26．益钙宁
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99页（19478字）
【中文释文】：
注射液
原东洋酿造研究所与折茂、成田等共同研究，从鳗鱼鳃后腺提取降钙素，纯化并确定了其化学结构。1975年又在榊原等的配合下，成功地合成了将二硫键变换为稳定烯键的由31个氨基酸构成的新降钙素衍生物——依降钙素。
该依降钙素的生物学效价很高约为6000依降钙素U／mg，理化及生物学性质均稳定。
益钙宁注射液10U，系含依降钙素的注射液制剂，临床上对钙代谢异常引起的骨质疏松症疼痛有效。
〔组成〕
益钙宁注射液10U，系1支1ml安瓿中含依降钙素10U依降钙素的无色澄清的注射液。
依降钙素活性是利用依降钙素参考标准品通过生物学测定法测定，用依降钙素单位表示。“1依降钙素U”等于“1MRCU”。
〔适应证〕
骨质疏松症引起的疼痛。
〔用法与用量〕
以依降钙素计，对成人通常1次肌肉注射1支(10依降钙素U)，1周2次。剂量应随症状适当增减。
〔使用注意〕
1．一般注意
(1)本剂系多肽制剂，有引起休克症状的可能性，故使用前对既往过敏史及药物过敏症等，应进行详细询问；
(2)有报道给大鼠皮下注射1年的慢性毒性试验中，大剂量能增加垂体肿瘤发生率，故不得长期冒然用药。
2．下述病人慎重用药
(1)易引起皮疹(红斑、风疹快)等过敏反应体质病人；
(2)支气管哮喘或有其既往史病人。
3．副作用
(1)休克，偶引起休克，故注意观察，若出现症状，应停药并适当处置；
(2)过敏症，出现皮疹、荨麻疹等时，应停药；
(3)循环系统，有时出现颜面潮红、热感、胸部压迫感、心悸；
(4)胃肠道，有时出现恶心、呕吐、食欲不振，偶出现腹痛、腹泻、口渴、胃灼热等；
(5)神经系统，有时出现眩晕、步态不稳，偶出现头痛、耳鸣、手足搐搦；
(6)肝脏，偶出现GOT、GPT上升；
(7)电解质代谢，偶出现低钠血症；
(8)注射部位，有时出现疼痛；
(9)其他，有时出现搔痒感，偶出现哮喘发作、出汗、指端麻木、尿频、水肿、视力模糊、咽喉部薄荷样爽快感、发热、寒战、无力感、全身乏力。
4．高龄者用药
通常，高龄者生理功能降低，故注意用量。
5．孕妇·哺乳妇用药
(1)尚未确立孕妇·哺乳妇用药的安全性，因此治疗孕妇或可疑妊娠者及授乳妇时，仅在有益性超过危险性时方可用药；
(2)动物实验报道，妊娠及哺乳期母体注射本剂，会减少乳汁分泌量，抑制新生儿体重增加；
(3)动物实验报道，妊娠末期母体静脉注射本剂，会急速降低血清钙，出现手足搐搦样症状。
6．小儿用药
尚未确立早产儿、新生儿、乳儿、婴儿或小儿用药的安全性(缺少临床经验)。
7．用药须知
肌肉注射时，为避免损伤组织和神经等，应注意下述内容。
(1)注意避开神经走向部位；
(2)反复注射时，要变换注射部位，例如左右交替注射；
(3)刺入注射针时，若有剧痛或血液回流，应速拔针，换部位注射。
8．其他
有报道，给大鼠皮下注射1年的慢性毒性试验中，大剂量能增加垂体肿瘤发生率。
〔药理学〕
1．对实验性骨质疏松症的作用 对低钙食、强的松龙处置及卵巢摘除引起的实验性骨质疏松症动物(大鼠、狗)，以骨强度、骨皮质厚度、骨密度、骨钙含量、尿中羟基脯氨酸排泄量等为指标进行探讨结果，证实了依降钙素的预防效果。
2．抑制骨吸收作用 依降钙素抑制正常幼年大鼠及荷癌家兔的骨吸收作用，减少骨中钙向血液游离。依降钙素在大鼠及小鼠的骨培养系统中，抑制各种促进骨吸收因子引起的骨内钙的释放。
3．对血清钙的作用 依降钙素降低正常动物(大鼠、狗、家兔)及实验性高钙血症动物(大鼠、家兔)的血清钙，其作用较哺乳动物源性降钙素强且持续时间长。
〔药代动力学〕
健康成人肌肉注射益钙宁0．5U／kg时，30min后出现血药浓度(放射免疫测定法)高峰，持续时间为120min。
〔临床研究〕
骨质疏松症引起疼痛的双盲对比试验及451例一般临床试验的概况如下。
一、临床效果
1．双盲对比试验的有效率为对照用药组48．6%(52／107)，本药用药组为67．6%(75／111)。
2．一般临床试验的有效率为66．3%(299／451)。
二、副作用
给予本药前后所进行的观察中，总病例17374例，其中发生副作用的为412例，发生率为2．4%。
主要症状为颜面潮红、热感、恶心、呕吐等。
〔基础研究〕
一、毒性
1．急性毒性：LD50(U／kg)
表6 不同给药途径益钙宁的急性毒性
2．慢性毒性 大鼠(雌、雄)每天肌肉注射5U(kg·d)、20U(kg·d)、80U(kg·d)，共26周，20U／kg及以上组见到一时性进食量减少及体重增加抑制外，未见其他异常。
3．生殖试验 妊娠前及妊娠初期用药试验(雌雄大鼠肌肉注射4U／kg、40U／kg、160U／kg)、胎仔器官形成期用药试验(大鼠肌肉注射4U／kg、20U／kg、40U／kg、80U／kg、160U／kg，家兔肌肉注射4U／kg、20U／kg、80U／kg)中，在整个用药期中体重增加抑制，但对母体动物交配率、妊娠率、胎仔、新生仔均无影响。
围产期及授乳期用药试验(大鼠肌肉注射4U／kg、20U／kg、80U／kg)中，80U／kg用药组出现分娩仔数减少、围产期死亡及新生仔死亡增加。20U／kg及80U／kg用药组新生仔发育迟缓，这是由于母体动物乳腺发育抑制，乳汁生成及乳汁量减少引起所致，但新生仔其后发育、外表分化、行为、繁殖能力及第三代妊娠末期胎仔均无影响。
4．局部刺激性试验 家兔肌肉注射本药时，对注射部位的影响几乎同于生理盐水。
5．抗原性试验 与辅药合并给豚鼠肌肉注射28U／kg、83U／kg、250U／kg时，250U／kg用药组出现全身性过敏反应，83U／kg以下组见到被动皮肤过敏反应，但单用本药时均未见反应。另给小鼠和大鼠用药，无论有无佐剂均未产生IgE抗体。
二、吸收，分布，代谢，排泄
1．血中浓度 大鼠肌肉注射125I依降钙素时，10～30min后达最高血药浓度。
2．体内分布 大鼠肌肉注射125I依降钙素时，多分布于肾、胃、肝，30～120min后达峰值，其后经时渐减。
3．代谢 依降钙素与大鼠脏器提取物反应时，主要在肾脏微粒体中代谢。
4．排泄 大鼠肌肉注射125I依降钙素时，尿中排泄为4h约42%，48h约74%，粪中排泄为48h约7%。
三、一般药理学
1．对肾脏的作用 依降钙素促进大鼠尿中排泄电解质(Na、K)，增加尿量，Na／K比升高。
2．对消化道的作用 依降钙素抑制大鼠胃酸分泌。抑制五肽胃泌素、碳酰胆碱及组胺引起的胃酸分泌亢进。
(U∶依降钙素单位)
〔性状〕
1．制剂性状 益钙宁注射液10U，系无色澄明注射液制剂。pH为5．0～6．5，渗透压比(与生理盐水对比)约1。
2．有效成分的理化性质
