stroke

Stroke is a leading cause of death and the primary cause of serious, long-term disability in the United States. Joint guidelines from the American Heart Association (AHA) and American Stroke Association (ASA), as well as recent guidelines from the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Antiplatelet Therapy, recommend aspirin, clopidogrel, or extended-release dipyridamole plus aspirin as acceptable first-line options for secondary prevention of ischemic events in patients with a history of ischemic stroke or transient ischemic attack (TIA). The ACCP strongly recommends the combination of extended-release dipyridamole plus aspirin over aspirin monotherapy (highest level of evidence) and suggests clopidogrel monotherapy over aspirin monotherapy (lower level of evidence). The AHA-ASA guidelines suggest that either extended-release dipyridamole plus aspirin or clopidogrel monotherapy should be used over aspirin monotherapy. Both guidelines recommend avoiding the combination of clopidogrel and aspirin for most patients with previous stroke or TIA. Results from recent trials evaluating combination antiplatelet therapy have been published that enhance the AHA-ASA recommendations and provide the foundation for the updated ACCP guideline. To identify pertinent combination antiplatelet trials, a MEDLINE search of the literature from 1967-2007 was performed. Two trials were identified--the European-Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA). The ESPRIT compared aspirin monotherapy with the combination of aspirin plus extended-release dipyridamole for prevention of secondary ischemic events in patients with a history of TIA or minor stroke. The CHARISMA trial compared aspirin plus clopidogrel with aspirin alone in a population at high risk for atherothrombotic events using the composite outcome of myocardial infarction, stroke, and death from cardiovascular causes. Data from ESPRIT add to evidence that the combination of aspirin plus extended-release dipyridamole is superior to aspirin alone. The findings of the CHARISMA trial reinforce recommendations from both AHA-ASA and ACCP that the combination of aspirin and clopidogrel be reserved for special populations requiring this antiplatelet combination (e.g., those who have had coronary artery stenting).     

Effects of long-term oral dipyridamole treatment on coronary microcirculatory function in patients with chronic stable angina: A substudy of the persantine in stable angina (PISA) study

AIMS: A meta-analysis of 13 randomized placebo-controlled trials demonstrated a benefit for dipyridamole therapy, particularly with longer duration of treatment. Although the mechanism of this effect is not well understood, dipyridamole increases endogenous tissue adenosine, which may have a beneficial effect on myocardial perfusion. Therefore, we measured the effects of dipyridamole on myocardial blood flow (MBF) and coronary flow reserve (CFR) by using positron emission tomography and H2O in patients with coronary artery disease. METHODS: Forty-four patients with angiographically documented coronary artery disease were double-blind randomized to either oral dipyridamole [200 milligrams (mg) twice daily (bd)] or placebo as add-on to conventional antianginal treatment for 24 weeks. MBF was measured at rest and during dobutamine stress at baseline and study completion for the region subtended by the most severe coronary artery stenosis (Isc) and remote myocardium subtended by arteries with minimal or no disease (Rem). CFR was calculated as MBF-peak/MBF-rest. RESULTS: Thirty-five patients completed the study. Isc MBF-rest decreased in patients receiving dipyridamole (0.10 mL/minute/g; P = 0.03) and increased in the placebo group (0.16 mL/minute/g; P = 0.01) during the 24-week study. No significant change in MBF-peak was demonstrated in either group. Consequently, Isc-CFR increased significantly in patients receiving dipyridamole (1.65 +/- 0.47 vs 1.83 +/- 0.67; P < 0.05). By contrast, Isc-CFR decreased significantly in those receiving placebo (1.74 +/- 0.44 versus 1.38 +/- 0.46; P < 0.03). No change was seen in Rem-CFR territories. CONCLUSIONS: At the end of treatment, a reduction in baseline MBF but no significant changes in hyperemic MBF were observed in ischemic myocardial territories, and therefore the significance of the observed improvement in CFR remains unclear.     

