發(fā)布時(shí)間：2018-05-09 08:41

  本文選題：格列本脲 + 藥代動(dòng)力學(xué)��； 參考：《南方醫(yī)科大學(xué)》2016年碩士論文

【摘要】：格列本脲,自1969年起作為一種降糖藥用于Ⅱ型糖尿病的治療,作用機(jī)制為促進(jìn)胰島素的釋放從而降血糖。近年來,低劑量格列本脲在各種神經(jīng)系統(tǒng)疾病中展示出多樣的腦保護(hù)作用,這引起了研究者們極大的興趣。格列本脲被證實(shí)在缺血性卒中、創(chuàng)傷性腦損傷、脊髓損傷等多種疾病的動(dòng)物模型中有神經(jīng)保護(hù)作用。此外,回顧性研究也顯示,格列本脲可以減輕缺血性卒中后的腦水腫。國外針對(duì)格列本脲腦保護(hù)作用的研究,在大鼠使用腹腔注射的給藥方式,在臨床試驗(yàn)中使用靜脈持續(xù)泵注的給藥方式。而格列本脲在我國作為一種口服降糖藥,具有價(jià)格低廉,口服吸收好等明顯的優(yōu)勢(shì)。國外研究所使用的靜脈注射劑型的格列本脲(RP-1127, Remedy Pharmaceuticals)有很好的安全性且很可能有臨床治療價(jià)值,但該劑型從臨床試驗(yàn)到上市必然仍要經(jīng)過漫長的時(shí)間。相比之下,口服制劑的格列本脲已經(jīng)作為一種相對(duì)廉價(jià)的降糖藥物在臨床上有數(shù)十年的使用歷史,其安全性已經(jīng)得到了廣泛的證實(shí)。值得注意的是,相比于用于2型糖尿病的降糖治療,格列本脲在神經(jīng)保護(hù)作用方面所需要的劑量更低[2],因此將具有更好的安全性。既往針對(duì)格列本脲的藥代動(dòng)力學(xué)研究,所使用的劑量均為針對(duì)治療糖尿病,產(chǎn)生降血糖所用的相對(duì)高劑量,而針對(duì)格列本脲的腦保護(hù)作用,文獻(xiàn)中所涉及的劑量均低于格列本脲作為口服降糖藥所需要使用的劑量。低劑量格列本脲的藥代動(dòng)力學(xué)尚未有研究,我們的研究將為下一步臨床試驗(yàn)做好準(zhǔn)備。我們進(jìn)行了如下實(shí)驗(yàn)研究：第一章低劑量格列本脲在大鼠的藥代動(dòng)力學(xué)研究第一節(jié)低劑量格列本脲口服給藥與腹腔注射給藥在正常大鼠體內(nèi)的藥代動(dòng)力學(xué)對(duì)比研究實(shí)驗(yàn)?zāi)康模貉芯康蛣┝扛窳斜倦蹇诜o藥與腹腔注射給藥在正常大鼠體內(nèi)的藥代動(dòng)力學(xué)特性。實(shí)驗(yàn)方法：20只大鼠隨機(jī)分為口服組和腹腔注射組(n=10)�？诜M大鼠灌胃給予格列本脲混懸液1 mg/kg。腹腔注射組給予格列本脲10μg/kg。兩組大鼠分別于給藥后5、15、30、60、90、 120、 150、 180、360、720 min采血,以LC-MS/MS法測(cè)定格列本脲在大鼠血漿中的濃度,并監(jiān)測(cè)血糖。WinNonlin藥代動(dòng)力學(xué)分析軟件計(jì)算藥代動(dòng)力學(xué)參數(shù)。實(shí)驗(yàn)結(jié)果：格列本脲的線性回歸方程y=1.1731x-0.0127。線性范圍1.02～204 ng/mL,相關(guān)系數(shù)R20.9996。所測(cè)定的格列本脲的高、中、低濃度的日內(nèi)、日間精密度的變異系數(shù)(CV)值均小于5%。高、中、低濃度的格列本脲在大鼠血漿中的平均回收率分別為(99.37±7.22)%、(101.63±5.91)%、(95.19±2.44)%。口服組大鼠血漿中格列本脲的藥時(shí)曲線較腹腔注射組右移,即達(dá)峰時(shí)間延長,兩組格列本脲峰濃度均在20-25 ng/mL之間。口服給藥1 mg/kg與腹腔注射給藥10μg/kg相比,格列本脲在大鼠體內(nèi)的藥物峰濃度(Cmax)、半衰期(t1/2)、藥時(shí)曲線下面積(AUClast)無顯著性差異(P0.05)。口服給藥組達(dá)峰時(shí)間(Tmax)較腹腔注射給藥組明顯延長,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。給藥前兩組大鼠基礎(chǔ)血糖水平在6 mmol/L左右,在12h的血糖監(jiān)測(cè)過程中,口服組大鼠血糖最低至4.9 mmol/L,腹腔注射組大鼠血糖最低至4.7mmol/L。兩組大鼠均未出現(xiàn)低血糖的情況。實(shí)驗(yàn)結(jié)論：本實(shí)驗(yàn)建立了一種精確簡便的低劑量格列本脲在大鼠的血藥濃度測(cè)定方法。口服1 mg/kg格列本脲,可以在大鼠體內(nèi)產(chǎn)生與腹腔注射給藥10 μg/kg相近的血藥濃度,兩種給藥方式并具有相似的藥時(shí)曲線下面積。低劑量的格列本脲在口服給藥及腹腔注射給藥時(shí)都是安全的,12h監(jiān)測(cè)過程中并未有低血糖的發(fā)生。第二節(jié)低劑量格列本脲口服給藥與腹腔注射給藥在MCAO大鼠體內(nèi)的藥代動(dòng)力學(xué)對(duì)比研究實(shí)驗(yàn)?zāi)康模貉芯康蛣┝扛窳斜倦蹇诜o藥與腹腔注射給藥在MCAO大鼠體內(nèi)的藥代動(dòng)力學(xué)實(shí)驗(yàn)方法：20只SD大鼠隨機(jī)分為兩組,MCAO口服組及MCAO腹腔注射組,n=10。兩組大鼠分別進(jìn)行MCAO模型后股靜脈插管。拔出線栓口立即給予相應(yīng)劑量的格列本脲,MCAO口服組大鼠灌胃給予格列本脲混懸液1mg/kg, MCAO腹腔注射組大鼠給予格列本脲10μg/kg。兩組大鼠分別于給藥后5、15、30、60、90、120、150、180、360、720 min,采血,以LC-MS/MS法測(cè)定格列本脲在大鼠血漿中的濃度,并監(jiān)測(cè)血糖。WinNonlin藥代動(dòng)力學(xué)分析軟件計(jì)算藥代動(dòng)力學(xué)參數(shù)。實(shí)驗(yàn)結(jié)果：所測(cè)定的格列本脲的高、中、低濃度的日內(nèi)、日間精密度的變異系數(shù)(CV)值均小于5%。高、中、低濃度的格列本脲在大鼠血漿中的平均回收率分別為(98.66±3.12)%、(103.19±6.72)%、(99.37±5.44)%。