Effects of low dose aspirin on platelet function in patients with recent cerebral ischemia

We tested the antiplatelet effects of low-dose aspirin in patients with occlusive cerebrovascular disease, because conventional dosage aspirin inhibits vascular synthesis of prostacyclin at the same time that it inhibits platelets. The effects on platelet function and thromboxane A2 synthesis of 40 mg of aspirin daily or 40 mg aspirin plus dipyridamole were measured in 23 patients starting within a week after the onset of cerebral ischemia. All patients had normal baseline platelet aggregation responses to four stimuli: arachidonate, epinephrine, adenosine diphosphate and collagen. The generation of thromboxane A2 by platelets, measured as serum thromboxane B2, was also normal. After 3 to 7 days of low dose aspirin therapy, platelet aggregation responses were suppressed to the extent observed with higher dosage aspirin. Serotonin release during platelet aggregation was inhibited by more than 95% and thromboxane B2 levels in clotted blood fell by more than 95%. Responses to aspirin treatment were similar in patients with transient ischemic attacks and in those with stroke and were also similar in both sexes. No differences in platelet responses were observed between patients receiving aspirin alone and aspirin plus dipyridamole. Thus 40 mg aspirin daily inhibited platelet responses as effectively as higher doses of aspirin in patients who had recent cerebral ischemia and showed a cumulative antiplatelet effect.     

尤瑞克林治疗大面积脑梗死的近期及远期疗效观察

目的探讨与分析尤瑞克林治疗大面积脑梗死的近期及远期临床疗效。方法30例大面积脑梗死患者随机分为两组各15例。治疗组给予尤瑞克林及常规治疗,对照组仅给予常规治疗。于治疗前及治疗后14d,按照美国国立卫生院卒中量表（NIHSS）对两组患者进行神经功能缺损程度评定并比较;同时比较两组的病死率、临床疗效;于治疗后14d对患者进行日常生活活动能力（ADL）评分,并于发病3个月再次进行日常生活活动能力（ADL）评分,并比较。结果与治疗前相比,治疗后14d两组NIHSS评分均下降,但尤瑞克林组优于对照组（P〈0．05）,且临床疗效显著,总有效率、显效率显著高于对照组,病死率较对照组降低（P〈0．05）。两组在治疗后3个月ADL评分较14d时均有所改善,但尤瑞克林组改善更明显（P〈0．05）。结论尤瑞克林可明显改善大面积脑梗死急性期的神经功能缺损,并改善远期预后。     

利培酮不同疗程不良反应比较

目的：比较精神分裂症患者服用利培酮在短程与长程治疗中的不良反应。方法：对入选病例作副反应量表(TESS)、锥体外系副反应量表(RSESE)、不自主运动量表(AIMS)评定。结果：在短程与长程治疗中，TESS单项分不同，以静坐不能、活动减退、心电图异常、体重增加和血象异常为明显，前12位不良反应频度排序有差别，AIMS总分有显著差异。结论：利培酮在短程与长程治疗中不良反应有较大差异，在长程治疗中对神经系统、心血管系统、体重、血象的影响不容忽视。     

Controlled trial of aspirin in cerebral ischemia: an addendum

Patients (303) who had had carotid territory transient ischemic attacks were randomly assigned to aspirin or placebo treatments. Patients with amaurosis fugax responded as well to aspirin as those with hemisphere events. Patients with lesions of the appropriate carotid artery responded better to aspirin therapy than patients with no lesion or an occlusion. The aspirin effect was the same across all risk-factor groups. Smoking had no effect on clinical outcome.     

Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL

BACKGROUND: HMG-CoA-reductase-inhibitors (statins) exhibit pleiotropic beneficial effects on the vascular system including induction of endothelial nitric oxide synthase (eNOS) expression which is critical for vasodilation. Recent studies suggest a beneficial effect of statins on cerebral vasoreactivity in patients with cerebral small vessel disease (SVD). CADASIL is a monogenic form of SVD caused by mutations in the Notch3 gene. Treatment options are limited and little is known about the therapeutic role of statins in CADASIL. METHODS: Twenty-four CADASIL subjects were treated with atorvastatin for 8 weeks. Treatment was started with 40 mg, followed by a dosage increase to 80 mg after 4 weeks. Transcranial Doppler sonography measuring mean flow velocity (MFV) in the middle cerebral artery was performed at baseline and the end of the treatment period. Vasoreactivity was assessed by hypercapnia and intravenous application of l-Arginine, which is the substrate for eNOS. RESULTS: There was no significant treatment effect on MFV (p=0.5) or cerebral vasoreactivity as assessed by hypercapnia (p=0.5) and intravenous l-Arginine (p=0.4) in the overall cohort. However, an inverse correlation was found between vasoreactivity at baseline and changes of both CO2 and l-Arginine-induced vasomotor response (both p<0.05). CONCLUSIONS: Short term treatment with atorvastatin resulted in no significant improvement of hemodynamic parameters in the overall cohort of CADASIL subjects.     