阿司匹林联合双嘧达莫用于缺血性脑卒中二级预防的Meta分析

目的以阿司匹林为对照组,系统评价阿司匹林双嘧达莫联合用药,对缺血性脑卒中二级预防的有效性和安全性。方法通过卒中、非致死性卒中、各种原因引起的死亡及非致死性卒中与各种原因引起的死亡联合事件发生的相对危险度,分析联合用药的有效性,通过出血性并发症及脑出血发生的相对危险度,分析联合用药的安全性。结果 a.与阿司匹林相比较,联合用药能更有效的预防卒中的发生(RR=0.86 95%CI[0.74,1.00]),使非致死性卒中的发生率降低22%(RR=0.78 95%CI[0.67,0.90]),也能明显降低非致死性卒中与各种原因引起的死亡联合事件的发生率(RR=0.87 95%CI[0.79,0.96])。但是,联合用药对各种原因引起的死亡无效(RR=0.98,95%CI[0.85,1.13])。b.与阿司匹林相比较,联合用药不会增加出血性并发症的发生率(RR=0.95,95%CI[0.80,1.12]),但可以使脑出血的发生率增加14%(RR=1.14,95%CI[0.54,2.42]),尽管这一结果无明显统计学意义。结论与阿司匹林相比较,联合用药对卒中、非致死性卒中及非致死性卒中与各种原因引起的死亡联合事件的预防更有效,联合用药不会增加出血性并发症的发生率,但能轻微增加脑出血的发生率。     

Role of antiplatelet therapy in cardiovascular disease II: Ischemic stroke

The etiology of cerebrovascular disease is heterogeneous, with the majority of strokes being of ischemic origin. Transient ischemic attack is now considered to be an important precursor and long-term risk factor for ischemic stroke. Given the lack of acute therapies for ischemic stroke, current treatments focus on secondary prevention through risk-factor management, pharmacotherapy and interventional approaches. As illustrated in this paper, antiplatelet agents (e.g. clopidogrel, aspirin, dipyridamole) are the cornerstone of therapy for prevention of recurrent ischemic stroke.     

Role of antiplatelet therapy in cardiovascular disease II: Ischemic stroke

The etiology of cerebrovascular disease is heterogeneous, with the majority of strokes being of ischemic origin. Transient ischemic attack is now considered to be an important precursor and long-term risk factor for ischemic stroke. Given the lack of acute therapies for ischemic stroke, current

treatments focus on secondary prevention through risk-factor management, pharmacotherapy and interventional approaches. As illustrated in this paper, antiplatelet agents (e.g. clopidogrel, aspirin, dipyridamole) are the cornerstone of therapy for prevention of recurrent ischemic stroke.     

Limitation of coronary reserve after successful angioplasty is prevented by oral pretreatment with an alpha1-adrenergic antagonist

Coronary vasoconstriction that occurs after percutaneous transluminal coronary angioplasty (PTCA) is abolished by intracoronary phentolamine. An impairment of coronary vasodilator reserve (CVR) has been observed < or = 7 days after successful PTCA. To ascertain whether pretreatment with the alpha1-adrenergic receptor blocker doxazosin could prevent the limitation of CVR after PTCA, we carried out a randomised, double-blind, controlled study on 26 patients with significant (> 75%) single vessel disease undergoing PTCA. Twelve patients received doxazosin 4 mg daily in addition to their standard treatment, while 14 patients received matching placebo, starting 11 days before PTCA. Myocardial blood flow (MBF) at baseline and after i.v. dipyridamole (0.56 mg/kg) was measured within 5 days after PTCA using positron emission tomography (PET) with oxygen-15-labelled water. Angioplasty was successful in all patients with a residual stenosis < or = 35%. At PET scanning, hemodynamic parameters were comparable in the two groups. In the territory subtended by the dilated artery, CVR was significantly higher in patients treated with doxazosin compared with those receiving placebo (2.78 +/- 0.1.21 vs. 1.95 +/- 0.68; p < 0.01). Conversely, CVR in the remote territories subtended by angiographically normal arteries was similar in the two groups (2.53 +/- 0.92 and 2.48 +/- 0.80, respectively; p = NS). Treatment with oral doxazosin in addition to standard antianginal therapy can prevent the impairment of CVR frequently observed despite successful PTCA.     

