大蒜素治疗急性脑梗死临床研究

1、*a clinical study of garlicin in treating acute cerebral infarctionshi zaixiang （史载祥）,zhang jiuliang （张久亮），mao jiansheng （毛建生）zhang tiezhong （张铁忠）,li haicong （李海聪）,du jinxing （杜金行）huang li （黄 力）and cao qifu （曹启富）the china-japan friendship hospital, beijing （100029）zi bohai （自伯海）*,shi yiting （石义亭）*,l

2、iu aihua （刘爱华）*,wei qing （魏青）* *abstract objective: to evaluate the effect of garlicin in treating acute cerebral infarction. methods: one hundred and one patients of acute cerebral infarction diagnosed by ct were treated with garlicin （garlicin group） and compared with another group of 53 patients

3、treated with ligustrazine （control group）. the neurologic deficiency score and neurologic function score were used for evaluation of effect.results: the effective rates of garlicin and ligustrazine were 89.36% and 84.85% respectively. the improvement scores of neurologic function were 18.46+10.69 an

4、d 11.94+6.79 respectively. the difference between the two groups was significant. before treatment the serum level of mda in the garlicin group was 6.015+1.26 nmol/ml, and it decreased to 4.87± 1.16 nmol/ml after treatment, the change being more significant than that of the control group （from

5、6.02+0.73 nmol/ml to 6.47±1.04 nmol/ml）. the rheological parameters and cerebral blood flow were also improved after garlicin treatment. conclusion: garlicin could increase the perfusion flow of brain, improve the microcirculation, and scavenge free radicals so as to relieve the ischemia and re

6、perfusion injury of the brain.key words garlicin, acute cerebral infarction, ligustrazine, malonyldialdehyde, hemorheologymethodspatientsamong the one hundred and fifty-four acute cerebral infarction patients （no more than 3 days after the onset of the disease） diagnosed according to the diagnostic

7、standard formulated in the second session of national conference on cerebrovascular diseases, 1986，80 were male and 74 female, aged 60.86±l 1.23 years. thirty-six persons, 22 males and 14 females, aged 57.47+6.60 years, confirmed to be healthy by x-ray chest fluoroscopy, electrocardiogram, exam

8、ination of liver function and renal function, and routine examination of blood, urine and stool, were enrolled as the normal control group in respect of serum malonyldialdehyde （mda） and hemorheology of leucocyte.the 154 patients were divided randomly into two groups, the garlicin group and the ligu

9、strazine group （control group）.in the garlicin group, there were 101 patients, including 48 males and 53 females, their mean age being62.9+9.31 years. the distribution of ischemic focus and frequency was: at basal nuclei in 57 patients, basal nuclei plus corona radiata in 5, basal nuclei plus occipi

10、tal lobe in 1, corona radiata in 5, frontal lobe in 3, parieto-occipital region in 3, temporal lobe in 2, parietal lobe in 2, thalamus in 3, brain stem in 1 and multiple focused on hemisphere in 19. among them 30 patients were complicated with hypertension, 7 with diabetes mellitus, 6 with both hype

11、rtension and diabetes mellitus, 9 with coronary heart disease, 2 with coronary heart disease, diabetes mellitus and hypertension and 1 with coronary heart disease and diabetes mellitusthe control group consisted of 53 patients, 32 males and 21 females, 57.92±950 old in average distribution of i

12、schemic focuses and frequency was: basal nuclei in 20 patients, basal nuclei plus corona radiata in 4, basal nuclei plus parietal lobe in 2， corona radiata in 4, frontal lobe in 1, temporal lobe in 1，parieto-occipital region in 2， cerebellum in 1, thalamus in 2, region neighboring ventricle of brain

13、 in 2, internal capsule in 1, parietal lobe in 2 and multiple focused on hemisphere in 11. sixteen patients were complicated with hypertension, 4 with diabetes mellitus, 4 with coronary heart disease, 1 with both diabetes mellitus and hypertension and 2 with both hypertension and coronary heart dise

14、ase.treatmentgarlicin injection, prepared by the pharmaceutical department of china-japan friendship hospital, was given to the garlicin group. 60 mg of it was added into 500 ml of 5% glucose solution and given every day for intravenous drip, with 2 weeks as one therapeutic course the second therape

