[Pharmacodynamics of the cerebral circulation. Results of a study on the action of 10 drugs on cerebral blood flow and energy metabolism in cerebrovascular patients]

Marc-Vergnes JP; Bes A; Charlet JP; Delpla M; Richardot JP; Geraud J
Pathol Biol (Paris) 1974 Nov;22(9):815-25

The authors studied the action of 10 drugs on cerebral blood flow and metabolism in patients with cerebro vascular insufficiency. The difficulties of this type of study are due to the techniques of measurement of cerebral blood flow which are traumatic, long and relatively inaccurate. Their traumatic character, which is mainly marked in the case of xenon 133 Xe clearance, limits their field of application and renders difficult experimental plans. The length of the examination restricts the possibilities offered during the same session. Finally, owing to the relatively inaccurate measurements, only important changes can be noted. However, during 2 successive series of measurements, carried out by 2 different methods of measurement of cerebral blood flow, only preparations containing hydergine induced a statistically significant increase in cerebral blood flow and oxygen consumption in the brain. This finding, which proves that a drug may modify the parameters, encourages better integration of pharmacodynamic tests in the physiopathological investigations carried out during the course of a disease.

Effects of ionic and nonionic contrast media on clot structure, platelet function and thrombolysis mediated by tissue plasminogen activator in plasma clots

Carr ME Jr, Carr SL, Merten SR
Department of Medicine, Medical College of Virginia, Richmond, USA.
Haemostasis (Switzerland), 1995, 25/4 (172-181)

Various radiographic contrast agents have anticoagulant or prothrombotic properties. Ionic agents are reported to have greater antithrombotic potential while nonionic agents are considered more thrombogenic. Some agents alter fibrin structure and bind to platelets in purified systems. This study compared the effects of iohexol, a nonionic agent, and iothalamate, an ionic agent, on fibrin assembly, clot structure, platelet function and clot dissolution in plasma. Plasma gels containing increasing concentrations of iothalamate were composed of thinner fibers with decreased fiber mass/length ratios (micro) and reduced gel turbidity. Such clots were more rigid and more resistant to fibrinolysis induced by tissue plasminogen activator (tPA). Gel elastic modula increased from 10,000 to 27,000 dyn/cm2 as iothalamate concentration increased from 0 to 20 mM. 50% lysis time increased from 800 to 1,250 s with the addition of 10 mM iothalamate. At 20 mM, iothalamate had no effect on ADP-induced platelet aggregation but prolonged the lag phase seen with collagen-induced aggregation. Platelet force development increased from 15,300 to 20,400 dyn with 20 mM iothalamate. The effects of iohexol were similar. Gel optical density dropped from 0.50 to 0.32, micro fell from 3.3 to 2.2 x 1013 D/cm, and elastic modulus rose from 11,000 to 24,000 dyn/cm2 as iohexol concentration was increased from 0 to 20 mM. Clots formed in the presence of 60 mM iohexol and tPA did not dissolve in 72 h while control clot 50% lysis time was 450 s. At concentrations greater than or equal to 40 mM, iohexol completely blocked collagen-induced platelet aggregation. Platelet force development increased from 7,660 to 19,600 with 40 mM iohexol. Contrast media possess profound fibrin-altering activities in plasma. Fibrin formed in the presence of some agents may be significantly more resistant to fibrinolysis.

Thrombolytic therapy: Recent advances. Treatment of myocardial infarction

Appl. Cardiopulm. Pathophysiol. (Netherlands), 1991/92, 4/3 (193-204)

The objectives of thrombolytic therapy in acute myocardial infarction are to restore coronary artery patency, salvage myocardium, reduce infarct size, and facilitate coronary artery repair. Urokinase and streptokinase are the two most frequently used thrombolytic agents. Both dissolve thrombi by converting circulating plasminogen, an inert precursor, into plasmin. One possible advantage of urokinase and streptokinase over new 'clot-specific' agents, recombinant tissue plasminogen activator (rt-PA) anisolylated SK-plasminogen activator complex (APSAC) and antibody directed UK, SK and rt-PA, is that the former have pronounced systemic fibrinolytic effects. This reduces blood viscosity and may prevent other thrombi from forming. Angiography is the most objective technique for assessing reestablished arterial patency, but being invasive, it presents disadvantages. Noninvasive criteria for coronary reperfusion include lowering of elevated ST-segments, shifting creatine kinase isoenzyme MB curves, and the appearance of reperfusion arrhythmias. Techniques for assessing myocardial salvage include thallium uptake, assessment of wall motion and myocardial thickening, ejection fraction, and positron emission tomography to assess infarct size. The role and appropriate timing of coronary artery repair after thrombolytic therapy are being studied intensely. There is no question that thrombolytic agents have made a significant beneficial impact and advance in the treatment of myocardial infarction. Considerable information has indicated that physicians must be educated in the details of use of thrombolytic agents and they must intensely educate their patients on the need to make themselves available to this treatment immediately when suggested by the symptoms and signs of this disease process.