Platelet density-dependent partition of platelet-von Willebrand factor between alpha granule and non-alpha granule pools

In this study, we demonstrate that platelets contain a small but significant amount of platelet-von Willebrand factor (vWf) not associated with alpha-granules. When platelets free of plasma proteins are exposed to micromolar concentrations of digitonin, plasma membrane permeabilization occurs without disruption of platelet granules. Employing this technique, we have found that upon exposure of a total platelet population to 8 microM digitonin, 5% of total platelet-vWf is released into the supernatant; this occurs without release of beta-TG from alpha-granules. When platelets of discrete buoyant density profiles are tested, this extragranular platelet-vWf increased with decreasing platelet density. These findings suggest that a redistribution of platelet-vWf from alpha-granule to non-granule sites occurs coincident with a decrease in platelet buoyant density.     

Ultrasound scanning in women with raised serum alpha fetoprotein: short term psychological effect

Thirty pregnant women with raised serum alpha fetoprotein (AFP) were interviewed before and after they received real-time ultrasound scanning to further diagnose fetal abnormalities. Thirty pregnant mothers receiving routine ultrasound scanning for dates served as the controls. The 'at risk' group were more anxious and concerned about the fetus before the scan. There was a greater reduction of state-anxiety following scanning in the raised AFP group than for the controls. Similar changes were found in the attitude towards the fetus, pregnancy and fetus' health between the risk and control subjects.     

The effect of cilostazol and aspirin pre-treatment against subsequent transient focal cerebral ischemia in rat

Abstract

Objectives:

Among several anti-platelet drugs to prevent recurrent stroke, cilostazol has shown various effects besides its anti-platelet activity. We examined whether 7 days of oral administration of cilostazol protects against subsequent cerebral ischemia, and whether or not the effect of combination therapy with aspirin is more protective.

Methods:

We used Sprague-Dawley (SD) rats and assigned them to four groups: vehicle, aspirin, cilostazol, and aspirin plus cilostazol combination therapy. After oral administration of anti-platelets for 7 days, we performed transient middle cerebral artery occlusion (MCAO) for 90 minutes, and examined infarct volume, neurological symptoms, and regional cerebral blood flow (rCBF). Immunostaining of Bax, Bcl-2, TUNEL, 4-HNE, 8-OHdG, and COX-2 was performed 24 hours after ischemia.

Results:

The cilostazol group and the combination therapy group showed significant decreases of infarct volume and significant improvements of rCBF during ischemia, compared with the vehicle or aspirin group. Significant decreases of Bax, TUNEL, 8-OHdG, and 4-HNE expression in the combination therapy group, compared with those in the vehicle or aspirin group, were shown in the boundary zone. COX-2 expression was unexpectedly increased in the combination therapy group.

Discussion:

Aspirin co-administration did not inhibit this effect. The addition of the oral administration of cilostazol either alone or with aspirin administration may be beneficial for subsequent cerebral ischemic damage in terms of reducing infarct volume, improving rCBF during ischemia, inhibiting the apoptotic pathway, and reducing oxidative stress.     

Platelet dysfunction in migraine: effect of self-medication with aspirin.

Circulating microembolic index (CMI) was determined by drawing one blood sample into EDTA-formalin and the other into DTA alone in patients with migraine and compared with matched normal controls. Platelet aggregates, if any, are fixed in EDTA-formalin but disaggregated by EDTA. Ratios of these two counts approximate "unity" in normals and are proportionately less than unity, depending on the number of platelet aggregates. 26 untreated migraineurs and 19 migraineurs with history of self-medication with aspirin taken within 72 hours of the test, were studied in headache-free intervals. Results were compared with those from 20 healthy, age and sex matched volunteers, without migraine, who were medication-free for at least one week. Mean CMI in untreated migraineurs (0.77 +/- 0.03 SEM) was significantly lower than the mean in normal controls (0.94 +/- 0.02, p. less than 0.002). Migraineurs with self administration of aspirin had mean CMI of 0.88 +/- 0.02, differing significantly from untreated migraineurs (p less than 0.01) but not from normal controls (0.1 less than p less than 0.2). Results suggest excessive platelet aggregation in migraineurs which tends to be corrected by treatment with platelet inhibitors such as aspirin.     

Combination therapy with low-dose aspirin and ticlopidine in cerebral ischemia

We compared combination therapy with low-dose aspirin plus ticlopidine to therapy with aspirin alone or ticlopidine alone in patients suffering transient ischemic attack or cerebral infarction. In 17, 24, and 23 patients, respectively, 300 mg/day aspirin, 200 mg/day ticlopidine, and 81 mg/day aspirin plus 100 mg/day ticlopidine were administered orally. Aspirin alone markedly inhibited platelet aggregation induced by arachidonic acid, partially inhibited platelet aggregation induced by adenosine diphosphate, and did not inhibit platelet aggregation induced by platelet activating factor. Ticlopidine alone inhibited platelet aggregation induced by adenosine diphosphate and platelet activating factor, but did not inhibit platelet aggregation induced by arachidonic acid. Combination therapy with aspirin plus ticlopidine markedly inhibited platelet aggregation induced by all three agonists. Plasma concentrations of beta-thromboglobulin and platelet factor 4 remained unchanged by aspirin alone, were slightly reduced by ticlopidine alone, and were markedly reduced by aspirin plus ticlopidine. Plasma concentration of thromboxane B2 was reduced by aspirin alone or with ticlopidine, but not by ticlopidine alone. The level of 6-ketoprostaglandin F1 alpha was reduced only by aspirin alone. Bleeding time was significantly prolonged by aspirin alone and by ticlopidine alone, although the greatest prolongation was produced by aspirin plus ticlopidine. Our results indicate that the combination of aspirin plus ticlopidine is a potent antiplatelet strategy, although the clinical importance of the changes observed need to be determined by a properly designed and controlled prospective study.     