15、utic course was given to part of the patients 2-3 days after the end of the first course.the control group received intravenous drip of ligustrazine 80 mg in 500 ml of 5% glucose every day with therapeutic course the same as that of garlicin group.normal saline was used instead of glucose solution f

16、or those complicated with diabetes mellitus in both groups. complications of patients were treated in the following way: (1) bacterial infection was treated with relevant antibiotics when necessary; (2) diabetes mellitus was treated w让h proper hypoglycemic agent; (3) hypertension was treated with pr

17、oper hypotensor; (4) intracranial hypertension caused by cerebral edema was treated with intravenous infusion of 20% mannitol.parameters of observationl serum mda content was determined according to the yagi s method.2. hemorheologic examinationvenous fasting blood sample 4 ml was withdrawn in the m

18、orning. after anticoagulation with 2 u ml of edta-2na, with 2 ml of dextran added to it and laid by for 30 min, the suspension of upper wbc layer was collected and centrifuged at1300 g for 10 min. then when the supernatant was removed, 4 ml of hank s balanced saline solution (hbss) was added, well m

19、ixed, the lymphocyte separation medium 4 ml (product of shanghai second biochemical reagent factory, with specific gravity of 1.077) was added slowly at the bottom of the tube, and centrifuged at 2000 g for 20 min. then the lymphocyte layer was removed, the residual rbc was disolved with distilled w

20、ater and 1.8% nacl, the hemoglobin fluid was removed, and the wbc suspension concentration was adjusted with hbss to 220x104/ml. the wbc suspension was filtrated with microporous filtering film, and with the conditions of other parameters constant, the filtration time (ft) of a certain volume of wbc

21、 suspension was measured to calculate the rheologic property of wbcthe filtration index (fi) was calculated with the following formula:fi = (wbc ft standard ft)/(standard ft )other rheologic parameters, such as whole blood viscosity, plasma viscosity, rbc electrophoresis time, hemocrit and fibrinoge

22、n content were all determined simultaneously for control.3. cerebral blood flow measurementcerebral blood flow was measured before and after 1 course of treatment with qfm-1000 blood flow meter (a product of japan), the doppler ultrasonic quantitative tachogram of common carotid artery of the affect

23、ed side was recorded and the volume and velocity of blood flow as well as the diameter of artery were calculated.resultscriteria of therapeutic effect evaluation1. neurologic deficit was scored according to the standard drawn up by the second session of national conference of cerebrovascular disease

24、, 1986.the scoring was carried out at admission, 2 weeks and 4 weeks after the beginning of treatment for therapeutic efficacy evaluatioru2.1njury of nervous system was classified into three degrees: (1) mild: with neurologic deficit less than 15 scores; (2) moderate: 16-30 scores; (3) severe: 31-45

25、 scores.table 1. comparison of clinical effect between the two groups (cases)grouptime(week)ncuredmarkedlyimprovedimprovedineffectivetotal effective rate (%)garlicin21011919402377.23*447918 j155 |89.36control25377192062.264337912584.85note: p<0.05, compared with the control group3. clinical effic

26、acy was evaluated by the following standard: (1) cured: symptoms and signs of nervous system disappeared basically or completely; (2) markedly improved: the neurologic deficit got improved by more than 10 scores; (3) improved: the neurologic deficit got improved by 4-10 scores; (4) ineffective: the

27、neurologic deficit was improved by <4 scores or exacerbated and the condition of the patients got worse or even died. for the patients with mild degree of nervous system injury who scored less than 10, the standard was that scores decreased by 30-50 % was considered as improved; and by 51-90 % as

28、 markedly improved.4. improvement of neural function was also evaluated at admission, 2 weeks and 4 weeks after the beginning of treatment according to the modified mathew s method，which is internationally acceptedanalysis on the comparability between groupsthe distribution of complications of the g

29、arlicin group and the control group was analysed by x 2 test, result showed x 2=2.818, degree of freedom was 3, p>0.05. result of analysis of infarcted focus distribution of the two groups showed x 2=2.07, degree of freedom=3 and p>0.05. these results showed that the two groups were comparable