Current Management of Transient Ischemic Attack

Transient ischemic attack (TIA) is a precursor to ischemic stroke. At least half of patients with TIA have a new, small ischemic lesion demonstrable on magnetic resonance imaging using a diffusion weighted sequence. The risk of subsequent major stroke is 10-20% in the next 3 months with much of that risk front-loaded in the first week. Strategies to identify and treat high-risk patients need to be defined. The optimal treatment approach and the timing of interventions, both medical and surgical, remains unknown. In general, aspirin is the first line of treatment to prevent further stroke. Other antiplatelet agents such as clopidogrel alone or in combination with aspirin and the combination aspirin/extended-release dipyridamole may be administered. Endarterectomy or carotid stenting is of great benefit to patients with TIA secondary to stenosis in the extracranial carotid artery.     

Beneficial effect of nipradilol (K-351) on acute myocardial ischemia. Study of the relationship between regional myocardial blood flow and energy metabolism

To examine the effects of nipradilol on ischemic myocardium, experiments were performed on regional myocardial blood flow (MBF) and energy metabolism in anesthetized, open-chest dogs. Nipradilol at a dose of 0.3 mg/kg was i.v.-administered 10 min after coronary ligation. MBFs at various sites, including ischemic and non-ischemic areas, were determined by the hydrogen gas clearance method. The levels of ATP and creatine phosphate (CP) at the site of MBF determination were measured 60 min after ligation, and mitochondrial function (RCI, QO2) in the ischemic and non-ischemic areas was determined. Following nipradilol administration, aortic pressure and heart rate were significantly lowered. In ischemic areas with MBF below 40 ml/min/100 g, nipradilol had no influence on MBF. However, the tissue level of ATP in nipradilol treated hearts was significantly higher as compared with untreated hearts. In the area of mild ischemia with MBF of 40-60 ml/min/100 g, nipradilol preserved the tissue ATP and CP levels in spite of a decrease in MBF. Moreover, an inhibition of the decrease in mitochondrial respiratory function was observed in ischemic areas with MBF below 20 ml/min/100 g. Thus, nipradilol administered following ischemia preserved ATP content and mitochondrial function in the ischemic myocardium with reduction of heart rate and aortic pressure. This suggests that nipradilol exerts a cardioprotective effect in acute ischemia. It seems that the cardioprotective effect is due to a decrease in myocardial oxygen demand and preservation of mitochondrial function.     

Antiplatelet therapy for the prevention of recurrent stroke and other serious vascular events: a review of the clinical trial data and guidelines

ABSTRACT

Background: One strategy of reducing the burden of stroke is the prevention of recurrent stroke, following an initial ischaemic stroke or transient ischaemic attack (TIA) of arterial origin, by means of antiplatelet therapy.

Scope: This review article surveys and discusses the current clinical trial data and guidelines for the use of antiplatelet therapy in the prevention of recurrent stroke/TIA of arterial origin (not stroke due to atrial fibrillation). Based on the latest available evidence, a new antiplatelet treatment algorithm for the long-term treatment of patients following atherothromboembolic ischaemic stroke or TIA is proposed.