MCAO口服組藥時(shí)曲線較MCAO腹腔注射組右移,即達(dá)峰時(shí)間延長,兩組格列本脲峰濃度均在20-25 ng/mL之間�？诜o藥1 mg/kg與腹腔注射給藥10μg/kg相比,格列本脲在MCAO大鼠體內(nèi)的藥物峰濃度(Cmax)、半衰期(t1/2)、藥時(shí)曲線下面積(AUClast)無顯著性差異(P0.05)。MCAO口服給藥組達(dá)峰時(shí)間(Tmax)較MCAO腹腔注射給藥組明顯延長,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。與第一節(jié)中口服給藥組大鼠相比,格列本脲在MCAO口服給藥組大鼠體內(nèi)的藥物峰濃度(Cmax)、達(dá)峰時(shí)間(Tmax)、半衰期(t1/2)、藥時(shí)曲線下面積(AUClast)無顯著性差異(P0.05)。與第一節(jié)中腹腔注射組大鼠相比,格列本脲在MCAO腹腔注射組大鼠體內(nèi)的藥物峰濃度(Cmax)、達(dá)峰時(shí)間(Tmax)、半衰期(t1/2)、藥時(shí)曲線下面積(AUClast)無顯著性差異(P0.05)。實(shí)驗(yàn)中兩組大鼠均未出現(xiàn)低血糖的情況。實(shí)驗(yàn)結(jié)論：口服1 mg/kg格列本脲,可以在MCAO大鼠體內(nèi)產(chǎn)生與腹腔注射給藥10μg/kg相近的血藥濃度,兩種給藥方式并具有相似的藥時(shí)曲線下面積。大鼠在2 h MCAO模型中,與未造模生理狀態(tài)下相比,低劑量格列本脲口服給藥與腹腔注射給藥均有相似的藥代動(dòng)力學(xué)特性。低劑量的格列本脲在口服給藥及腹腔注射給藥時(shí)都是安全的,監(jiān)測(cè)過程中并未有低血糖的發(fā)生。第三節(jié)亞低溫下低劑量格列本脲在大鼠的藥代動(dòng)力學(xué)研究背景與目的：臨床研究提示低劑量格列本脲在多種神經(jīng)系統(tǒng)疾病中通過抑制SUR1-TRPM4通道發(fā)揮多效性保護(hù)作用。我們的研究數(shù)據(jù)表明在體內(nèi)及體外格列本脲均增強(qiáng)亞低溫的有效性。但是亞低溫條件下低劑量的格列本脲藥代動(dòng)力學(xué)尚不明確。我們假設(shè)亞低溫條件下低劑量的格列本脲藥物代謝動(dòng)力學(xué)變化源于CYP2C9活性的改變,CYP2C9活性通過雙氯芬酸作為探針?biāo)幬锶z測(cè)。本研究的目的是評(píng)估老鼠亞低溫狀態(tài)對(duì)低劑量格列本脲藥物代謝動(dòng)力學(xué)的影響并初步闡述其可能的機(jī)制。實(shí)驗(yàn)方法：雄性SD大鼠被隨機(jī)分為常溫組與低溫組。兩組分別注射33ug/kg格列本脲及10 mg/kg雙氯芬酸鈉。在9個(gè)不同時(shí)間點(diǎn)采集血標(biāo)本。LC-MS/MS檢測(cè)大鼠血漿格列本脲及雙氯芬酸鈉濃度,并通過WinNonlin軟件計(jì)算二者藥代動(dòng)力學(xué)參數(shù)。實(shí)驗(yàn)結(jié)果：亞低溫條件下格列本脲的總體清除率有顯著下降(下降58%；16.00±4.1 to 6.72±2.1 mL/min/Kg; p 0.001)。兩組半衰期改變沒有顯著差異(亞低溫組2.71±1.7h,正常體溫組1.64±0.34h; p=0.157)。AUClast在亞低溫組(77.8±18 h*ng/ml)較正常體溫組(33.2±11 h*ng/ml)顯著升高(p0.001)。血糖水平均高于70mg/dL。雙氯芬酸總體清除率從正常體溫組的10.33±1.53mL/min/Kg下降至亞低溫組的7.20±1.66mL/min/Kg。(p0.01)。實(shí)驗(yàn)結(jié)論：亞低溫改變低劑量格列本脲藥代動(dòng)力學(xué)參數(shù),使格列本脲在大鼠的血漿清除率下降,血藥濃度升高。亞低溫狀態(tài)下CYP2C9的活性降低。第二章低劑量格列本脲在重癥腦血管病患者的小樣本臨床研究研究目的：初步驗(yàn)證口服低劑量格列本脲在重癥腦血管病患者的安全性,并測(cè)定格列本脲血藥濃度。資料和方法：前瞻性研究2015年06月至2015年12月因重癥腦血管病入住南方醫(yī)科大學(xué)南方醫(yī)院神經(jīng)危重癥監(jiān)護(hù)病房的患者。納入條件：1)臨床和影像學(xué)診斷為腦梗塞或腦出血；2)年齡為17-75歲；3)起病72小時(shí)內(nèi)入院；4)入院后空腹血糖7.0 mmol/L。受試者經(jīng)鼻飼管或口服給藥,首次給藥負(fù)荷劑量1mg,8小時(shí)后追加劑量0.5mg,之后每8小時(shí)追加0.5mg,至首劑72h后停藥。首次給藥后2h、4h、6h、8h、10h、16h、18h、24h、48h、72h測(cè)定格列本脲血藥濃度,血糖,血清胰島素水平。結(jié)果：格列本脲血藥濃度最高達(dá)56 ng/mL,于給藥后4h測(cè)得。24h后,格列本脲的血藥濃度波動(dòng)在20-40 ng/mL之間。沒有患者出現(xiàn)低血糖的臨床表現(xiàn),血糖值最低4.2 mmol/L�；颊呓o藥前的血清胰島素為25.72±12.31 pmol/L,給藥后最高達(dá)67.82 pmol/L。結(jié)論：低劑量口服格列本脲在重癥腦血管病患者具有良好的安全性,不伴有嚴(yán)重不良反應(yīng)。
[Abstract]:Glibenclamide, which has been used as a hypoglycemic agent in the treatment of type 2 diabetes since 1969, plays a role in promoting insulin release and reducing blood sugar. In recent years, low dose glibenclamide has shown a variety of brain protection in various nervous system diseases, which has aroused great interest in the researchers. There are neuroprotective effects in animal models of a variety of diseases such