Selective decrease in lysis of old thrombi after rapid administration of tissue-type plasminogen activator

Kanamasa K, Watanabe I, Cercek B, Yano J, Fishbein MC, Ganz W
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.
J. Am. Coll. Cardiol. (USA), 1989, 14/5 (1359-1364)

The safety of thrombolytic therapy of acute myocardial infarction could be improved if a method were developed to dissolve fresh occlusive coronary thrombus without simultaneously dissolving hemostatic thrombi outside the coronary arteries. This study is based on the assumption that, in a patient with evolving acute myocardial infarction, hemostatic thrombi are likely to be older than the thrombus responsible for occlusion of the coronary artery. It explored whether the relative rates of lysis of fresh and old thrombi could be influenced by the rapidity of recombinant tissue-type plasminogen activator (rt-PA) administration. In each of 17 dogs, two 1 h and two 24 h old thrombi were produced by inserting copper coils into both jugular and both femoral veins. After 24 h and 1 h, respectively, the coils with the thrombi were removed, weighed and inserted into the adjacent carotid and femoral arteries. A 1 mg/kg body weight dose of rt-PA was given either over 180 or over 30 min. The coils were removed and weights of the residual thrombi determined at the end of the 180 min infusion (Group I), at the end of the 30 min infusion (Group IIA) and 45 min after the 30 min infusion (Group IIB). The 24 h old thrombi were lysed significantly less than the 1 h old thrombi in all three experimental group: 53.9 plus or minus 4.8% (mean plus or minus SE) versus 86.1 plus or minus 2.5% in Group I (p < 0.001), 16.6 plus or minus 3.5% versus 65.2 plus or minus 6.0% in Group IIA (p < 0.001) and 21.6 plus or minus 5.4% versus 91.7 plus or minus 1.7% in Group IIB (p < 0.001). The 24 h old thrombi were also lysed significantly less by the 30 min infusion than by the 180 min infusion (p <0.001 for both). The ratio of lysis of 1 and 24 h old thrombi was markedly higher in Groups IIA (7.95 plus or minus 2.16) and IIB (6.52 plus or minus 1.50) than in Group I (1.71 plus or minus 0.17)(p < 0.01 for both). These findings suggest that rt-PA administered rapidly over a shorter period is less likely to lyse older thrombus, whereas the effect on fresh thrombus is preserved and probably enhanced. Clinical studies are needed to confirm the conclusions of this experimental study.

Antioxidant Curcuma extracts decrease the blood lipid peroxide levels of human subjects

Ramirez-Bosa A, Solfer A, Gutierrez M, Alvarez J, Almagro E
Age (USA), 1995, 18/4 (167-169)

Extracts of the rhyzome of Curcuma longa are widely used as food additives in India and other Asiatic and Central American countries. Moreover, it has been recently shown that these extracts ('turmeric'), as well as 'curcumin' and related phenolic compounds isolated from Curcuma, have a powerful lipid antioxidant action, when tested in in vitro systems. This justifies the present attempt to find out whether hydroalcoholic extracts of Curcum longa also exert an antioxidant effect in human subjects. Our data show that a 45- day intake (by healthy individuals ranging in age from 27 to 67 years) of Curcuma hydroalcoholic extract (at a daily dose equivalent to 20 mg of curcumine) results in a significant decrease in the levels of serum lipid peroxides. These peroxides probably play an important pathogenic role in normal senescence and age-related diseases such as atherosclerosis. Therefore, hydroalcoholic extracts of Curcuma longa (that have very low toxicity and have been cleared as food additives in the above countries) may find use in future preventive geriatrics after further clinical studies.

Inhibition of tumor necrosis factor by curcumin, a phytochemical

Chan MM
Department of Biological Sciences, Rutgers, State University of New Jersey, Piscataway 08855-1059, USA.
Biochem Pharmacol 1995 May 26;49(11):1551-6

Curcumin, contained in the rhizome of the plant Curcuma longa Linn, is a naturally occurring phytochemical that has been used widely in India and Indonesia for the treatment of inflammation. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) induces the production of interleukin-1beta (IL-1), and, together, they play significant roles in many acute and chronic inflammatory diseases. They have been implicated in the pathogenesis of intracellular parasitic infections, atherosclerosis, AIDS and autoimmune disorders. This report shows that, in vitro, curcumin, at 5 microM, inhibited lipopolysaccharide (LPS)-induced production of TNF and IL-1 by a human monocytic macrophage cell line, Mono Mac 6. In addition, it demonstrates that curcumin, at the corresponding concentration, inhibited LPS-induced activation of nuclear factor kappa B and reduced the biological activity of TNF in L929 fibroblast lytic assay.

Inhibitory effect of curcumin, an anti-inflammatory agent, on vascular smooth muscle cell proliferation

Huang HC; Jan TR; Yeh SF
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei.
Eur J Pharmacol 1992 Oct 20;221(2-3):381-4

The effects of curcumin, an anti-inflammatory agent from Curcuma longa, on the proliferation of blood mononuclear cells and vascular smooth muscle cells were studied. Proliferative responses were determined from the uptake of tritiated thymidine. In human peripheral blood mononuclear cells, curcumin dose dependently inhibited the responses to phytohemagglutinin and mixed lymphocyte reaction at the dose ranges of 10-6 to 3 x 10-5 and 3 x 10-6 to 3 x 10-5 M, respectively. Curcumin (10-6 to 10-4 M) dose dependently inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by fetal calf serum. Curcumin had a greater inhibitory effect on platelet-derived growth factor-stimulated proliferation than on serum-stimulated proliferation. Cinnamic acid, coumaric acid and ferulic acid were much less effective than curcumin as inhibitors of serum-induced smooth muscle cell proliferation, suggesting that the cinnamic acid and ferulic acid moieties alone are not sufficient for activity, and that the characteristics of the diferuloylmethane molecule itself are necessary for activity. Curcumin may be useful as a new template for the development of better remedies for the prevention of the pathological changes of atherosclerosis and restenosis.