Findings: Meta-analyses of randomised clinical trials in patients with TIA and ischaemic stroke of arterial origin indicate that, compared with control, the relative risk reduction (RRR) for recurrent stroke and other serious vascular events is 13% (95% confidence interval [CI] 6% to 19%) with aspirin, 13% (4% to 21%; p = 0.046) with dipyridamole and 34% (24% to 43%) with the combination of aspirin and dipyridamole. Compared with aspirin, the relative risk of recurrent stroke and other serious vascular events is reduced by 7.3% (95% CI –5.7% to 18.7%) with clopidogrel and 18% (9% to 26%; p = 0.0003) with the combination of aspirin and dipyridamole. The combination of aspirin and clopidogrel is not significantly more effective in preventing serious vascular events than clopidogrel alone (RRR 6.4%; –4.6% to 16.3%) in the long-term treatment of patients with previous ischaemic stroke and TIA, mainly because of a cumulative excess of bleeding complications. The relative risks and benefits of long-term treatment with clopidogrel and the combination of aspirin and dipyridamole are being compared in an ongoing large clinical trial (PRoFESS). Current Australian therapeutic guidelines for antiplatelet therapy among patients with TIA and ischaemic stroke of arterial origin have incorporated important new findings from recently published clinical trials and recommend aspirin or the combination of dipyridamole plus aspirin as the preferred long-term antiplatelet therapy.

Conclusion: Whilst awaiting the results of the PRoFESS trial, the combination of dipyridamole plus aspirin is the preferred antiplatelet regimen to reduce the risk of recurrent vascular events among patients with TIA and ischaemic stroke of arterial origin.     

Systemic and regional hemodynamics assessment in rats with fluorescent microspheres

The aim of this study was to validate in rats an alternative to the radioactive microspheres (RM) reference technique, the fluorescent microspheres (FM), for the simultaneous determination of cardiac index (CI) and regional blood flows (RBF). Validation of the FM method was performed in three steps: (a) comparison of CI and RBF values obtained simultaneously by FM and RM, (b) determination of the repeatability of the measurements by using two successive injections of FM, and (c) evaluation of the ability of the FM method to assess vasodilating effects (by using dipyridamole). CI values (range, 242-513 ml/min x kg; n = 20) obtained with FM correlated with those obtained with RM (r = 0.82: p<0.001), and agreement was found between FM and RM (error 95% confidence interval for one pair, +/-125 ml/min x kg). FM RBF values, although smaller than corresponding RM RBF values, were correlated with the latter (range, 0.1-7 ml/min x g; n = 71; r = 0.99; p< 0.001). Agreement was dependent on RBF values, e.g., error 95% confidence intervals for one pair were 0.08-0.13 and 3.86-6.48 for 0.1 and 5 ml/min x g, respectively. Two successive FM injections at a 10-min interval (conscious rats) provided similar values (n = 14) for CI (306+/-24 vs. 346+/- 18 ml/min x kg), and renal (5.1+/-0.2 vs. 6.2+/-0.3 ml/min x g), left (6.1+/-0.3 vs. 5.8+/-0.4 ml/min x g) and right (4.8+/-0.4 vs. 4.7+/-0.3 ml/min x g) myocardial RBF. Corresponding error 95% confidence intervals were +/-187 ml/min x kg, +/-2.8, +/-2.2, and +/-2.0 ml/min x g, respectively. Dipyridamole (2, 4, 6, and 8 mg/kg x min for 10 min, i.v.; n = 9-13 per group, conscious rats) significantly and dose dependently increased left and right myocardial blood flows, whereas renal blood flow was not affected. We conclude that the FM technique (a) is reliable and in agreement with the RM method, (b) provides repeatable measurements of systemic and regional hemodynamics, and (c) allows detection and quantification of vasodilating effects in rats.     

Antiplatelet therapy in cerebrovascular disorders

Antiplatelet treatment is a mainstay in acute and long-term secondary stroke prevention. Aspirin is still most widely used worldwide, however, there is increasing evidence from small randomised trials that dual antiplatelet therapy combining aspirin with dipyridamole or clopidogrel might be more effective in the acute and early chronic post-ischemic phase (i.e. first 90 days). Both clopidogrel and the combination of aspirin and extended-release dipyridamole are recommended by current guidelines in long-term secondary stroke prevention in patients who are at high risk for a recurrent ischemic stroke, since they are more effective compared with aspirin monotherapy.Antiplatelet agents are the therapy of choice in patients with ischemic stroke due to intracranial stenosis and patent foramen ovale. In contrast, oral anticoagulation is clearly superior to single or double antiplatelet therapy in patients with cardioembolic stroke, mainly caused by atrial fibrillation.Concerning newer antiplatelet agents, only cilostazol appears to be a promising therapeutic option in patients with ischemic stroke in the near future, but so far, only studies in Asian stroke patients have been performed.     