as sexual apoplexy, traumatic brain injury, and spinal cord injury. In addition, a retrospective study has also shown that glibenclamide can reduce cerebral edema after ischemic stroke. Study on the protective effect of glibenclamide abroad and the use of intraperitoneal injection in rats and use in clinical trials in rats As an oral hypoglycemic agent, glibenclamide has the advantages of low price and good oral absorption in our country. The intravenous injection of RP-1127 (Remedy Pharmaceuticals) used by foreign research institutes has good safety and is likely to be of clinical value, but the dosage form is from Clinical trials are bound to take a long time to go on the market. In comparison, the oral preparation of glibenclamide has been used as a relatively cheap antidiabetic drug for decades, and its safety has been widely confirmed. It is worth noting that glibenclamide is compared to the hypoglycemic treatment for type 2 diabetes. The dose required for the neuroprotective effect of a lower dose of [2] is better. The pharmacokinetic study of glibenclamide has been used for a relatively high dose for the treatment of diabetes and the production of hypoglycemia, while the brain protection against glibenclamide is low in the literature. The pharmacokinetics of glibenclamide as oral hypoglycemic agents. Pharmacokinetics of low dose glibenclamide have not yet been studied. Our study will prepare for further clinical trials. We have conducted the following experimental studies: the first of the low dose glibenclamide pharmacokinetics in rats, the first low dose glenben The pharmacokinetic study of oral administration of urea and intraperitoneal injection in normal rats: the pharmacokinetic characteristics of low dose of glibenclamide oral administration and intraperitoneal injection in normal rats. Experimental methods: 20 rats were randomly divided into oral and intraperitoneal injection group (n=10). Oral administration of rats was administered to rats. Glipebenclamide suspension was given to the stomach for 1 mg/kg. intraperitoneal injection to give glipezourea 10 g/kg. two groups of rats in the group of rats after administration of 5,15,30,60,90, 120, 150, 180360720 min. The concentration of glibenclamide in rat plasma was measured by LC-MS/MS, and the pharmacokinetic parameters of blood glucose.WinNonlin pharmacokinetic analysis software were monitored. The linear regression equation y=1.1731x-0.0127. of glibenclamide was 1.02 ~ 204 ng/mL, and the coefficient of variation (CV) of daytime precision was less than 5%. in high, medium and low concentration of R20.9996., and the average recovery rate of glibenclamide in rat plasma was (99.), respectively. 