Change of fatty acid composition, platelet aggregability and RBC function in elderly subjects with administration of low dose fish oil concentrate and comparison with those in younger subjects

Terano T, Kobayashi S, Tamura Y, Yoshida S, Hirayama T
Second Department of Internal Medicine, Chiba University, School of Medicine.
Nippon Ronen Igakkai Zasshi 1994 Aug;31(8):596-603

Anti-thrombotic and anti-atherogenic effects of eicosapentaenoic acid (EPA) through the modulation of various cell functions related to thrombogenesis have been reported recently. We previously reported that the administration of EPA at low doses could more effectively elevate the plasma EPA concentration in elderly subjects than in younger ones. Magnetic resonance imaging examination of the brain often reveals lacunar lesions in elderly subjects without any signs or symptoms of cerebrovascular diseases. In this study we clarified the effect of administration of low doses of fish oil concentrate on platelet and RBC function in elderly subjects, compared with younger subjects. Thirty-six elderly subjects (mean age 78) without any signs or symptoms of cerebrovascular diseases, all receiving the same diet in the same lodging house for the aged, were divided into 3 groups. Different amounts of fish oil concentrate (0.25-0.5 g/day of EPA) were administered to the 3 groups, daily for more than 1 month. Changes of plasma fatty acid composition, platelet aggregability, whole blood viscosity and RBC deformability was examined before and after EPA administration. One month after EPA treatment, the plasma EPA content had increased dose dependently, with suppression of platelet aggregation and improvement of RBC function. In younger subjects receiving the same amount of EPA, the elevation of plasma EPA was less than that observed in the elderly. In summary, low dose EPA administration can improve the function of platelet and RBC to an anti-thrombotic state and would be useful to prevent the occurrence of cerebrovascular diseases in elderly subjects without any side effects.

Premature Carotid Atherosclerosis: Does It Occur in Both Familial Hypercholesterolemia and Homocystinuria? Ultrasound Assessment of Arterial Intima-Media Thickness and Blood Flow Velocity"

Rubba P, Mercuri M, Faccenda F, Iannuzzi A, Irace C, Strisciuglio P, Gnasso A, Tang R, Andria G, Bond MG, et al
Institute of Internal Medicine and Diseases of Metabolism, Medical School, University Federico II, Naples, Italy.
Stroke, May 1994;25(5):943-950

This study evaluated 12 patients with homocystinuria due to cystathionine B-synthase deficiency, 10 patients with homozygous familial hypercholesterolemia and 11 healthy controls for the possibility that different patterns of carotid wall damage and cerebral blood flow hemodynamics were present. B-mode ultrasound mean maximum intima-media thickness was 1.4 mm in patients with familial hypercholesteremia, 0.6 mm in patients with homocystinuria and 6 mm in control subjects. The difference between hypercholesterolemic and homocystinuric patients or control subjects was statistically significant. Diastolic blood flow velocities were significantly reduced in the middle cerebral arteries of hypercholesterolemic patients compared with homocystinuric patients or control subjects, whereas systolic or mean velocities did not differ. The pulsatility index, a possible indicator of vascular resistance in cerebral circulation, was significantly higher in hypercholesterolemic patients compared with the homocystinuric patients or healthy control subjects. There was a direct relationship demonstrated between the pulsatility index of the middle cerebral artery and the mean maximum intima-media thickness of the carotid arteries on the same side. The authors conclude familial hypercholesterolemia is responsible for diffuse and focal thickening of the coronary arteries and possibly for the hyperlipidemic endothelial dysfunction seen in the small resistance arteries leading to a disturbed cerebral blood flow. Patients with homocystinuria seldom have plaques in their carotid arteries. In fact, their arteries are similar to healthy controls with regards to intima-media thickness and blood flow velocity in the middle cerebral artery. It is not likely that typical atherosclerotic lesions precede thrombotic events in homocystinuria. It may be that arterial dilations caused by medial damage lead to thrombosis in homocystinuric patients. The mechanism underlying the thrombotic events seen in early-treated vitamin B6 responsive homocystinuric patients is not known.

Fibrinogen, Arterial Risk Factor in Clinical Practice

Potron G, Nguyen P, Pignon B
Clinical Hemorrheology, 1994;14(6):739-767

Ten large studies have confirmed that fibrinogen is a risk factor of equal or higher value than total cholesterol. Fibrinogen is an independent risk factor and is an independent and prognostic risk factor for coronary artery disease. After a stroke an elevated fibrinogen is an index of the severity of the condition. In peripheral arterial disease it is an indicator of the risk to reocclusion after surgery. Fibrinogen's role in arterial occlusion include the composition of the atheroma plaque, thrombi formation, endothelial injury and hyperviscosity. Fibrinogen can be increased by inflammation, aging and smoking. Drugs that may reduce fibrinogen include fibrates and the platelet inhibitor ticlopidin. Physical exercise if sustained can reduce fibrinogen.