一般名：依降钙素(JAN)
依降钙素(r-INN)
化学名：1-丁酸-7-(L-2-氨基丁酸)-26-L-天冬氨酸-27-L-缬氨酸-29-L-丙氨酸降钙素(鲑鱼)
分子式：C148H244N42()47
分子量：3363．82
性状：本品系吸湿性白色粉末，无臭，极易溶于水、冰醋酸、甲酸，易溶于甲醇，几乎不溶于乙醇、吡啶、丙酮、正丁醇、醋酸乙酯、乙醚、氯仿和苯。
本品水溶液(1／100)的pH为4．5～6．5。
〔使用须知〕
本品安瓿系标点安瓿(净切割安瓿)，故切割安瓿时，颈部圆符号置上手持，然后向相反方向(下方)折断。
1．警告 本品系剧药、指定医药品。
2．贮存 室温保存。
3．有效期 标记于外盒(2年)。
〔包装〕
益钙宁注射液10U∶10支
〔生产厂家〕
日本旭化学工业株式会社
【外文释文】：
(Elcatonin preparation)
The former Tokyo Jozo Research Laboratories，in collaboration with Orimo et al．and Narita et al．，extracted calcitonin from the ultimobranchial glands of eel，purified it，and established its chemical strcucture．Securing the coopcration of Sakakibara et al．，in furtherance of the idea of synthesizing the calcitonin，the Laboratories in 1975 successfully synthesized a new calcitonin derivative，named Elcatonin consisting of 31 amino acids with a stable ethylene linkage by means of substituting the disulfide linkage of calcitonin．
Elcatonin has a biological specific activity of as high as about 6000 Elcatonin units per mg and is physicochemically and biologically stable．
Elcitonin Inj．10U．is an iniectable preparation containing Elcatonin．Clinically，it is effective in the treatment of pain associated with osteoporosis due to disturbances in calcium metabolism．
Composition
Elcitonin Inj．10U．is a clear，colorless injectable solution of elcatonin containing 10 Elcatonin units in each ampoule of 1 ml．
The activity of elcatonin is determined by biological assay using the Elcatonin Reference Standard and expressed in elcatonin units．1 Elcatonin unit is equivalent to 1 MRC unit．
Indications
Pain due to osteoporosis
Dosage & administration
Adults-In general，one ampoule(10 Elcatonin units)is administered at a time intramuscularly twice a week．The dosage should be adjusted according to the patient’s symptoms．
Precautions
i．General precautions
(1)As Elcitonin Inj．10U．a polypeptide preparation，is associated with a potential of causing shock symptoms，orally inquire the patient thoroughly about past history of allergy，drug hypersensitivity，etc．before use．
(2)As there is a report that in a 1-year subcutaneous chronic toxicity study in rats，the incidence of pituitary tumors increased with a high dosage，the preparation should not be administered carelessly for a long period．
2．It should be carefully administerd to the following patients：
(1)Patients with constitution to easily cause hypersensitive reactions such as rash(erythema，wheals，etc．)and so on．
(2)Patients with bronchial asthma or with a history of it．
3．Adverse reactions
(1)Shock：Careful monitoring should be performed during Elcitonin therapy，since shock may rarely occur．If such shock appears，the drug should be discontinued and an appropriate treatment given．
(2)Hypersensitivity：lf rash，urticaria，etc．occur，the drug should be discontinued．