37 + 7.22)%, (101.63 + 5.91)%, (95.19 + 2.44)%. The plasma concentration of glibenclamide in the oral group was longer than that in the intraperitoneal injection group, that is, the peak time was prolonged and the peak concentration of the two groups of glibenclamide was 20-25 ng/mL. The drug peak concentration of glibenclamide in rats was compared with the oral administration of 1 mg/kg and the intraperitoneal injection of 10 u g/ kg (Cmax). There was no significant difference in the area (AUClast) under the curve of the drug time (t1/2). The peak time (Tmax) in the oral administration group was significantly longer than that in the intraperitoneal injection group (P0.05). The basal blood glucose level of the two groups of rats before the administration was 6 mmol/L left right, and the blood sugar of the oral group was the lowest to 4.9 during the 12h monitoring of blood glucose. Mmol/L, the blood glucose of the rats in the group of intraperitoneal injection group was the lowest to 4.7mmol/L. two rats. The experimental conclusion: a simple and simple method for measuring the blood concentration of low dose glibenclamide in rats was established. Oral 1 mg/kg glibenclamide, which could be produced in rats, was similar to that of the intraperitoneal injection of 10 mu g/kg. The concentration of blood, two ways of administration and the area under the curve of similar drug. Low dose of glibenclamide is safe in oral administration and intraperitoneal injection. There is no hypoglycemia in the 12h monitoring process. The pharmacokinetics of second segments of low dose glibenclamide oral administration and intraperitoneal injection in MCAO rats Objective: To study the pharmacokinetics of low dose of glibenclamide oral administration and intraperitoneal injection in MCAO rats: 20 SD rats were randomly divided into two groups, MCAO oral group and MCAO intraperitoneal injection group, and n=10. two groups of rats respectively after MCAO model femoral venous intubation. The dose of glibenclamide, MCAO oral group rats were given gastric perfusion of glibenclamide suspension 1mg/kg, MCAO intraperitoneal injection group rats were given glipenourea 10 g/kg. two groups of rats after the administration of 5,15,30,60,90120150180360720 min, blood, LC-MS/MS method to determine the concentration of glibenclamide in rat plasma, and monitoring the blood sugar.WinNonlin medicine The kinetic analysis software was used to calculate the pharmacokinetic parameters. Experimental results: the variation coefficient (CV) of daytime precision was less than 5%. in high, medium and low concentrations, and the average recovery of glibenclamide in rat plasma was (98.66 + 3.12)%, (103.19 + 6.72)%, (99.37 + 5.44)%.MCAO in the middle and low concentration of rat plasma. The curve of the oral group was more than that of the MCAO group, that is, the peak time was