Fibrinogen and Cardiovascular Disorders

Lip GY
Department of Cardiology, Stobhill Hospital, Glasgow.
Quarterly Journal of Medicine, 1995;88:155-165

This is an extensive review article on the role of fibrinogen and cardiovascular disease. Fibrinogen is involved in blood coagulation and is an important determinant of blood viscosity and blood flow. Elevated plasma fibrinogen levels have been epidemiologically shown to increase the risk for cardiovascular disorders. These include ischemic heart disease, stroke and other thromboembolic events. Increased plasma fibrinogen may promote a prothrombotic or hypercoagulable state, and may, in part, explain the risk of stroke and thromboembolism in conditions such as atrial fibrillation and cardiac dysfunction. Human fibrinogen is a large glycoprotein (340,000 Da) composed of 3 pairs of nonidentical polypeptide chains (A alpha, B beta and gamma) joined together by disulphide bonds. Fibrinogen is an important determinant of both rheological characteristics of blood flow and of platelet aggregability. Fibrinogen is an essential component of the blood coagulation system, being the precursor of fibrin. Usual plasma levels are between 1.5 and 4.5 g/l, a concentration far greater than the minimum concentration needed of 0.5 to 1 g/l for haemostasis. In 9 out of 10 studies, plasma fibrinogen levels correlated significantly with the degree of coronary artery disease. A positive correlation between plasma fibrinogen and fibrin D-dimer has been seen in patients with atrial fibrillation. Intermediate levels of plasma fibrinogen have also been found in patients with paroxysmal atrial fibrillation. Psychological and mental stress can increase plasma fibrinogen levels. Fibrinogen levels are significantly associated with cerebrovascular disease. Plasma fibrinogen concentrations have been shown to be an important independent predictor of coronary death in patients with intermittent claudication. In patients with systemic hypertension, fibrinogen concentrations and plasma viscosity are independent predictors of blood pressure. In diabetic patients, a significant positive correlation has been found between plasma fibrinogen and fasting glucose levels, serum cholesterol levels, glycosylated hemoglobin and urinary albumin excretion rates. In individuals who use oral contraceptives, an increased risk of thrombotic events measured by elevated platelet aggregation and plasma fibrinogen levels has been discovered. There appears to be a hormonal influence on fibrinogen levels. Smoking has a dose- effect relationship on plasma fibrinogen levels. In obese patients with a body mass index of more than 30, plasma viscosity and fibrinogen levels are significantly increased. Strenuous exercise is associated with lower fibrinogen and cholesterol concentrations. Increased alcohol consumption may have a small but significant effect on decreasing plasma fibrinogen levels. The role of social class and psychosocial factors in determining plasma fibrinogen levels is controversial. Plasma fibrinogen levels are increased in patients with hyperlipidaemia. Dental disease is associated with myocardial infarction, and increased fibrinogen and white blood cell counts may partly explain this. The genetic influence on plasma fibrinogen formation, and genetic heritability, may account for 51% of the variance of plasma fibrinogen levels. There is a wide range of reference values for plasma fibrinogen with a mean "normal" value between 2.3 and 3.1 g/l in different population studies. Elevated plasma fibrinogen levels are consistently associated with various cardiovascular disorders. Because the process of atherogenesis has similarities to inflammatory diseases, the elevation of plasma fibrinogen levels may reflect the severity of the vascular disorder as a secondary phenomenon rather than act as a true prognostic factor. The strong hereditary determination of fibrinogen makes it less likely that raised fibrinogen levels are simply a secondary response to cardiovascular disorders. Raised plasma fibrinogen levels are known to precede in cardiovascular disorders. Raised plasma fibrinogen levels are likely to reflect a pre-existing prothrombotic, or hypercoagulable, state. Acts to lower fibrinogen levels include ceasing smoking and increasing exercise. Drugs that may lower fibrinogen include ticlopidine, stanzolol, oxypentifylline, calcium dobesilate, propanolol, nislodipine and the fibrates. These drugs have other pharmacologic effects other than lowering fibrinogen concentrations and are not practical therapeutic options. There is controversy with regards to diet lowering plasma fibrinogen levels. Fish oil supplementation may result in the reduction in plasma fibrinogen levels. Moderate alcohol consumption, increased garlic, regular exercise, weight loss and better diabetic control are also favorable to lowering fibrinogen levels.

Can Lowering Homocysteine Levels Reduce Cardiovascular Risk?

Stampfer MJ, Malinow MR
The New England Journal of Medicine, February 2, 1995;332(5):328-329.

Consistent findings have emerged from more than 20 case-control and cross-sectional studies of over 2,000 subjects indicating that patients with stroke and other cardiovascular diseases tend to have higher levels of homocysteine than those without the disease even though most have values within the normal range. In the Physician's Health Study, the 271 men who later had myocardial infarctions had significantly higher mean base-line levels of homocysteine than matched controls who were free of infarction. Men whose homocysteine levels were in the highest 5 percent had three times the risk of myocardial infarction than those with lower levels, even after adjustment for coronary risk factors. The prevalence of carotid-artery stenosis has been shown to be related to increasing plasma levels of homocysteine. One hypothesis regarding homocysteine's effects on cardiovascular disease is that damage stems from a toxic effect by homocysteine on vascular endothelium, which impairs the production of endothelium-derived relaxing factor. Homocysteine may stimulate the proliferation of smooth muscle cells, which is part of atherogenesis. Homocysteine can also act as a thrombogenic agent. The most dramatic elevations of homocysteine, which lead to life threatening vascular abnormalities at a young age, are due to an enzyme defect. Inadequate folic acid intake is the main determinant of homocysteine-related increase in carotid-artery thickening. Folic acid, vitamins B6 and B12, all play an important role in homocysteine metabolism. Homocysteine levels reach a stable low level only when folic acid intakes of approximately 400 ug per day or more are sustained. Folic acid supplements in the range of 1 to 2 mg per day are generally innocuous, and usually are sufficient to reduce or normalize high homocysteine levels, even if the elevation is not due to inadequate folic acid supplementation. When folic acid consumption is high the minor and common genetic variances have no clinical significance. But when folic consumption is marginal the risk may be elevated. In the Physician's Health Study, 5 percent of the controls had plasma homocysteine levels above 15.8 umol/L, the level which is associated with a three-fold increased risk of myocardial infarction. In the older and less highly selected population of the Framingham Heart Study, 21 percent had high levels of homocysteine. The author notes, "Because the weight of evidence is substantial and the intervention appears to be benign, it may be possible to make broad preliminary recommendations based on trials of secondary prevention or disease progression rather than wait for large, expensive and prolonged trials of primary prevention. In the meantime, it will be prudent to ensure adequate dietary intake of folate".