Safety of clopidogrel and aspirin for stroke prevention: implications of the CHARISMA trial.

Antiplatelet therapy is universally recommended for the prevention of recurrent events in patients with noncardioembolic ischaemic stroke or transient ischaemic attack (TIA), acute and chronic coronary artery disease, or peripheral arterial disease. However, choosing which antiplatelet agents to use in these situations remains controversial. The use of aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is recommended as initial therapy in patients with noncardioembolic ischaemic stroke or TIA to reduce the risk of recurrent stroke and other cardiovascular events. Based on the results of the MATCH trial, combination therapy with aspirin plus clopidogrel is not recommended for patients with ischaemic stroke or TIA due to the increased risk of haemorrhage.The results of the CHARISMA trial support this recommendation; despite previous data demonstrating a favourable benefit-risk profile of aspirin plus clopidogrel in patients with acute coronary syndrome, this combination should not be used in patients at high risk for atherothrombosis and those with previous stroke or TIA. In these patients, the CHARISMA trial demonstrated a lack of significant clinical efficacy and an increased risk of bleeding with clopidogrel plus aspirin compared with aspirin alone.Further research is needed to assess the benefit-risk ratio of clopidogrel plus aspirin in specific subpopulations of patients at high risk for atherothrombotic events, and to determine the role of clopidogrel plus aspirin in preventing cardioembolic stroke or early recurrent stroke after symptomatic large-vessel atherostenosis. Recent and ongoing studies are seeking to better define the roles of different antiplatelet regimens in preventing recurrent stroke.     

Prasugrel: A Guide to Its Use in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention in the US

Oral prasugrel (Effient®; Efient®) provides rapid, potent inhibition of platelet aggregation. It is indicated (in combination with aspirin) for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). In the pivotal clinical trial in this patient population, prasugrel-based therapy was associated with a significantly lower incidence of ischemic events than clopidogrel-based therapy. However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged ≥75 years, those weighing <60 kg and those with a history of stroke or transient ischemic attack at the greatest risk. Prasugrel appears to have an overall favorable risk: benefit ratio in ACS patients undergoing PCI who do not have these three easily identifiable clinical characteristics. Limited pharmacoeconomic analyses suggest that prasugrel-based therapy is an economically attractive treatment strategy relative to clopidogrel-based therapy from a US healthcare payer perspective.     

Effects of histamine H1-receptor stimulation on coronary hemodynamics in man

Exogenous histamine in man induces significant cardiovascular effects mediated by activation of H1 and H2-receptors present on human heart and on coronary arteries. We studied the effects of selective H1-receptor stimulation on human coronary hemodynamics in 10 patients undergoing cardiac catheterization. All patients were pretreated with cimetidine before the histamine infusion (0.5 micrograms/kg/min i.v. for 5 min). Six of these patients had normal coronary arteries and four had single vessel coronary artery disease (CAD) and vasospastic angina. During the study heart rate was held constant (100 beats/min) by coronary sinus pacing. We measured mean aortic pressure (MAP), coronary sinus blood flow (CSBF), coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO2) at rest, during histamine infusion, and 10 min after the end of the infusion. During infusion, MAP decreased from 103 +/- 5 to 85 +/- 6 mmHg (p less than 0.02) and CVR from 1.00 +/- 0.16 to 0.81 +/- 0.14 mmHg/ml/min (p less than 0.05); CSBF and MVO2 did not significantly change. All parameters returned to baseline at the end of the infusion. The response was similar in patients with normal coronary arteries and in 3 patients with CAD. Only one patient with CAD developed angina with ST segment elevation in D3, reduction in CSBF and an increase in CVR. These results indicate that H1-receptor stimulation in man induces significant coronary dilatation and that histamine infusion after cimetidine pretreatment is unlikely to provoke coronary spasm in patients with vasospastic angina.     