prolonged, and the peak concentration of the two groups was 20-25 ng/mL. The drug peak concentration (Cmax), the half life (t1/2) and the area under the curve (AUClast) in the MCAO rats were no significant difference compared with the oral administration of 1 mg/kg and the intraperitoneal injection 10 mu g/kg (t1/2). P0.05) the peak time of.MCAO oral administration group (Tmax) was significantly longer than that of MCAO intraperitoneal injection group, and the difference was statistically significant (P0.05). Compared with the first oral administration group, the peak concentration (Cmax), peak time (Tmax), half life (t1/2), and the area under the curve of drug time (AUClast) in the group of MCAO oral administration rats were compared with the first oral administration group. There was no significant difference (P0.05). Compared with the first abdominal injection group, the drug peak concentration (Cmax), peak time (Tmax), half life (t1/2), and the area under the curve (AUClast) were no significant difference (P0.05) in the rats of MCAO intraperitoneal injection group (P0.05). No hypoglycemia was found in the two groups of rats in the experiment. Experimental conclusions: 1 mg/kg glibenclamide was taken orally in MCAO rats to produce a blood drug concentration similar to that of the intraperitoneal injection of 10 u g/kg, the two kinds of administration and the area under the curve of similar drug. In the 2 h MCAO model, the low dose glibenclamide oral administration was similar to that of the intraperitoneal injection. Pharmacokinetic characteristics. Low dose of glibenclamide is safe in oral administration and intraperitoneal injection. There is no hypoglycemia in the monitoring process. Research background and purpose of pharmacokinetics of low dose glibenclamide at third sub hypothermia in rats: clinical study suggests that low dose glibenclamide is in a variety of nervous system diseases. Our data show that both in vivo and in vitro glibenclamide enhance the effectiveness of mild hypothermia. However, low dose of glibenclamide pharmacokinetics under mild hypothermia is not clear. We hypothesized that low dose of glibenclamide metabolizing power under mild hypothermia conditions The changes in CYP2C9 activity and CYP2C9 activity were detected by diclofenac as a probe drug. The purpose of this study was to assess the effects of hypothermia on the pharmacokinetics of low dose glibenclamide and to preliminarily describe the possible mechanisms. Experimental methods: male SD rats were randomly divided into normal and low temperature groups. The two groups were injected with 33ug/kg glibenclamide and 10 mg/kg diclofenac sodium respectively. Blood samples were collected at 9 different time points to detect the concentration of glibenclamide and