79．善得定
出处：按学科分类—医药、卫生 军事医学科学出版社《临床常用进口药物手册》第437页（20075字）
【中文释文】：
(奥曲肽)人工合成生长抑素八肽
〔成分〕
奥曲肽(游离肽)
安瓿(1ml)0．05mg、0．1mg或0．5mg
小瓶(5ml)0．2mg／ml
*国际非专利药名记载
〔特性〕
善得定是一种人工合成的人生长抑素的八肽衍生物，它保留了生长抑素的类似药理作用，且作用持久。本品能抑制胃肠胰内分泌系统的肽以及生长激素的分泌。
在动物中，善得定抑制生长激素、高血糖素和胰岛素的作用较生长抑素更强，且对生长激素和高血糖素具有明显的选择性抑制作用。长期(26周)给药；大鼠的剂量达1mg／kg·d-1(腹膜内注射)，狗的剂量达0．5mg／kg·d-1(静脉注射)，但均能被很好耐受。
健康受试者的研究表明，善得定对下列情况有抑制作用：
由精氨酸、运动以及胰岛素性低血糖刺激引起的生长激素的释放。
餐后的胰岛素、高血糖素、胃泌素、胃肠胰系统其它肽的分泌，以及由精氨酸引起的胰岛素和高血糖素的分泌。
由促甲状腺素释放激素刺激引起的促甲状腺素的释放。
在肢端肥大症病人(包括那些手术、放射治疗或多巴胺受体激动剂治疗失败者)中，善得定能降低生长激素和(或)生长调节素C的血浆浓度。临床上，所有病人的血生长激素浓度均减少(50%或更多)，且半数病例可呈正常化(血浆生长激素＜5ng／ml)。本品能明显减轻大多数病人的临床症状如头痛、皮肤增厚、软组织肿胀、多汗、关节疼痛和感觉异常等。另外，善得定可使某些垂体大腺瘤的瘤体缩小。
在胃肠胰内分泌系统肿瘤的病人中，由于善得定的多种内分泌作用，故其可以减轻多种临床症状。对曾接受过手术、肝动脉栓塞、各种化疗如链脲菌素、5-氟尿嘧啶等治疗但仍具有对肿瘤有关的严重症状者，本品可改善临床病情，缓解症状。善得定对不同肿瘤的作用如下：
一、类癌瘤
善得定可改善潮红及腹泻等症状，并使某些病人的血浆5-羟色胺和尿5-羟吲哚乙酸减少。在一些疗效不明显的病例中，继续治疗则不应超过1周，尽管此类病人从未发生过持续的严重副作用。
二、血管活性肠肽瘤
这些肿瘤的生化特点是：过量产生血管活性肠肽。在大多数病例中，善得定可缓解严重分泌性腹泻的典型症状，从而改善病人的生活质量，并可改善相应发生的电解质异常如低钙血等，因此可停止补充液体和电解质。计算机断层扫描显示：用药后，某些病人的肿瘤生长延缓或停止，有些甚至缩小，特别在某些肝转移的病人中，临床好转通常伴血浆活性肠肽浓度的降低，有些可降至正常水平。
三、高血糖素瘤
本病的特征为坏死松解性游走性皮疹，应用善得定后，大多数病例获得极为明显的改善。此外，本品对许多轻度糖尿病没有明显作用，因该作用并非很强，故通常尚不能减少所需的胰岛素或口服降糖药的量。本品使那些受影响病人的腹泻减少而体重增加。虽然善得定通常可使血浆高血糖素浓度迅速降低，但长期用药并不能维持其下降，不过病人的症状却继续获得改善。
四、胃泌素瘤综合征
对因慢性胃泌素刺激所致胃酸过多引起的复发性消化性溃疡，通常采用选择性H2受体拮抗剂和抗酸剂治疗，但是，这种治疗可能并不完善，因为治疗后腹泻症状可以依然存在。单用善得定或与H2受体拮抗剂合用可使半数病人的胃酸分泌减少，腹泻和其它症状减轻。并可解除其它可能因肿瘤产生的肽所致的症状如潮红等。有些病人的血浆胃泌素浓度降低。
五、胰岛瘤
善得定可使血循环中免疫反应胰岛素浓度短暂地(约2h)降低。对可以手术的肿瘤病人，本品可助其手术前恢复并维持血糖正常。在不可手术的良性或恶性肿瘤病人中，本品有助于某些病人的血糖抑制但不伴血胰岛素浓度的持续下降。
六、生长激素释放因子瘤
这些罕见肿瘤的特征为：仅分泌生长激素释放因子或同时分泌其它活性肽。在于今所观察到的两例反应性肢端肥大症状中，善得定改善其中一例的特征和症状，其原因可能是生长激素释放因子和生长激素分泌受抑制，继而可能使肿大的垂体缩小。
〔药代动力学〕
善得定皮下注射后吸收迅速而完全，给药后30min血浆浓度达峰值，其消除半衰期为100min。静脉注射后，其消除呈现双相性，半衰期分别10min和90min。药物的表观分布容积为0．27L／kg。总体清除率为160ml／min，血浆蛋白结合率达65%，本品与血细胞的结合则极微。
〔适应证及应用〕
经手术、放射治疗或多巴胺受体激动剂治疗失败的肢端肥大症病人，用以控制症状，降低生长激素及生长调节素C的血药浓度。本品亦适用于不能或不愿手术的肢端肥大症病人，以及放射治疗尚未生效的间歇期病人。用以解除与胃胰内分泌肿瘤有关的症状。有充分证据显示，本品对下列肿瘤有效：
1．具有类癌综合征的类癌瘤。
2．血管活性肠肽瘤。
3．高血糖素瘤。
本品对下列肿瘤有效率均为50%(至今应用本品治疗的病例尚少)：
1．胃泌素瘤／胃泌素瘤综合征(通常与选择性H2受体拮抗剂合用，并可酌情加用抗酸剂)。
2．用于胰岛瘤术前恢复和维持正常血糖。
3．生长激素释放因子瘤。
善得定治疗并非抗癌治疗仅限于缓解症状和征兆。故不能治愈这些病人。
防止胰腺术后并发症。
〔剂量和用法〕
一般剂量
肢端肥大症
初始量为0．05～0．1mg作皮下注射，每8～12h一次，然后，根据生长激素血药浓度、临床症状及耐受性每月评估而调整剂量。多数病人的最适剂量为0．2～0．3mg／d，但不能超过1．5mg／d的最大用量。
善得定治疗一个月后，若生长激素浓度无下降、临床症状无改善，则应考虑停药。
〔胃肠胰内分泌肿瘤〕
初始量为0．05mg作皮下注射，每天1～2次，然后，可根据疗效、肿瘤分泌的激素浓度及耐受性，逐渐提高剂量至0．2mg，每天3次。仅在特殊情况下，方可采用较大剂量。维持量则根据个体情况可作上下浮动。老年病人对善得定的耐受量未见降低，不需改变剂量。善得定用于儿童的经验极有限。
病人必须在医师或护士的指导下方可自行皮下注射。注射前应使药液达室温以减少局部不适，应避免短期内在同一部位多次注射。小瓶盖穿刺不应超过10次以防止污染。
〔禁忌证〕
对本品过敏者。
〔注意事项〕
由于分泌生长激素的垂体肿瘤有时可能扩散而引起严重的并发症(如视野缺损)，故应仔细观察所有病人，若发现有肿瘤扩散的迹象，则应考虑转换治疗。少数长期用本品治疗的病人，曾报道有胆石形成。故最好在治疗前及用药后每隔6～12个月作超声波检查。
在治疗胃肠胰内分泌肿瘤时，偶而发生症状失控而致严重症状迅速复发。
在胰岛瘤病人中，由于善得定对生长激素和高血糖素分泌的抑制大于对胰岛素分泌的抑制，且其抑制后者的作用时间较短，故有可能增加低血糖的深度和时间，此类病人在进行善得定治疗或作剂量改变时，应接受严密观察。较频繁地给予善得定，可减少血糖浓度的明显波动。需接受胰岛素治疗的糖尿病病人，给予善得定后，其胰岛素用量可能减少。
动物生育研究显示：善得定对胎儿无任何危害。尚无用善得定治疗孕妇或哺乳妇女的经验，这些病人仅在迫不得已的情况下方可使用。
〔副作用〕
善得定的主要副作用是局部和胃肠道的。
局部反应包括疼痛，注射部位针刺或烧灼感，伴红肿。这种现象极少超过15min。注射前使药液达室温，则可减少局部不适。
胃肠道副作用包括厌食、恶心、呕吐、痉挛性腹痛、气胀、稀便、腹泻及脂肪痢。虽然所测得的大便脂肪排出可能增多，但无证据显示善得定长期治疗可引起吸收不良而导致营养不良。在罕见病例中，胃肠道副作用可类似急性肠梗阻伴进行性腹胀、严重上腹痛、腹部触痛和肌紧张。给药前后应避免进食(即在两餐之间或卧床休息时注射)，则可减少胃肠道副作用的发生。
由于善得定可抑制胰岛素的释放，故本品可降低病人餐后的糖耐量，少数缓慢给药者可引致持续的高血糖症。
个别病人发生肝或胆的功能失调，这些包括下列各项：
无胆汁郁积性急性肝炎，在停用本品后转氨酶恢复正常。
缓慢发生的血胆红素过多伴碱性磷酸酶、γ-谷氨酰转移酶增高及转氨酶轻度增高。
胆石形成。
〔相互作用〕
善得定可降低肠道对环孢素的吸收，而使西咪替丁的吸收延缓。