The Lipoprotein(a). Significance and Relation to Atherosclerosis

Heller FR, Parfonry A, Hondekijn JC
Service de Medecine Interne, Hopital de Jolimont, Haine St Paul, Belgique.
ACTA Clinica Belgica, 1991;46(6):371-383

Lipoprotein(a) is very similar to low density lipoprotein, but possesses a unique protein moiety called apolipoprotein (A). The plasma concentration of lipoprotein(a) is mainly under genetic control. Nicotinic acid (vitamin B3) and neomycin are able to reduce its concentration. Epidemiologic studies suggest that high levels of lipoprotein(a), greater than 30 mg per dl, are an independent risk factor for atherosclerosis of the coronary and carotid arteries. The risk is highest in those with hypercholesterolemia. High lipoprotein(a) levels could also favor thrombosis. Reducing hypercholesterolemia is important when lipoprotein(a) levels are greater than 30 mg per dl.

Diminished production of malondialdehyde after carotid artery surgery as a result of vitamin administration

Rabl H.; Khoschsorur G.; Hauser H.; Petek W.; Esterbauer H.
Austria
Medical Science Research (United Kingdom), 1996, 24/11 (777-780)

The objective of this study was to establish the antioxidative effect of the vitamins E, C and retinyl palmitate (vitamin A), contained in a multivitamin solution, in carotid artery revascularisation surgery. 57 patients, 67.84 plus or minus 5.72 years of age, 39 men and 18 women, were divided into a control group (27 subjects) and a group with 30 subjects (mean age 68.46 plus or minus 5.09 years) who received the vitamin treatment immediately before the start of reperfusion of the brain. The control group (mean age 67.14 plus or minus 6.37 years) received physiological sodium chloride as placebo. All of the patients suffered from ischaemic cerebrovascular insufficiency manifested as TIA (transitory ischaemic attack) due to haemodynamically significant stenosis of the extracranial part of the ICA (internal carotid artery). Oxidative burst was measured by malondialdehyde (MDA) - thiobarbituric acid reactive substances (TBARS) perioperatively before and 0.5, 1, 2 and 3 h after revascularisation. In the control group MDA-TBARS significantly increased from 0.91 plus or minus 0.49 to 1.15 plus or minus 0.41 nmol mL-1 (p < 0.003) 1 h after reperfusion onset and returned to baseline after 2-3 h. In the vitamin-treated group MDA-TBARS steadily decreased during the reperfusion period (1.11 plus or minus 0.39, 0.91 plus or minus 0.42, 0.81 plus or minus 0.29, 0.78 plus or minus 0.39, 0.72 plus or minus 0.24 nmol mL-1). The significant difference in MDA-TBARS between control and treatment groups, 1 h after the start at reperfusion was 1.15 plus or minus 0.41 vs 0.81 plus or minus 0.29 nmol mL-1; (p < 0.001). As an indirect parameter of reperfusion injury 13% (4/30 patients) of the patients in thetreatment group suffered... The perioperative use of antihypertensive drugs was 20% (6/30) in the treatment group, as compared to 78% (21/27) in the control group. These results suggests that vitamin treatment prior to reperfusion might be of beneficial effect, alleviating lipid peroxidation and leading to a better clinical course as regards the central nervous system.

Spermine partially normalizes in vivo antioxidant defense potential in certain brain regions in transiently hypoperfused rat brain

Farbiszewski R.; Bielawska A.; Szymanska M.; Skrzydlewska E.
Poland
Neurochemical Research (USA), 1996, 21/12 (1497-1503)

Activities of the antioxidant enzymes such as superoxide dismutase (Cu,Zn-SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) as well as the level of reduced glutathione and the concentration of thiobarbituric acid-reactive substance (TBARS) in brain regions in transiently hypoperfused rat brain with or without intravenous infusion of spermine were evaluated. Cerebral hypoperfusion was induced by temporary occlusion of common carotid arteries for 30 min and subsequently, by reperfusion for 60 min. Infusion of spermine reversed the decrease in SOD activity in the cerebral cortex, striatum, hippocampus, hypothalamus and midbrain, and amounted to 50.1 U, 61.5 U, 50.3 U, 30.0 U, 38.0 U, respectively, while GSH-Px restored to normal values only in the cerebral cortex and striatum and amountter use of spermine no changes in GSSG-R were seen in the hypothalamus and midbrain. The activity of GSSG-R was in accordance with the control for the striatum and amounted to 39.0 IU after using spermine, GSH content returned to normal values in the striatum and midbrain after i.v. use of spermine and amounted to 210 and 240 nmol/g of wet tissue, respectively. In addition, the production of TBARS dropped markedly (P < 0.05) in the hippocampus and midbrain and amounted to 100 and 105 micromol/g of wet tissue, respectively. Partially beneficial effect of spermine could result from the inhibition of free radical generation and capability of chelate formation with iron ions.