30、.clinical effect of garlicinas shown in table 1, after two weeks of treatment, the total effective rate in the garlicin group was 77.23% and that in the control group was 62.26%, the difference between the two groups was significant (p<0.05). yet after 4 weeks of treatment they were 89.36% and 84

31、.85%, with no significant difference found between them (p>0.05).the improvement of injury of nervous system was shown in table 2, which was expressed by improved scores, and calculated by deducting the scores obtained after treatment from the scores obtained before treatment results of the death

32、s were excluded from the series because the therapeutic course of them was less than 2 weeks. comparison of the two groups showed that the effect of garlicin was significantly higher than that of ligustrazine either by 2 weeks of treatment or 4 weeks.table 2. comparison of improved scores between th

33、e two groups(scores,元 ±s)group2 w.post-treat.4 w. post-treat.nscoreinscoregarlicin1004.95±4.58468.70+5.12*control523.42±3.44326.41+4.09水note: pv005, compared with control groupeffect of garlicin evaluated by mathew，s methodresults showed there was no significant difference over neural

34、 functions between the two groups before treatment, p>0.05, after 2 weeks or 4 weeks of treatment, the improved scores of the garlicin group were markedly higher than those of the control group (see table 3). in this series, the scores improved were calculated with the same formula as mentioned a

35、bove, but the scores of the deaths (score as zero) were not excluded.table 3. comparison of improvement of nervous function between the two groups (mathew" s score,天 ±s)groupadmission2 w. post-treat.4 w. post-treat.nscorenscoren| scoregarlicin10169.23+18.421019.78+11.18'4618.46+10.69&q

36、uot;control5367.89+19.20535.39±8.523211.94+6.79* * *notes: p<0.02,p<0.005, compared with control groupeffect of garlicin on serum level of mdastatistic analysis showed no significant difference in ages between the patients of acute cerebral infarction and healthy subjects of the normal co

37、ntrol group, p>0.05, and therefore, the physiological difference in serum level of mda originating firom age could be ruled out. compared with the healthy subjects, the serum mda of the patients was raised obviously, p<0.01 (see table 4).table 4. comparison of serum mda between patients and he

38、althy subjects (亍 ±s)groupnage (year)mda(nmol/ml)patienti5762.95±9.836.122±1.291*health3657.47+6.603.873+0.669水note: pvo.ol, compared with healthy personsafter treatment, serum level of mda was determined in 33 patients in the garlicin group and 21 in the control group. among them 4 c

39、ases in the former group and 2 cases in the latter were complicated with diabetes mellitus, distribution of diabetes mellitus in the two groups showing no significant difference, x =0.022, and degree of freedom=l, p>005serum level of mda of the garlicin group was significantly higher than that of

40、 the normal control group before treatment, 1 week and 2 weeks after treatment, p<0.05 but 3 weeks after treatment, the difference became insignificant. however, difference between the level of pro-treatment and the level 1 or 2 weeks after treatment was significant.serum levels of mda of the con

41、trol group determined before treatment, 1，2 and 3 weeks after treatment were all higher than those of the normal control group determined at the coitesponding times, and the level after 3 weeks of treatment was not significantly different from the levels determined before treatment, 1 and 2 weeks af

42、ter treatment, p>0.05. in comparison of the two treated groups, their mda levels determined before treatment, 1 and 2 weeks after treatment showed no significant difference, but after 3 weeks of treatment, the difference between the levels of the two groups became significant, p<0.01. (see tab

43、le 5)effect of garlicin on hemorheologic parametersl effect on rheological property of leucocytes (rpl)as shown in table 6, rpl (wbc infiltration index) of acute cerebral infarction patients was obviously higher than that of the healthy subjects, pvo.ol. it was much improved after one course of trea

44、tment, p<0.01 as compared with that of pre-treatment.2 effect on other rheological parametersafter treatment, the levels of hematocrit(hc), whole blood viscosity(wbv), plasma viscosity(pv), fibrinogen(fb) and electrophoretic time of rbc(etr) were all lowered significantly, p<0.05 or <0.01 (