〔过量处理〕
未见急性过量引起严重反应的报道。至今最大的成人单次用量为10mg静脉注射。所观察到的体征和症状为心率略减、面部潮红、腹部绞痛、腹泻、胃部空虚感及恶心；给药后24h内症状消退。有报道某病人意外用药过量，持续静脉滴注(以0．25mg／h代替0．025mg／h，共用药48h)，而未见发生副作用。
〔贮存规定〕
为延长贮存期，善得定安瓿与小瓶必须保存在2～8℃。逐步应用者可在室温下存放达2周。药物应在注明的限期内使用。
〔生产厂家〕
瑞士巴塞尔山得士制药公司
【外文释文】：
Synthetic octapeptide derivative of somatostatin
Composition
Ampoules(1ml)
Octreotide acetate，equivalent to octreotide*(as free peptide)：0．05mg，0．1mg or 0．5mg
Multidose vials(5ml)
Octreotide acetate，equivalent to octreotide*(as free peptide)：0．2mg／ml
*INN rec．
Properties／Actions
Sandostatin is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects but a considerably longer duration of action．It inbibits the secretion of peptides of the gastroenteropancreatic(GEP)endocrine system and of growth hormone(GH)，In animals Sandostatin is more potent than somatostatin in inhibiting GH，glucagon and insulin release，as well as being more selective for GH and glucagon．
Chronic administration(26 weeks)of doses up to 1 mg／kg a day(given intraperitoneally)in the rat and of up to 0．5 mg／kg a day(given intravenously)in the dog was well tolerated．
In healthy volunteers Sandostatin has been shown to inhibit：
·Growth-hormone release in response to arginine，exercise or insulin-induced hypoglycaemia．
·Postprandial release of insulin，glucagon，gastrin and other peptides of the GEP system，and the release of insulin and glucagon in response to arginine．
·Release of thyroid-stimulating hormone(TSH)in response to thyrotropin-releasing hormone(TRH)．
In acromegalic patients(including those who have failed to respond to surgery，irradiation or dopamine agonist treatment)Sandostatin lowers plasma levels of GH and／or somatomedin C．A clinically relevant GH reduction(by 50%or more)occurs in almost all patients，with normalization(plasma GH＜5 ng／ml)in about 50%of cases．In most patients there is a marked improvement in clinical manifestations such as headache，skin thickening，soft-tissue swelling，hyperhidrosis，arthralgia and paraesthesia．In patients with a large pituitary adenoma，Sandostatin treatment may result in a degree of tumour shnnkage．
In patients with tumours of the GEP endocrine system，Sandostatin exerts a beneficial effect on various clinical features by virtue of its wide spectrum of activity．Thus patients with persistence of severe tumour-related symptoms despite surgery，hepatic artery embolization，chemotherapy(e．g．streptozocin or 5-fluorouracil)，etc．may show appreciable clinical improvement．
The effects of Sandostatin in various tumour syndromes are as follows：
Carcinoid syndrome
Flush and diarrhoea in particular may show improvement，accompanied in some cases by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid．In the absence of a positive response，however，Sandostatin should not be continued beyond one week．
VIPoma syndrome
So called because its principal biochemical feature is overproduction of vasoactive intestinal peptide(VIP)，VIPoma syndrome is characterized clinically by severe secretory diarrhoea．This is relieved by treatment with Sandostatin in most cases，with consequent improvement in the quality of life．
Associated fluid and electrolyte depletion(e．g．hypokalaemia)is reduced，enabling enteral and parenteral replacement to be withdrawn．In some patients computer tomography suggests slowing or a rest of tumour growth-and even shrinkage-particularly in the case of liver metastases．Clinical improvement is usually accompanied by reduction or even normalization of plasma VIP levels．