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.     

Intravenous aspirin at reperfusion does not reduce infarct size in the dog with a residual critical stenosis.

Platelet-related events being associated with the increment of infarct size at reperfusion in the presence of a residual stenosis, we tested in dogs whether intravenous aspirin (ASA) could limit infarct size. The left anterior descending coronary artery was occluded for 90 min and reperfused for 6 h in the presence of a residual critical stenosis. Controls received saline, and treated groups were given 2, 6, or 12 mg/kg ASA, i.v., 5 min before reperfusion. Infarct size did not differ significantly between groups (control, 43.80+/-6.28%; ASA, 2 mg/kg: 41.07+/-7.78%; ASA, 6 mg/kg: 37.55+/-3.44%; ASA, 12 mg/kg: 29.40+/-5.41%), as well as transmural collateral blood flow and [111In]-platelet accumulation in the infarcted myocardium (2.5-3.6 x 10(5) platelets/g). However, myocardial neutrophil accumulation was significantly reduced (p < 0.05) in groups given 6 (15.0+/-2.6 x 10(6)/g tissue) and 12 mg/kg (18.4 +/-3.8) ASA, but not in the 2-mg/kg group (21.0+/-5.2), as compared with control group (32.0+/-7.2). Ex vivo platelet aggregation to collagen was abolished during reperfusion in all treated groups (p < 0.05). Transcardiac arteriovenous differences in 6-keto-PGF1alpha were reduced significantly 1 h after reperfusion in groups given 6 or 12 mg/kg ASA (94.7+/-13.1 and 71.7+/-19.2 pg/ml, respectively) but not in the 2-mg/kg group (178.3+/-78.2 pg/ml), as compared with control (405.4+/-171.6 pg/ml). ASA-insensitive platelet activation at the site of stenosis or inhibition by ASA of prostacyclin production by jeopardized myocardium may explain the observed lack of benefit of ASA.     

Dual antiplatelet therapy for prevention of recurrent ischemic events.

The advantages of dual antiplatelet therapy over monotherapy in preventing recurrent ischemic events are examined. Atherosclerosis is an insidious systemic process involving multiple vascular beds, including the cerebral, coronary, and peripheral arteries. Atherosclerotic plaque rupture is one of the inciting events in the progression of platelet activation, aggregation, and thrombus formation. Patients with any clinical manifestation of atherosclerosis are vulnerable to others in different vascular beds since the disease develops throughout the vasculature, and different vascular events have common predisposing risk factors. Ischemic coronary heart disease and cerebrovascular disease are two of the three most frequent causes of death in the United States. The efficacy of aspirin in the secondary prevention of myocardial infarction (MI) and stroke has been demonstrated in numerous trials. While dipyridamole has not been linked with a greater odds reduction than aspirin in the development of MI, stroke, and vascular death, ticlopidine and clopidogrel have been associated with a greater reduction in the development of acute MI, stroke, and vascular death than aspirin. Clinical trials evaluating the efficacy and safety of combination antiplatelet therapy in the prevention of recurrent ischemic events are ongoing. The rationale for using a combination of two mechanistically different antiplatelet agents is supported by ex vivo and clinical studies. Inhibition of platelet aggregation and thrombus formation is enhanced with dual antiplatelet therapy. Combination antiplatelet regimens with different mechanisms of action to inhibit multiple sites in the thrombotic pathway may further improve long-term clinical outcomes. Dual antiplatelet therapy may have advantages over monotherapy in the prevention of recurrent ischemic events.     