Effects on cyclo-oxygenase of low and high dose aspirin

The study was undertaken to develop clinically applicable methods to detect the influence of low dose treatment with acetylsalicylic acid (ASA) on the platelet function. The cyclooxygenase activity of the platelets was measured by determination of the metabolite 12-HHT after challenge with arachidonic acid. Two healthy subjects received 600 mg ASA in a single dose. Two hours after intake the salicylate concentration level in plasma was 600 nmol/ml, with a 90 per cent reduction after 24 hours. The platelet cyclooxygenase activity (12-HHT) was completely and irreversibly inhibited within two hours after ASA intake. Five subjects received 75 mg ASA for eight consecutive days. The salicylate concentrations two hours after the intake of the first and last tablet were within 65 and 71 nmol/ml plasma, indicating that no accumulation of salicylate occurred during the treatment period. The decrease in cyclooxygenase activity during low dose treatment varied in the different subjects between 60 and 90 per cent. The rate of recovery of cyclooxygenase activity after termination of the low dose ASA treatment was faster than after the large single dose.     

氯氮平短程与长程不良反应比较

目的：比较精神分裂症患者服用氯氮平在短程与长程治疗中的不良反应。方法：对入组患者作副反应量表(TESS)评定。结果：在短程与长程治疗中，TESS总分及某些单项分有显著差异，单项前10位频度亦有显著差别。结论：在长程治疗中，氯氮平不良反应发生率下降、严重程度减轻，但对神经系统、心血管系统、体重及血象的影响仍应重视。     

The antiplatelet effect of daily low dose enteric-coated aspirin in man: A time course of onset and recovery

We have studied the onset and recovery of inhibition of platelet function by low dose aspirin. Enteric-coated aspirin 50mg daily was administered to five human volunteers for five weeks and then 100mg daily was given for a further five weeks. We studied platelet aggregation and thromboxane formation in response to a range of stimuli: ADP, adrenaline, arachidonate and collagen, and also measured thromboxane formation after coagulation of whole blood (serum thromboxane). The onset of inhibition of platelet aggregation was progressive over several days for each of the four platelet stimuli, and was synchronous with the inhibition of thromboxane formation. Maximum inhibition occurred by day three for the weak stimuli ADP and adrenaline, by day five for the stronger stimuli arachidonate and collagen, but did not occur until day eight for serum thromboxane. Further inhibitory effects on both aggregation and thromboxane generation were observed after 100mg daily. Two weeks after the cessation of aspirin the responses to collagen and arachidonate and serum thromboxane had returned to normal. Platelet aggregation in response to the weaker stimuli, ADP and adrenaline, still showed detectable inhibition two weeks after cessation of aspirin, but had returned to normal by four weeks. These experiments provided no evidence for an effect of aspirin on platelets separate to its effect on cyclooxygenase. The onset and recovery of inhibition of platelet function by low dose aspirin was dependent on the strength of the stimulus studied.     

Clinical and biochemical aspirin resistance in patients with recurrent cerebral ischemia

Background and aim

Stroke recurrence is an important public health concern. One half of survivors remain disabled, and one seventh requires institutional care. Aspirin remains the cornerstone of primary and secondary stroke prevention; meanwhile, aspirin resistance is one of the possible causes of stroke recurrence. We aimed to evaluate the clinical and biochemical aspirin resistance in patients with recurrent ischemic stroke.

Patients and methods

We studied demographic characteristics, vascular risk factors, stroke subtypes, radiologic findings and biochemical aspirin resistance tests using both arachidonic acid (AA) and adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) on admission and 24 h after observed aspirin ingestion.

Results

Of the 82 patients with recurrent cerebral ischemia included in this study, 37 (45%) patients were poor compliant with aspirin. There were no statistically significant differences between the two groups regarding the demographic characteristics, stroke severity, laboratory tests, radiological findings or vascular risk factors. On admission, 19.6% and 4.8% of patients showed aspirin resistance, while 24 h after supervised 300 mg single aspirin dose ingestion, it was 9.8% and 2.4% using ADP and AA-induced LTA respectively. Of the eight aspirin resistant patients, two only showed resistance using both AA and ADP. Aspirin resistance was statistically significantly higher in the male gender, older age, hyperlipidemia, smokers and in all lacunar strokes using AA.

Conclusion

Biochemical aspirin resistance in one's series was rather rare (2.4%) and was more prevalent in patients with lacunar strokes. Clinical aspirin failure may often be contributed to poor compliance with aspirin intake.