CN1923206A - Application of ketanserin in preparing medicine for preventing cerebral apoplexy - Google Patents

Application of ketanserin in preparing medicine for preventing cerebral apoplexy Download PDF

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CN1923206A
CN1923206A CNA2006101163209A CN200610116320A CN1923206A CN 1923206 A CN1923206 A CN 1923206A CN A2006101163209 A CNA2006101163209 A CN A2006101163209A CN 200610116320 A CN200610116320 A CN 200610116320A CN 1923206 A CN1923206 A CN 1923206A
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brs
apoplexy
ketanserin
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苏定冯
刘爱军
于旭红
吴明月
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Second Military Medical University SMMU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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Abstract

The invention relates to a research on the prediction of artery pressure baroreflex sensitivity, BRS on dead brain, and the research of antihypertensive ketone selin on dead brain. Wherein, (1), BRS can be used as one independent factor to predict the occur of dead brain, that the occur time of BRS-high animal is later then the lower one; (2), ketone selin can effective improve BRS, without affected by its amount, to delay the dead brain and prolong life time.

Description

The application of ketanserin in the medicine of preparation prevention of brain apoplexy
Technical field
The present invention relates to medical technical field, is the relevant application of medicine ketanserin (ketanserin, Ketanserine) in the medicine of preparation prevention of brain apoplexy that improves arterial pressure sensitivity reflex function.
Background technology
Hypertension incidence rate height, up to 18%, there are 1.6 hundred million hypertensive patients in China at present the China adult.Apoplexy is the most important complication of hypertension, and in a single day apoplexy takes place, and consequence is serious, and patient is non-extremely promptly residual.The annual New Development apoplexy 1,500 ten thousand in the whole world, wherein 5,000,000 people's death, the permanent maimed person of 5,000,000 people.Make the survivor restore funcitons, time and effort consuming.Therefore, with regard to apoplexy, it is more important than treatment to prevent that it from taking place.The how generation of prevention of brain apoplexy? except bringing high blood pressure down, still there are not other effective measures at present.And particularly for cerebral infarction, the blood pressure lowering treatment can not stop the generation of apoplexy fully.Therefore, be necessary the pathophysiological mechanism of apoplexy is carried out deep research, find out other factor of determinations except blood pressure, intervene at these factors, propose new control strategy, thereby the generation of prevention of brain apoplexy better reduces the harm of apoplexy significantly.
(arterial baroreflex ABR) is the most important regulatory mechanism of cardiovascular activity to arterial baroreceptor reflex, and (baroreflex sensitivity, height BRS) embodies the power of its function to arterial baroreflex sensitivity.Studies show that BRS under various disease states, in various degree infringement is all arranged as hypertension, diabetes, apoplexy, hyperlipidemia or the like.La Rovere etc. discovers, the patient after heart infarction takes place, and the poor prognosis that the low person of BRS is obviously high than BRS, life span is short.We up-to-date experimental result confirm that BRS can be used as independently spontaneous hypertensive rat (Stroke-pronespontaneously hypertensive rats, SHR-SP) generation of mortality apoplexy of factor prediction apoplexy tendency.Its importance is not second to the effect of blood pressure.Significantly than low the delaying of BRS, life span obviously prolongs for the rat that BRS is high, apoplexy time of origin.
Since the height of BRS is closely related with apoplexy, improve the generation of BRS with regard to possible prevention of brain apoplexy, life-saving with medicine.Ketanserin is a kind of hypertensive medicine that is used for the treatment of, and can improve reflection function, but does not see relevant report with the generation of ketanserin prevention of brain apoplexy, life-saving so far.
Summary of the invention
The medicine that the purpose of this invention is to provide a kind of energy prevention of brain apoplexy, thus the generation of prevention of brain apoplexy better reduces the harm of apoplexy significantly.
Since the height of BRS is closely related with apoplexy, improve the generation of BRS with regard to possible prevention of brain apoplexy, life-saving with medicine.