Positron-labeled antioxidant 6-deoxy-6-(18F)fluoro-L-ascorbic acid: Increased uptake in transient global ischemic rat brain

Yamamoto F.; Shibata S.; Watanabe S.; Masuda K.; Maeda M.
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-82 Japan
Nuclear Medicine and Biology (USA), 1996, 23/4 (479-486)

The in vivo uptake and distribution of 6-deoxy-6-(18F)fluoro-L-ascorbic acid (18F-DFA) were investigated in rat brains following postischemic reperfusion. Global cerebral ischemia was induced in male Wistar rats for 20 min by occlusion of four major arteries. Two time paints were chosen for 18F-DFA injection to rats subjected to cerebral ischemia, at the start of recirculation and 5 days following recirculation. The rats were then killed at 2 h after tail-vein administration of 18F-DFA and tissue radioactivity concentration was determined. Increased uptake of radioactivity in particular brain regions, including the cerebral cortex, hypothalamus, and amygdala following injection of 18F-DFA, compared to the sham operated control, was observed 5 days after reperfusion. Similar results were also obtained in in vitro experiments using brain slices. Abnormal in v45Ca, a marker of regional postischemic injury, was observed in these brain regions in tissue dissection experiments. Furthermore, metabolite analysis of nonradioactive DFA using 19F-NMR showed that DFA remained intact in the postischemic reperfusion brain. The present results indicate that 18F-DFA increasingly accumulates in damaged regions of postischemic reperfusion brain.

Stroke is an emergency

[No authors listed.]
Disease-a-Month (USA), 1996, 42/4 (202-264)

Stroke is an emergency. Ischemic stroke is similar to myocardial infarction in that the pathogenesis is loss of blood supply to the tissue, which can result in irreversible damage if blood flow is not restored quickly. Public education is needed to emphasize the warning signs of stroke. Patients should seek medical help immediately, using emergency transport systems. Therapy geared toward minimizing the damage from an acute stroke should be started without delay in the emergency room. This includes measures to protect brain tissue, support perfusion pressure, and minimize cerebral edema. Strategies for improving recovery should also begin immediately. All major medical centers need stroke teams and stroke units. Stroke prevention should be given high priority as a public health strategy. Risk factor management should be part of general health care and should begin in childhood, with emphasis on nutrition, exercise, weight control, and avoidance of tobacco. Health screening and early treatment of hypertension and hypercholesterolemia has decreased the incidence of stroke and heart disease, but these efforts need to be expanded to reach all segments of the population. Basic research has opened the door to new therapies aimed at re-establishing blood flow and limiting tissue damage. Clinical trials have already led to changes in stroke prevention, including studies of carotid endarterectomy and ticlopidine and warfarin therapy (for patients with atrial fibrillation). Trials in progress are testing the usefulness of ancrod, neuroprotective agents, antioxidant agents, anti-inflammatory agents, low-molecular-weight heparin, thrombolytic drugs, and angioplasty. Any delay starting therapy after an acute stroke will reloss of brain tissue. Clinicians should remember that for a stroke patient, time is brain tissue.

Antithrombotic agents in cerebral ischemia

Albers G.W.
Dept. of Neurology/Neurological Sci., Stanford Stroke Center, Stanford University Medical Center, 701 Welch Road, Palo Alto, CA 94304-1704 USA
American Journal of Cardiology (USA), 1995, 75/6 (34B-38B)

The choice of antithrombotic agent in cerebral ischemia depends on the pathogenesis: thrombosis, embolism, or hemorrhage. Antiplatelet agents are considered most beneficial in thrombotic stroke, anticoagulants are most effective in cardioembolic stroke; antithrombotic agents are generally contraindicated in hemorrhagic stroke. A meta-analysis of 18 trials documented a 23% reduction in stroke risk with antiplatelet agents; aspirin is typically the antiplatelet agent of choice for stroke prevention. There are no definitive data regarding the optimal aspirin dose for stroke prevention and this issue remains controversial. Ticlopidine is the most effective antiplatelet agent, but its adverse effect profile restricts its use. Anticoagulants are highly effective for preventing cardioembolic stroke, but their effectiveness in non-cardioembolic stroke is uncertain because of lack of trial data. Results of the ongoing Warfarin/Aspirin Recurrent Stroke Study (warfarin (INR 1.8-2.8) vs aspirin (325 mg/day)) may clarify this issue. There is renewed interest ta indicate that reperfusion within a few hours of stroke onset appears to be effective in preventing neuronal damage. In addition, when given within 6 hours of stroke onset, thrombolytic appear to be relatively safe. Several direct thrombin inhibitors are being evaluated. Experimentally, hirudin, hirulog, D-Phe-L-Pro-L-Arg-CH2Cl (PPACK), and argatroban are clearly more effective than heparin in inhibiting platelet deposition and thrombus formation, and also show promise in preventing reocclusion after thrombolysis for both experimental thrombotic and embolic stroke. However, the risk of hemorrhage in patients with cerebrovascular disease is unknown for these agents. New antiplatelet agents, most of which inhibit the platelet IIb/IIIa receptor, have also shown a significant reduction in ischemic complications in experimental thrombosis models.