Glucagonoma
In most cases there is substantial improvement is the necrolytic migratory rash which is characteristic of this condition．Sandostatin has little effect on the slight sugar diabetes to which these patients are prone and doses of insulin or oral hypoglycaemic agents do not generally have to be reduced．Diarrhoea，where present，responds，resulting in weight gain．In many cases there is an immediate fall in plasma glucagon but this is not sustained；clinical improvement，however continues．
Gastrinoma／Zollinger-Ellison syndrome
Recurrent peptic ulceration due to chronic gastrin-stimulated hypersecretion of gastric acid does not always respond to selective H2-receptor blockade and antacids，while diarrhoea，which may be prominent，is rarely alleviated．In such cases Sandostatin possibly in conjunction with an H2-receptor blocker may inhibit overproduction of gastric acid and induce an improvement in the clinical manifestations(including diarrhoea)in up to 50%of cases．Other manifestations assumed to be due to peptide production by the tumour(e．g．flush)may also respond．Plasma gastrin levels fall in some patients．
Insulinoma
There is a fall in circulating immunoreactive insulin，but this is not generally sustained(about two hours)．In patients with operable tumours Sandostatin may be given preoperatively to help achieve and maintain normoglycaemia．In patients with inoperable benign or malignant tumours blood-sugar regulation may be improved in some cases even without a sustained reduction in circulating insulin．
GRFoma
This a rare type of tumour that produces growth-hormone-releasing factor(GRF)alone or in conjunction with other active peptides，causing signs and symptoms of acromegaly．In one of the two cases so far investigated Sandostatin treatment in clinical improvement probably due to inhibition of GRF and GH secretion possibly accompanied by a reduction in the size of the pituitary．
Prevention of complications following pancreatic surgery
In patients undergoing pancreatic surgery，peri-and postoperative Sandostatin reduces the incidence of typical postoperative complications(e．g．pancreatic fistula，abscess followed by sepsis，acute postoperative pancreatitis)．
Pharmacokinetics
After subcutaneous injection octreotide is rapidly and completely absorbed．Peak plasma concentrations are reached 30 min after administration，elimination after subcutaneous administration takes place with a half-life of 100 min．After intravenous injection elimination is biphasic with half-lives of 10 and 90 min，respectively．The volume of distribution is 0．27L／kg and the total body clearance 160ml／min．Plasma protein binding amounts to 65%．The amount of octreotide bound to blood cells is negligible．
Indications／Uses
Symptom control and reduction of GH and somatomedin-C levels in acromegalic patients who have failed to respond to surgery，radiotherapy or dopamine agonist treatment，are unable or unwilling to undergo surgery，or are in the latency period before radiotherapy becomes fully effective．
Relief of signs and symptoms associated with GEP endocrine tumours：
1．Tumour types for which there is adequate evidence of efficacy：