(3)Circulatory system：Hot flushes，hot feeling，pressure in chest or palpitation may occasionally occur．
(4)Gastrointestinal tract：Nausea，vomiting，anorexia may occasionally occur and abdominal pain，diarrhea，thirst，heartburn，etc．，may rarely occur．
(5)Nervous system：Dizziness or light-headed feeling may occasionally occur and headache，tinnitus or tetany may rarely occur．
(6)Liver：The rise in GOT and GPT may rarely occur．
(7)Electrolyte metabolism：Hyponatremia may rarely occur．
(8)Injection site：Pain at the injection site may occasionally occur．
(9)Others：Itching may occasionally occur．Asthmatic attack，sweating，tingling of the fingertip，pollakiuria，edema，vision blurred，refreshing menthol-like stimulation at the pharyngeal mucosa，fever，rigor，weakness or general malaise may rarely occur．
4．Use in the elderly
As physiological functions are generally declined in the elderly，exercise caution in the dosage of the drug when it is used in such patients．
5．Administration to pregnant women and nursing mothers
(1)Since the safety for use in pregnant women and nursing mothers has not been established，administration to pregnant women，women suspected of being pregnant or nursing mothers should be done only if the potential benefit justifies the potential risk to the patient．
(2)In animal experiments，it has been reportd that lactation is decreased and bodyweight gain of neonates is inhibited when this drug is administered to females during pregnancy or lactation period．
(3)In animal experiments，it has been reported that serum calcium level is drastically decreased and tetany-like symptom develops when this drug is administered intravenously to females in perinatal period．
6．Administration to infants and children
The safety for use in premature babies，newborns，sucklings，infants and children has not been established(for lack of clinical experience)．
7．Cautions in use
In case of intramuscular injection，the following cautions should be exercised in order to avoid the effect on the tissues and nerves．
(1)Regions where nerves are known to be present should be avoided．
(2)In case of repeated injections，change the injection site，for example，left and right alternately．
(3)The needle should be pulled out immediately and the injection site changed when a sharp pain is felt by the patient or backflow of blood in the syringe is observed．
8．Others
In a 1-year subcutaneous chronic toxicity study in rats，it has been reported that the incidence of pituitary tumors increased in a massive dose．
Pharmacology
1．Effects on experimental osteoporosis
Osteoporosis-preventive effect was observed by investigating the strength，cortex thickness，density and calcium of the bones and urinary hydroxyproline levels of rats and dogs with experimental osteoporsis induced by a low calcium diet and either treatment with prednisolone or ovariectomy．
2．Inhibition of bone resorption