diclofenac sodium in the plasma of rats, and the pharmacokinetic parameters were calculated by the WinNonlin software. The results were as follows: the total clearance rate of glenepourea under mild hypothermia was significantly lower. Drop (58%; 16 + 4.1 to 6.72 + 2.1 mL/min/Kg; P 0.001). There was no significant difference in the half life change of the two group (mild hypothermia group 2.71 + 1.7h, normal body temperature 1.64 + 0.34h; p=0.157).AUClast in mild hypothermia group (77.8 + 18 h*ng/ml) significantly higher than normal body temperature group (33.2 + 11 h*ng/ml) (p0.001). The average blood sugar water was higher than that of 70mg/dL. diclofenac The total clearance rate decreased from 10.33 + 1.53mL/min/Kg in the normal temperature group to 7.20 1.66mL/min/Kg. (P0.01) in the sub hypothermia group. Experimental conclusion: low hypothermia changed the pharmacokinetic parameters of low dose glibenclamide, which made the plasma clearance rate of glibenclamide decreased and the blood concentration increased. The activity of CYP2C9 decreased under the mild hypothermia state. Second chapters A small sample of low dose glibenclamide in patients with severe cerebrovascular disease: a preliminary study of the safety of oral low dose glibenclamide in patients with severe cerebrovascular disease and the determination of serum concentration of glibenclamide. Data and methods: a prospective study from 06 months to December 2015 2015 for severe cerebrovascular disease in southern medicine Patients in the neurocritical care unit of the Southern Hospital of the University were included in the conditions: 1) clinical and imaging diagnosis of cerebral infarction or cerebral hemorrhage; 2) age 17-75 years old; 3) onset within 72 hours of onset; 4) after admission to the hospital, the fasting blood glucose 7 mmol/L. was administered by nasal feeding tube or oral administration, for the first time the dose was 1mg, and the additional dose of 0.5mg after 8 hours. After the first dose of 0.5mg, after the first dose of 72h, 2h, 4h, 6h, 8h, 10h, 16h, 18h, 24h, 48h were first given, and 72h measured the blood concentration of glibenclamide, blood glucose and serum insulin. Results: the blood concentration of glibenclamide was up to 56. After the administration, the blood concentration of glybenclamide fluctuated between 20-40. There was a clinical manifestation of hypoglycemia in the patients. The serum insulin was 25.72 + 12.31 pmol/L before the 4.2 mmol/L. patients, and the highest level of 67.82 pmol/L. after administration: low dose of glibenclamide in patients with severe cerebrovascular disease had good safety and no serious adverse reaction.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R743

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