·Carcinoid tumours with features of the carcinold syndrome
·VIPomas
·Glucagonomas
2．Tumour types for which there is evidence of efficacy in about 50%of cases(limited number of patients treated so far)：
·Gastrinomas／Zollinger-Ellison syndrome(usually in conjunction with selective H2-antagonist therapy with or without antacids)
·Insulinomas(for preoperative prevention of hypoglycaemia and maintenance)
·GRFomas
The effect of Sandostatin is limited to the alleviation of signs and symptoms；it will not cure the underlying condition．
Prevention of complications following pancreatic surgery．
Dosage and administration
Acromegaly
0．05-0．1 mg by subcutaneous injection every 8-12 hours initially，then monthly adjustment in the light of circulating GH，clinical response and tolerability．For most patients the optimum daily dose will be 0．2-0．3mg．
A maximum dose of 1．5mg per day should not be exceeded．
If there is no reduction in GH levels and no clinical response by the end or one month of treatment，discontinuation should be considered．
Gastroenteropancreatic endocrine tumours
0．05mg Once or twice daily by subcutaneous injection initially，gradually increasing to 0．2mg three times daily depending on tolerability and therapeutic effect(clinical response，levels of tumour-produced hormones)．Higher doses may be required in some cases．Maintenance dosage requires individual titration．
Complications following pancreatic surgery
0．1mg Three times daily by subcutaneous injection on seven successive days，the first injection being administered at least one hour before the start of the operation．
No evidence has been found that elderly patients tolerate Sandostatin less well or require a different dosage than other patients．Experience with Sandostatin in children is very limited．
N．B．
Patients who are to self-administer the drug by subcutaneous injection must receive precise instructions from the physician or nurse．
To reduce local discomfort，the solution should be allowed to reach room temperature before injection．Repeated injection at short intervals at the same site should be avoided．To prevent contamination the cap of the multidose vial should not be punctured more than ten times．
Restrictions on use
Contraindications
Hypersensitivity to the drug
Precautions／Warnings
As HG-secreting pituitary tumours may expand，thereby causing serious complications(e．g．restriction of the visual field)，all patients should be carefully monitored．If evidence of tumour expansion is detected alternative methods of management should be considered．
As gallstone formation has been reported in a few patients on long-term Sandostatin，gallbladder ultrasonography should be performed before and at 6-12 month intervals during treatment with Sandostatin．
Sudden loss of symptomatic control with recurrence of severe symptoms has been reported in a few patients with GEP endocrine tumours receiving Sandostatin．
In patients with an insulinoma Sandostatin may exacerbate and prolong hypoglycaemic episodes because of its greater relative potency in inhibiting secretion of growth hormone and glucagon than of insulin．Such patients should be closely monitored，particularly initially and whenever the dose of Sandostatin is changed．Marked fluctuations in blood glucose may be controlled by more frequent administration of smaller doses．