The inventor is studying aspect the prevention of brain apoplexy in predicting function and antihypertensive drug ketanserin that apoplexy takes place BRS.Find that 1. BRS can be used as an independent factor, the generation of prediction apoplexy: the animal low that BRS is high than BRS, the apoplexy time of origin is delayed (P=0.0045) significantly, and its predicting function that apoplexy is taken place is not second to the effect of blood pressure; 2. ketanserin can improve BRS effectively, and its power and its dosage that improves BRS is irrelevant.With after animal experiment study has verified that the big low dose of ketanserin all can significantly delay apoplexy and take place, prolong the apoplexy rat life-span, the prevention of brain apoplexy effect of low dose of ketanserin and blood pressure lowering are irrelevant.
We up-to-date experimental result confirm that BRS can be used as independently spontaneous hypertensive rat (Stroke-prone spontaneously hypertensive rats, the SHR-SP) generation of mortality apoplexy of factor prediction apoplexy tendency.Its importance is not second to the effect of blood pressure.Significantly than low the delaying of BRS, life span obviously prolongs for the rat that BRS is high, apoplexy time of origin.
Technical scheme of the present invention is that medicine ketanserin (ketanserin, Ketanserine), the especially Xiao Jiliang ketanserin that will improve arterial pressure sensitivity reflex function are used at the medicine for preparing the prevention of brain apoplexy.
Description of drawings
Fig. 1 BRS is as factor prediction SHR-SP rat brain apoplexy generation separately.
Fig. 2 SBP is as factor prediction SHR-SP rat brain apoplexy generation separately.
The high low dose group of Fig. 3 ketanserin all significantly prevents SHR-SP rat brain apoplexy to take place.
The specific embodiment
Below example is further illustrated the present invention by experiment.
Embodiment 1: the predicting function that systolic pressure (SBP) and BRS take place the SHR-SP apoplexy:
With the SHR-SP rat about 82 7 monthly ages, male and female have concurrently.Under narcotism, carry out femoral artery, femoral venous catheter, support, recover to connect after 2 days the clear-headed autonomous pressure measuring system of computerization, stablized 4 hours, recording blood pressure is measured BRS, continues then to support, dead rat is not in recording interval in record operation back apoplexy time of origin and the existence situation, postoperative 15 days.Finish in the time of 400 days after surgery.Animal almost all dies from apoplexy at last.
We are divided into 2 groups according to the big young pathbreaker rat of BRS: (BRS＜0.3ms/mmHg, n=48) (BRS＞0.3ms/mmHg, n=34), two groups of blood pressures do not have too big-difference to low BRS-L group with high BRS group.Two groups postoperative survival curve has the difference of significance, and (Log-Rank checks x 2Value 8.06, P=0.0045), the charming appearance and behaviour half death time in the animal postoperative: low BRS-L group is 65 days, and high BRS group is 213 days, and latter's life span is the former 3.3 times.Specifically see Fig. 1.
BRS prediction SHR-SP apoplexy takes place among the figure.82 rats are divided into 2 groups according to its average BRS value: BRS＞0.3ms/mmHg (n=34); BRS＜0.3ms/mmHg (n=48).There is significant difference (P＜0.01) in two groups of postoperative survival curves.
We are divided into 2 groups according to SBP with rat again: (SBP＞220mmHg, n=41) (SBP＜220mmHg, n=41), two groups of BRS values do not have too big-difference to high SBP group with low SBP group.Two groups survival curve has the difference of significance, and (Log-Rank checks x 2Value 5.91, P=0.015), the charming appearance and behaviour half death time in the animal postoperative: high SBP group is 82 days, and low SBP group is 190 days, and latter's life span is the former 2.3 times.Specifically see Fig. 2.
SBP prediction SHR-SP apoplexy takes place among the figure.82 rats are divided into 2 groups according to its average SBP value: SBP＜220mmHg (n=41); SBP＞220mmHg (n=41).There is significant difference (P＜0.05) in two groups of postoperative survival curves.
Embodiment 2: the single stomach tube is to the influence of ketanserin to SBP, diastolic pressure (DBP) and the BRS of SHR-SP
12 8 the monthly age male SHR-SP rat, under narcotism, carry out femoral artery, femoral vein and gastric intubation, support, recover after 2 days to connect the clear-headed autonomous pressure measuring system of computerization, stablized 4 hours, 1 hour blood pressure of continuous record is measured BRS.Animal is divided 2 groups then, stomach tube is given ketanserin 0.3mg/kg and 3.0mg/kg respectively, and 1 hour blood pressure of continuous record is measured BRS again.The results are shown in Table 1.Ketanserin small dose group (0.3mg/kg) has no significant effect (SBP:228 ± 25.6 vs, 232 ± 22.3mmHg to blood pressure; DBP:163 ± 18.9 vs, 165 ± 19.1mmHg, P＞0.05), heavy dose of (3.0mg/kg) then significantly blood pressure lowering (SBP:199 ± 15.9 vs, 232 ± 24.1mmHg; DBP:133 ± 16.5 vs 162 ± 25.6mmHg), big low dose of influence to blood pressure presents dose dependent.For the influence of BRS, little, heavy dose of group all can significantly increase (0.41 ± 0.12vs, 0.19 ± 0.11ms/mmHg, 0.40 ± 0.13 vs, 0.17 ± 0.11ms/mmHg, P＜0.05), and BRS improves situation and dosage is irrelevant.