45、see table 7)table 5. change of serum mda level of the two groups (nmol/ml, 天土s)grouppre-treat.1 w. post-t.2 w. post-t.3 w. post-t.nmdanmdanmdanmdagarlicin336.015+1.2633650+1.3533 5.554+1.32294.87±1.16*acontrol216.060+0.73216.645±1.0220 6.720+1.16196.47±1.04notespv001, compared with pr

46、e-treatment;' p<0.01, comparedwith control groupeffect of garlicin on cerebral blood flowresult showed that after treatment the cerebral blood flow (cbf) and velocity of the infarcted side of brain got improved markedly as compared with those before treatment, pvo.05, while the diameter of ve

47、ssels remained unchanged, (see table 8)table 6. effect of garlicin on wbc infiltration index (天 ±s)groupn wbc inf. indexhealthy subj.36 0.8651+0.4603garlicin g.pre-t.|33 6.1397±4.4602*post-t.28 1.6261 ±1.3427?*notes: p<0.01,compared with healthy subjects;ap<0>01, compared wit

48、h pre-treatmenttable 7. effect of garlicin on hemorheologic parameters (x ±s)param.npre-treat.post-treat.hc(%)4245.36+5.5243.07+4.38wbv( 11.02s1)4212.92+8.6910.04+5.76"pv(94.5s_,)321.92+0.231.62+0.11*fb(mg%)42416.76+85.98338.86+93.79'etr(s)1018.39+1.7515.88+1.34"*水*notes: p<0.0

49、5,p<0.01,compared with pre-treatmenttable & effect of garlicin on cerebral blood flow (天 ±s)cbfnpre-treat.post-treat.vol.(ml/s)325.98+2.557.72±2.44*vel.(cm/s)329.97±4.1813.52+5.06*diame.(mm)32& 49+0.818.60+0.80*notes: p<0.01,compared with pre-treatmentdiscussion1. to res

50、tore the blood supply of ischemic area is the prerequisite in treating acute cerebral infarction. it was found in recent years that the nervous function is not improved, neither is mortality reduced by surgical operation of cerebral artery by-pass, suggesting that the pathogenesis of post-ischemia i

51、njury of brain occurred during the ischemia-reperfusion process01'5). therefore, the key of treatment is, while improving the blood supply of the infarcted area, attention should be paid to relieving thereperfusion injury of brain.it had also been proved by researches on the mechanism of post-is

52、chemia injury of brain in recent years that the large amount of oxygen free radicals produced during the cerebral ischemia-reperfusion process is one of the major factors that cause cerebral injury"'.large amount of oxygen free radicals which surpass the auto-protective energy of cells, cou

53、ld attack the unsaturated fatty acid in the membrane of cells and organelles to produce the cascade reaction and cause the irreversible injury of cell membrane. the lipid peroxide produced during the cascade reaction would enter into blood and raise the blood content of lipid peroxide. mda is the st

54、able terminal product of lipid peroxide metabolism, so the degree of brain cell injury could be estimated indirectly by determination of the mda level(7). in this study, result showed that serum content of mda in acute cerebral infarction patients was markedly higher than that in the normal control

55、groupresults showed that the serum levels of mda before treatment, 1 week and 2 weeks after treatment in the garlicin group were higher than those of normal, which is in accordance with what has been reported in literature.it got lowered to nearly normal after 3 weeks of treatment, but it didn t dec

56、rease in the control group which was treated with ligustrazine. this suggests that garlicin, superior to ligustrazine, has the action of scavenging free radicals and relieving the cerebral injury. and this result was conformed by those obtained in the previous researches by the authors.2. the action

57、 of white blood cells (wbc) in pathogenesis of acute cerebral infarction has received lots of attention. during the cerebral ischemia-reperfusion process, wbc is activated by some active substance and acts in the following way: (1) the decrease of deformability and/or increase of adhesion of wbc cou

58、ld obstruct the capillary and impede the collateral circulation establishing so as to cause the expansion of the infarcted area; (2) wbc would agglutinate and adhere to the focus of cerebral vessels, and cause severe local injury by releasing activated oxygen, various bioactive substances and enzymes. furthermore, the products of cerebral ischemic necrosis might induce changes of wbc in rheologic characters so as to form a vicious cycle; (3) to aggravate the cerebral ischemia by changes in hemodynamics and hemorheology; (4) simple obstacle of wbc would result in microinfarction