Sandostatin may alter the insulin requirement of patients with insulin-dependent diabetes mellitus．
Pregnancy and lactation
Reproduction studies in animals do not suggest that there is any risk of foetal damage but there is no experience of the use of Sandostatin in women who are pregnant or breastfeeding．Such patients should therefore be given the drug only if absolutely necessary．
Adverse reactions
The main adverse reactions to Sandostatin are local and gastrointestinal．
Local reactions include pain or a sensation of stinging，tingling or burning at the site of injection，with redness and swelling．They rarely last more than fifteen minutes and can be attenuated by allowing the solution to reach room temperature before injecting．Gastrointestinal side effects include loss of appetite，nausea，vomiting，abdominal cramps，abdominal bloating，flatulence，constipation，loose stools，diarrhoea，and steatorrhoea．However，al though faecal fat excretion may increase，there is no evidence that long-term treatment with Sandostatin leads to nutritional deficiency due to malabsorption．In rare instances，gastrointestinal side effects may resemble acute intestinal obstruction with severe epigastric pain and abdominal tenderness，distension and bloating．Gastrointestinal side effects can be attenuated by allowing as long an interval as possible between Sandostatin administration and mealtimes，i．e．by injecting it between meals or at bedtime．
Long-term administration of Sandostatin may lead to the formation of gallstones(see“Precautions”)．
Because of its inhibitory effect on insulin release，Sandostatin may reduce glucose tolerance，possibly giving rise to postprandial hyperglycaemia．In rare instances a state of permanent hyperglycaemia may be induced by long-term administration．
These have been isolated reports of liver dysfunction associated with Sandostatin administration．These consist of the following：
·Acute hepatitis without cholestasis，with normalization of transaminase values on withdrawal of Sandostatin；
·Slowly progressive hyperbilirubinaemia in association with elevation of alkaline phosphatase，gamma glutamyl transferase and，to a lesser extent，transaminase levels．
Interactions
Sandostatin has been found to reduce the intestinal absorption of ciclosporin and to slow that of cimetidine．
Overdosage
No life-threatening reactions have been reported after acute overdosage．
The largest single dose so far given to an adult was 1．0 mg by intravenous bolus injection．The signs and symptoms observed were a transient fall in heart rate，facial flushing，abdominal cramps，diarrhoea，an empty feeling in the stomach and nausea，all of which resolved within 24 hours．
One patient has been reported to have received an accidental overdosage of Sandostatin by continuous infusion(0．25mg per hour for 48 hours instead of 0．025mg per hour)．
He experienced no side effects．
The management of overdosage is symptomatic．
Other information
Shelf-life
For prolonged storage Sandostatin ampoules and multidose vials should be kept at a temperature between 2-8℃．For day-to-day use they may be stored at room temperature for up to 2 weeks．
The drug should not be used after the expiry date(=EXP)printed on the pack．
Manufacturer
Sandoz Pharma，Ltd．，Basle，Switzerland