Platelet activity and stroke severity

Joseph R, Han E, Tsering C, Grunfeld S, Welch KM
Department of Neurology, Henry Ford Hospital and Health Sciences Center, Detroit, MI 48202.
J Neurol Sci 1992 Mar;108(1):1-6

Although platelets constitute the major component of a thrombus, its role in determining the clinical severity of thrombotic stroke is unknown. Therefore, we investigated the relationship between platelet ionized calcium ((Ca(i)2+ )), a measure of platelet activity and presumably proneness to thrombosis, and clinical stroke severity in 45 consecutively studied acute ischemic stroke patients. Even though there was no correlation between the clinical neurological scores and the levels of baseline and activated platelet (Ca(i)2+), stroke was less severe in patients who had been taking aspirin at the time of stroke onset. These results raise several important questions: (a) is the extent of platelet activation a reflection of thrombus volume, (b) does the clinical severity of neurological deficit reflect the causative thrombus volume, and (c) whether the beneficial effect of aspirin in stroke prophylaxis is through its inhibition of platelets alone.

The use of antithrombotic drugs in artery disease

Gallus A.S.
School of Medicine, Flinders University of South Australia, Flinders Medical Centre, Bedford Park, SA 5042 Australia
Clin Haematol 1986 May;15(2):509-59

Evaluating the use of antithrombotic drugs in artery disease has been a long and difficult process, which is far from complete. The aims of treatment have ranged from the primary prevention of myocardial infarction or stroke, through the restoration of blood flow to ischaemic organs in order to salvage threatened tissue, to the prevention of recurrent vascular occlusion. Drugs studied in depth by clinical trial include the oral anticoagulants, antiplatelet drugs (especially aspirin), and thrombolytic agents. Their results are considered under the headings of coronary artery disease, cerebral ischaemia, and peripheral vascular disease. Aspirin, with or without dipyridamole, prevents progression of unstable angina to myocardial infarction or death, probably reduced long-term mortality after myocardial infarction, and prevents aortocoronary bypass graft occlusion. It of stroke or death in patients with transient cerebral ischaemia, diminishes cardiovascular morbidity after a thrombotic stroke, and may improve the outcome after some kinds of surgery for peripheral vascular disease. The benefits of oral anticoagulant treatment to prevent artery occlusion remain poorly defined. Oral anticoagulants prevent systemic embolism in many groups of high-risk patients, and probably reduce the risk of recurrence after embolism has occurred. Whether their long-term use to prevent reinfarction in patients with a previous myocardial infarct can be justified remains uncertain. They are of little or no proven value in patients with transient cerebral ischaemia or thrombotic stroke. On the other hand, there is increasing support for early thrombolytic treatment after myocardial infarction, especially since two multicentre trials have now shown reduced mortality in patients treated with intracoronary streptokinase within 4-6 hours of infarction and a further large multicentre study also demonstrate reduced mortality in patients treated with early intravenous streptodkinase. In addition, the local infusion of streptokinase leads to recanalization in a high proportion of patients with a recent peripheral artery occlusion who are poor candidates for surgery.

Medical management in the endovascular treatment of carotid-cavernous aneurysms

Polin RS, Shaffrey ME, Jensen ME, Braden L, Ferguson RD, Dion JE, Kassell NF
Department of Neurosurgery, University of Virginia Health Sciences Center, Charlottesville, USA.
J Neurosurg 1996 May;84(5):755-61

Carotid-cavernous aneurysms account for between 1.9% and 9.0% ofintracranial aneurysms. Entirely intercavernous aneurysms are believed to have a relatively benign course, with cranial nerve findings or headache being the usual initial symptomatology; however, subarachnoid hemorrhage or carotid-cavernous fistula formation can result from rupture. Over the past 15 years endovascular parent artery occlusion has essentially replaced surgical carotid occlusion as the treatment of choice. The authors describe a series of 39 consecutive patients at the University of Virginia Health Sciences Cid-cavernous aneurysm. Aggressive invasive hemodynamic monitoring and maintenance of a state of normo- to mild hypervolemia in the asymptomatic patient was used throughout the periprocedural period. Rapid institution of hypervolemic-hypertensive therapy can reverse early neurological deficits related to hypoperfusion in these patients. Only one individual managed with this protocol developed neurological deficits not reversible with hypertensive-hypervolemic therapy. Heparin therapy was administered for 48 hours after occlusion, with patients receiving subsequent aspirin therapy for 6 months to combat distal embolism secondary to thrombosis. Long-term complications were not seen in patients receiving aneurysm trapping; however, two individuals with proximal carotid occlusion developed late optic neuropathy and one had recurrent transient ischemic attacks that ceased with supraclinoidal carotid clipping.

Mechanism of hydrogen peroxide and hydroxyl free radical-induced intracellular acidification in cultured rat cardiac myoblasts

Wu M.-L.; Tsai K.-L.; Wang S.-M.; Wu J.-C.; Wang B.-S.; Lee Y.-T.
Department of Internal Medicine, Medical College, National Taiwan University Hospital, 7, Chung-Shan South Rd, Taipei Taiwan
Circulation Research (USA), 1996, 78/4 (564-572)

