脂質(zhì)體運(yùn)用于胰島素口服給藥治療糖尿病的可能性外文翻譯

1、<p>　　POSSIBILITY OF THE USE OF LIPOSOMES FOR ORAL ADMINISTRATION OF INSULIN IN DIABETES MELLITUS</p><p>　　Insulin is secreted by pancreatic cells of vertebrate peptide hormones, hypoglycemic have a uni

2、que effect, so far remains the drug of choice of insulin-dependent diabetes. Because it is easy to gastrointestinal proteolytic enzymes degrade the oral invalid. Insulin injections are currently the most effective agents

3、 for the treatment of diabetes, usually after sc or im, its main drawback is slow to absorb the injection site, long-term injection will bring a lot of pain and inconvenience to the pat</p><p>　　In insulin-d

4、ependent diabetes mellitus, treatment with subcutaneous injections of insulin in adequate doses not only does not prevent the development of diabetic complications in many cases, in particular, liver pathology, but also

5、promotes the appearance of lipodystrophies. Insulin injected in this way enters the general circulation earlier than the liver. On the contrary, under physiological conditions it immediately enters the liver through the

6、portal vein from the pancreas, and 50-60% of the</p><p>　　The purpose of the present work was to investigate the effectiveness of insulin introduced per os in liposomes on the course of diabetes mellitis. Th

7、e liposomes were produced by the Bangham method [ii] from a mixture of phosphatidylcholine and cholesterol in an 8:2 mole ratio on the basis of I0 mg lipids per ml of suspension,followed by ultrasonic treatment. The meth

8、od was described in detail in .Simple bovine insulin was used in a dose of about two units per rat, calculated so that about 5% ins</p><p>　　38 rats with severe diabetes mellitis.Blood was collected for the

9、investigation before the animals were fed.The concentration of immunoreactive insulin and the binding peptide (C-peptide) was determined in the blood serum (after sacrifice of the animals) by a radioimmune method. In rat

10、s with severe diabetes mellltus (see Table I), against a background of serious general condition (pronounced listlessness, thirst~ anorexia, dryness Of the mucosa and fur),substantial hyperglycemia and pronounced h</p

11、><p>　　Thus, the administration of insulin in liposome s to the experimental animals per os has a positive effect on them, which is expressed in an improvement of their condition, a lowering of the hyperglycemi

12、a, and a substantial increasein insulinemia, although the level of the C-peptide remains lowered. Evidently the results obtained associated with the release of insulin from the liposomes administered per os. The pronounc

13、ed hypoglycemic action of the introduction of liposomal insulin once a day ca</p><p>　　Thus, the introduction of insulin into liposomes provides a pronounced therapeutic and prolonged effect in animals with

14、severe alloxan diabetes mellitus (a reduction of the listlessness, thirst, lowering of the blood sugar level, significant rise in the level of insuinemia, and increase in lifetime). The positive effect detected after the

15、 administration of insulin in liposomes per os is associated with the penetration of this exogenous hormone into the organism, since an increase in the level of</p><p>　　脂質(zhì)體運(yùn)用于胰島素口服給藥治療糖尿病的可能性</p><

16、;p>　　胰島素是脊椎動(dòng)物胰臟細(xì)胞分泌的多肽類激素, 對(duì)降血糖有獨(dú)特的療效, 迄今為止仍為胰島素依賴性糖尿病患者的首選藥物。由于容易被胃腸道的蛋白水解酶降解, 故口服無效。目前胰島素注射劑是臨床用于治療糖尿病的最有效的制劑, 一般經(jīng)sc或im, 其主要缺點(diǎn)為注射部位吸收速度緩慢, 長期注射會(huì)給患者帶來許多痛苦和不便, 甚至?xí)霈F(xiàn)炎癥、硬結(jié)、過敏等副反應(yīng)。研究使用方便, 療效確切, 安全可靠的胰島素新制劑是國內(nèi)外醫(yī)藥界共同關(guān)注的課題

17、。脂質(zhì)體是一種定向藥物載體, 屬于靶向給藥系統(tǒng), 由與細(xì)胞膜成分相同的磷脂組成, 藥物被包封在磷脂雙分子層內(nèi)部, 可增強(qiáng)藥物的穩(wěn)定性, 適于包封一些大分子多肽等易于被破壞的藥物, 本身與生物膜的相容性很高, 可促進(jìn)藥物的吸收, 藥物通過磷脂雙分子層緩控釋放, 可起到緩釋的作用。脂質(zhì)體可制成各種大小的粒徑, 通過改變磷脂的組成還可使脂質(zhì)體具有不同的表面性質(zhì), 因此可適用于各種給藥途徑。胰島素以二聚體的形式存在, 分子內(nèi)部是由非極性的側(cè)鏈組

18、成的一個(gè)疏水核, 全部的極性側(cè)鏈分布在外表面, 結(jié)構(gòu)特點(diǎn)為表面親水, 內(nèi)核疏水。脂質(zhì)體為雙分子膜, 其結(jié)構(gòu)特點(diǎn)為表面親水, 雙分子層內(nèi)部</p><p>　　對(duì)于胰島素依賴型糖尿病，在許多情況下足夠劑量的胰島素的皮下注射治療不僅不阻止糖尿病并發(fā)癥的發(fā)展，而且還促進(jìn)脂肪營養(yǎng)障礙的出現(xiàn)，尤其是存在肝臟病理的病人。胰島素以這種方式注射進(jìn)入大氣環(huán)流，然后進(jìn)入肝臟。相反，在生理?xiàng)l件下，它會(huì)通過胰腺門靜脈立即進(jìn)入肝臟，而且新