Table 1 single stomach tube to ketanserin to the clear-headed hemodynamic influence of autonomic activities SHR-SP rat
Figure A20061011632000061
SBP(mmHg) DBP(mmHg) BRS(ms/mmHg)
Before the administration after (n=6) administration before (0.3mg/kg) administration after (n=6) administration (3.0mg/kg) 232±22.3 228±25.6 232±24.1 199±15.9* 165±19.1 163±18.9 162±25.6 133±16.5* 0.19±0.11 0.41±0.12* 0.17±0.08 0.40±0.13*
Compare with data before the administration *Each dosage group sample size of P＜0.05 is 6.
Embodiment 3: ketanserin long term administration (3 months) is to the hemodynamic influence of SHR-SP
With 29 5 male SHR-SP of monthly age, be divided into 3 groups at random: matched group (n=9), ketanserin low dose group (0.3mg/kg/d, n=10) and high dose group (3.0mg/kg/d, n=10), medicine is sneaked into successive administration in the feedstuff, the record body weight change.After the administration 4 months, measure blood pressure, interval aroused in interest (HP) and BRS according to experiment 1 method.The result shows: give ketanserin for a long time, compare with the blank group, big small dose group does not all have remarkable influence to body weight, ((166 ± 14.5 vs 160 ± 23.1mmHg) all do not have remarkable influence to ketanserin 0.3mg/kg group, and the 3.0mg/kg group then can significantly reduce SBP (202 ± 22.3 vs 231 ± 25.7mmHg), DBP (144 ± 17.4 vs 160 ± 23.1mmHg) for 231 ± 12.8 vs 231 ± 25.7mmHg), DBP for SBP; Little, heavy dose of group all can significantly improve BRS, and (0.37 ± 0.16,0.36 ± 0.13 vs 0.16 ± 0.09ms/mmHg) has nothing to do with dosage.Specifically see Table 2.
Table 2 ketanserin long term administration (3 months) is to the clear-headed hemodynamic influence of autonomic activities SHR-SP (X ± SD)
Contrast (N=9) Ketanserin 0.3mg/kg (N=10) Ketanserin 3.0mg/kg (N=10)
SBP(mmHg) DBP(mmHg) BRS(ms/mmHg) 231±25.7 160±23.1 0.16±0.09 231±12.8 166±14.5 0.37±0.16** 202±22.3* 144±17.4 0.36±0.13**
Compare with matched group *P＜0.05, *P＜0.01
Embodiment 4: the ketanserin long term administration is to the influence of SHR-SP life span
With 81 3 male SHR-SP of monthly age, be divided into 3 groups at random, matched group (n=34), ketanserin low dose group (0.3mg/kg/d, n=24) and high dose group (3.0mg/kg/d, n=23), medicine is sneaked into successive administration in the feedstuff, the record apoplexy death time.Experiment stops when rat 550 ages in days.The result shows: the survival curve of the large and small dosage group of ketanserin is compared with matched group, and (Log-Rank checks x to have the difference of significance 2Value is 59.12, P＜0.0001), animal half apoplexy causes death and dies the time: matched group is 319 days, compares with matched group, and small dose group is 410 days, the dead time of origin of apoplexy delays 34%; Heavy dose of group is 428 days, and the dead time of origin of apoplexy delays 47%.Specifically see Fig. 3.
The ketanserin long-term treatment is to the preventive effect of SHR-SP rat lethal apoplexy among the figure.Rat is divided into three groups: matched group (n=34); Ketanserin 0.3mg/kg organizes (n=24); Ketanserin 3.0mg/kg group (n=23) .2 administration group survival curve relatively has significant difference (P＜0.0001) with matched group.
By the animal experiment study of the foregoing description, verified that the big low dose of ketanserin all can significantly delay apoplexy and take place, prolong the apoplexy rat life-span, the prevention of brain apoplexy effect of low dose of ketanserin and blood pressure lowering are irrelevant.(dosage≤0.3mg/kg) can be used for preparing the medicine of prevention of brain apoplexy in the antihypertensive drug ketanserin of non-hypotensive dose.

Claims (1)

1. the application of ketanserin in preparation prevention of brain apoplexy medicine.
CNA2006101163209A 2006-09-21 2006-09-21 Application of ketanserin in preparing medicine for preventing cerebral apoplexy Pending CN1923206A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107427255A (en) * 2015-03-12 2017-12-01 财团法人峨山社会福祉财团 The method that the generation time point of infarct area is estimated based on brain image

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CN1686139B (en) * 2005-04-30 2012-07-11 福建师范大学 Application of ketosolin in new type analgesic for treatig inflammatory pain

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107427255A (en) * 2015-03-12 2017-12-01 财团法人峨山社会福祉财团 The method that the generation time point of infarct area is estimated based on brain image
CN107427255B (en) * 2015-03-12 2021-04-06 财团法人峨山社会福祉财团 Method for estimating the time point of occurrence of an infarct region based on brain images

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