After a transient ischemic attack of the cardiac vascular system, reactive oxygen-derived free radicals, including the superoxide (O2-.) and hydroxyl (.OH) radicals can be easily produced during reperfusion. These free radicals have been suggested to be responsible for reperfusion-induced cardiac stunning and reperfusion-induced arrhythmia. Hydrogen peroxide (H2O2) is often used as an experimental source of oxygen-derived free radicals. Using freshly dissociated single rat cardiac myocytes and the rat cardiac myoblast cell line, H9c2, we have shown, for the first time, that an intriguing pH(i) acidification (similar0.24 pH unit) is induced by the addition of 100 micromol/L H2O2 and that this dose is without effect on the intracellular free Ca2+ levels or viability of the cells. Using H9c2 as a model cardiac cell, we have shown that it is the intracellular production of .OH, and not O2-. or H2O2, that results in this acidification. We have excluded any involvement of (1) the three known cardiac pH(i) regulators (the Na+-H+ exchanger, the Cl--HCO3 exchanger, and the Na+-HCO3 cotransporter), (2) a rise in intracellular Ca2+ levels, and (3) inhibition of oxidative phosphorylation. However, we have found that H2O2-induced acidosis is due to inhibition of the glycolytic pathway, with hydrolysis of intracellular ATP and the resultant intracellular acidification. In cardiac muscle and in skinned cardiac muscle fiber, it has been shown that a small intracellular acidification may severely inhibit contractility. Therefore, the sustained pH(i) decrease caused by hydroxyl radicals may contribute, in some part, to the well-documented impairment of cardiac mechanical function (ie, reperfusion cardiac stunning) seen during reperfusion ischemia

Thrombolysis of the cervical internal carotid artery before balloon angioplasty and stent placement: Report of two cases

Guterman L.R.; Budny J.L
Gibbonpartment of Neurosurgery, 3 Gates Circle, Buffalo, NY 14209-1194 USA
Neurosurgery (USA), 1996, 38/3 (620-624)

The application of endovascular techniques to the treatment of cervical carotid artery bifurcation atherosclerosis has been delayed because of the fear of causing embolic events while traversing the diseased portion of the artery with an angioplasty balloon catheter. Symptomatic carotid arteries often contain fresh or partially digested intraluminal thrombus. Before we cross certain carotid bifurcation lesions with angioplasty catheters, we deliver 100,000 to 200,000 units of urokinase in an attempt to digest loose thrombus. We have witnessed changes in the angiographic appearance of the diseased portion of the vessel after urokinase treatment, such as widening of the lumen, that suggest clot lysis. We present two patients who had symptomatic internal carotid artery stenosis. Angiography showed irregular narrowing of the internal carotid artery origin. One patient was selected for angioplasty instead of carotid endarterectomy because of severe cardiac risk factors. The other patient had major angiographic risk factors manifested by poor collateral circulation. The angiographic findings and history of transient ischemic attacks led us to suspect the presence of soft, loose plaque debris or thrombus in both cases. Therefore, we performed thrombolysis with urokinase before angioplasty. Repeat angiography showed widening of the arterial lumen and smoothing of theplaque profile. Subsequent angioplasty and stent placement were uneventful. Intraarterial thrombolysis can produce a change in the angiographic appearance of symptomatic atherosclerotic lesions of the cervical carotid artery bifurcation. Digestion of intralesional thrombus may provide a safer environment for deployment of endovascular remodeling devices by decreasing the likelihood of embolic phenomena. We believe thrombolysis should be done before angioplasty in select patients.

Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia

Algra A.; Van Gijn J.
Clinical Epidemiology Unit, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht Netherlands
Journal of Neurology Neurosurgery and Psychiatry (United Kingdom), 1996, 6 0/2 (197-199)

There is continuing debate about the relative efficacy of low (< 100 mg per day), medium (300 to 325 mg per day), and high (> 900 mg per day) doses of aspirin in patients after a transient ischaemic attack or non-disabling stroke. The purpose of this study was to resolve the issue. Thus a minimeta-analysis was performed on data from 10 randomised trials of aspirin only v control treatment in 6171 patients after a transient ischaemic attack or non-disabling stroke. The data on the trials were listed in an appendix of the report on the second cycle of the Antiplatelet Trialists' Collaboration. There was virtually no difference in relative risk reduction for low, medium, and high doses of aspirin (13%, 9%, and 14%respectively). This equivalence corresponds with the results of the UK-TIA trial in a direct comparison of 300 and 1200 mg. The Dutch TIA trial showed no difference in efficacy of 30 and 283 mg. It is concluded that aspirin at any dose above 30 mg daily prevents 13% (95% confidence interval 4-21) of vascular events and that there is a need for more efficacious drugs.

Mild hyperhomocysteinemia and hemostatic factors in patients witharterial vascular diseases.

Freyburger G; Labrouche S; Sassoust G; Rouanet F; Javorschi S; Parrot F
Laboratoire d'Hematologie, Hopital Pellegrin, Bordeaux, France.
Thromb Haemost (Germany) Mar 1997, 77 (3) p466-71

Mild hyperhomocysteinemia, due to genetic or to environmental factors, is now recognized as a risk factor for premature arterial disease, including peripheral arterial occlusion, thrombotic stroke and myocardial infarction. It is defined by either an increased level of fasting homocysteine or by an increased level after loading with methionine, which is more frequently altered than the former. We studied the hemostatic parameters in 88 patients with premature arterial disease (mean age 43 +/- 11 years). We confirmed previously known hemostatic alterations described in vascular patients when compared to controls, but found that, among patients, some of these parameters were more altered in hyperhomocysteinemic patients. Whenfasting homocysteine was increased, higher alterations were found in factors VIIIc, vonantithrombin complexes were more elevated. When post-methionine load homocysteine was increased, alterationsin fibrinolytic parameters were more pronounced.