19、近分泌胰島素的50-60％被保留。鑒于此，有必要尋求引入缺乏的生物體的激素的一種新手段，更接近生理通路，是可以理解的。如果胰島素被保護(hù)免受胃腸道的蛋白水解酶的作用，那么引入經(jīng)口胰島素將是最方便的。我們已經(jīng)做過多次嘗試引入不用注射的胰島素進(jìn)入生物體。因此，例如，大家已經(jīng)認(rèn)為用胰島素制備的混合物在舌頭下被吸附具有血管舒張作用；然而，在一段長時(shí)間內(nèi)使用大劑量的制劑的必要性阻止了該方法的臨床實(shí)踐。也有人建議胰島素作為水 - 油乳劑給予動(dòng)物十二指

20、腸的降血糖效果。大量的研究已經(jīng)被報(bào)道，即以乳液或栓劑的形式引入胰島素到直腸?？诜o藥后已檢測出胰島素的合成聚合物可引起血糖水平的降低。已經(jīng)在糖尿病患者中檢測到在推進(jìn)劑吸入胰島素的穩(wěn)定懸浮液后可降低高血糖。在最近幾年的嘗試已經(jīng)進(jìn)行了引入每個(gè)劑量胰島素到脂質(zhì)體中，磷脂進(jìn)行超聲波處理來制備。它已經(jīng)表明，胰島</p><p>　　本工作的目的是探討每劑量胰島素在治療糖尿病的過程中脂質(zhì)體引入的有效性。脂質(zhì)體是由磷脂酰膽堿和

21、膽固醇于8:2的摩爾比的混合物由Bangham方程方法產(chǎn)生，在每毫升懸浮液中的10毫克脂質(zhì)體的基礎(chǔ)上進(jìn)行的，隨后進(jìn)行超聲處理。該方法在有些文獻(xiàn)上被詳細(xì)描述過。簡單的牛胰島素被用于每鼠約2個(gè)單位的劑量，計(jì)算，使得大約5％的胰島素被并入脂質(zhì)體。在實(shí)驗(yàn)中，我們使用128個(gè)非近交系的小白鼠。糖尿病發(fā)展于以每公斤體重150毫克的劑量在動(dòng)物腹腔注射四氧嘧啶水合物。每劑量脂質(zhì)體用于38只老鼠進(jìn)行胰島素給藥治療重癥糖尿病。在喂養(yǎng)調(diào)查的動(dòng)物之前收集血液。

22、免疫反應(yīng)性胰島素的濃度與結(jié)合肽（C肽）血液中的血清（動(dòng)物處死后）通過放射免疫法測定的。在患重癥糖尿病的大鼠中，在嚴(yán)重的全身情況背景（發(fā)音為精神萎靡，口渴?厭食，干燥的黏膜和毛發(fā)）下，大量的高血糖和顯著的高胰島素血癥被記錄在案。在血清中的C肽含量明顯比健康動(dòng)物低。如果不進(jìn)行治療，那么這些動(dòng)物在四氧嘧啶水合物給藥后的第一個(gè)星期內(nèi)就會(huì)死亡。胰島素在脂質(zhì)體中口服給藥后的僅1小時(shí)就能注意到在血液中的葡萄糖含量減少，.通過給藥后第4個(gè)小時(shí)的反應(yīng)愈演

23、愈烈。在某些動(dòng)物低血糖的臨床</p><p>　　因此，胰島素脂質(zhì)體經(jīng)口給藥用于動(dòng)物的實(shí)驗(yàn)證明這種方式對(duì)他們有積極的作用，這表現(xiàn)在它們的健康狀況提高了，高血糖降低了，以及胰島素血癥的大量增加，盡管C肽的含量依然低。顯然，這得到的結(jié)果與胰島素從每劑量給藥脂質(zhì)體的釋放有關(guān)。引入脂質(zhì)體胰島素具有顯著的降血糖作用，每天一次可以通過脂質(zhì)體的作用增加肝細(xì)胞對(duì)胰島素的敏感性，并通過大量的引入胰島素直接到肝臟的通道，這與皮下注射

24、的條件是相反的。簡單胰島素以相同劑量進(jìn)行皮下注射，每天一次與對(duì)照組動(dòng)物比較，24小時(shí)后健康狀況沒有得到改善，血糖水平在這個(gè)期間仍然是高的，盡管胰島素血癥增加。每劑量簡單的胰島素給藥也沒有改善動(dòng)物的身體狀況。</p><p>　　因此，在患有嚴(yán)重四氧嘧啶糖尿病的動(dòng)物中引進(jìn)胰島素到脂質(zhì)體提供了一個(gè)顯著的治療和長期的影響（減少了精神萎靡，口渴，降低血糖水平，胰島素血癥的水平顯著上升，并增加壽命）。每劑量胰島素脂質(zhì)體在給