The role of substance P in cerebral ischemia

Tackykinins are involved in the inflammatory process of a large number of diseases. The role of the tachykinins in ischemic brain injury was evaluated by the serum levels of Substance P (SP), one of the most known tachykinins and detected by a competitive enzyme immunoassay. The study was performed in 15 human females and 3 human males with typical manifestation of complete stroke (12 cases) or transient ischemic attack (6 cases). The mean SP level in the serum of patients with transient ischemic attack (0.53+/-0.25 ng/ml) and of patients with complete stroke (0.31+/-0.14 ng/ml), showed significantly higher values than in controls (0.10+/-0.02 ng/ml). Moreover, in transient ischemic attack, the SP values were significantly higher than in cerebral complete stroke. But SP levels, based on the timings of classification of patients (i.e. before 12 hours: 0.34+/-0.15 ng/ml vs. 12 to 24 hours: 0.26+/-0.11 ng/ml) with brain injury, did not show any significant difference. Both values anyway were significantly higher than in controls. Our original results demonstrate the SP increase during cerebral ischemia. Further studies are necessary to verify if SP has an effective physiopathological role in the neurological ischemic damage, or if it is only a concomitant phenomenon. Our data, if confirmed, will be particularly important, not only to improve the knowledge of cerebral ischemic injury, but also for diagnosis and therapeutic approaches.     

Effect of dipyridamole and aspirin on the platelet-neutrophil interaction via the nitric oxide pathway

This study was designed to determine the influence of the combination of aspirin and dipyridamole on the interaction in vitro between neutrophils and platelets through the nitric oxide (NO) pathway. Collagen-induced platelet aggregation (impedance method) was determined in platelet-rich plasma and in platelet-rich plasma+neutrophils, and cGMP (enzyme immunoanassay) and NO levels (electrochemical method, with a ISO-200 electrode) were also measured. The 50% inhibitory concentration (IC(50)) of aspirin was 139+/-11 microM in platelet-rich plasma, 367+/-21 microM in platelet-rich plasma+L-N(G)-nitro-arginine-methyl-ester (L-NAME), and 42+/-3 microM in platelet-rich plasma+L-arginine. The IC(50) for dipyridamole in platelet-rich plasma was not affected by L-NAME or L-arginine; the combination of aspirin with 20 microM dipyridamole (which has no effect per se) led to an IC(50) of 51+/-2 microM in platelet-rich plasma, 101+/-7 microM in platelet-rich plasma+L-NAME, and 13+/-2 microM in platelet-rich plasma+L-arginine. The cGMP levels showed the greatest increases in the aspirin plus dipyridamole group. Dipyridamole and aspirin increased the leukocyte production of NO: 50% increases were obtained at concentrations of 285+/-31 microM aspirin, 110+/-9 microM dipyridamole, and 16+/-2 microM aspirin+dipyridamole. Dipyridamole alone at a concentration of 20 microM had no significant effect on NO levels. We conclude that the combination of aspirin and dipyridamole significantly increases the antiplatelet effect of leukocytes, through an increase of NO, and that this effect is further evidence of the therapeutic benefits of this combination of drugs.     

Effect of acute administration of L-acetyl carnitine on cerebral blood flow in patients with chronic cerebral infarct

The effect of L-acetyl carnitine (L-AC) on cerebral blood flow (CBF) was evaluated in 20 patients with chronic cerebrovascular disease, who suffered an ischaemic stroke at least 6 months before the study. All patients performed a CT scan and were investigated with xenon-133 by brain dedicated single photon emission computed tomography (SPECT, Tomomatic 32, Medimatic Inc., Copenhagen). A single high dose (1.5 g) of L-acetyl carnitine was intravenously administered to 10 patients, while sodium acetate as placebo was injected to 10 other subjects. Cerebral blood flow (ml/min x 100 g) was evaluated before and 45 min after the injection. No changes were observed after placebo injection (43 +/- 12 ml/min x 100 g versus 43 +/- 10 ml/min x 100 g). CBF increased (from 42 +/- 9 ml/min x 100 g to 46 +/- 9, P less than 0.05) in both ipsilateral and contralateral hemisphere, the ischaemic area, but not in the stroke corresponding zone. It was concluded that L-acetyl carnitine at the i.v. dosage of 1.5 g acutely enhanced CBF in patients with chronic cerebral infarct.