In normal juvenile rats and tumor-bearing rabbits，elcatonin inhibits bone resorption and thereby decreases the release of calcium from bone into the blood．In rat or mouse bone cultures，elcatonin inhibits the release of bone calcium which is induced by various factors promoting the resorption of bone．
3．Effects on serum calcium
Elcatonin lowers serum calcium in normal animals(rats，dogs and rabbits)and experimentally induced hypercalcemic animals(rats and rabbits)．This effect is more powerful and long than that of calcitonins derived from mammals．
Pharmacokinetics
When 0．5 elcatonic units／kg of Elcitonin Inj are administered intramuscularly to healthy volunteers，a peak of blood concentration(radioimmunoassay)is observed at 30min，and lasted 120 min．
Clinical studies
The outlines of double blind clinical studies and general clinical studies on 451 cases having the pain of osteoporosis were as follows：
(Clinical effects)
1．The efficacy rate in double blind clinical studies accounted for 67．6%(75／111)in elcatonin group while it is 48．6%(52／107)in control group．
2．The efficacy rate in general clinical studies accounted for 66．3%(299／45 1)．
(Adverse reactions in clinical studies)
Adverse reactions were noted in 412 cases(2．4%)out of a total of 17 374 cases in investigation carried out before and after the authorization of this drug．The chief symptoms were hot flushes，hot feeling，nausea，vomiting and so on．
Basic studies
(Toxicity)
1．Acute toxicity
LD50 values(elcatonin units／kg)of elcatonin for mice and rats are given in the following table．
Table 6
2．Chronic toxicity
When Elcatonin is intramuscularly administered to rats(male and female)for 26 weeks in daily doses of 5U／kg，20 U／kg and 80 Elcatonin U／kg，no particular abnormalities are observed except that a transient decrease in food intake and the associated suppression of body weight gain are noted in the groups of rats receiving not less than 20 Elcatonin U／kg．
3．Reproductive tests
In the fertility study(4 U／kg，40 U／kg and 160 U／kg intramuscularly to male and female rats)and teratogenicity study(4 U／kg，20 U／kg，40 U／kg，80 U／kg and 160U／kg intramuscularly to rats and 4 U／kg，20 U／kg and 80 U／kg intramuscularly to rabbits)，a decrease of body weight gain was observed throughout the period of administration，but no influences were observed on the copulation and pregnacy rate of the parent animals，as well as on the fetuses and newborns．In the peri-and post-natal study(4 U／kg，20 U／kg and 80 U／kg intramuscularly to rats)，following an increase of peri-and neo-natal death，a decrease of offspring was observed in the 80 U／kg group．Also，delay in the development of offspring was observed in the 20 U／kg and 80 U／kg groups，and these findings presumably were due to an inhibition of the mammary glands growth and a decrease both in galactosis and lactation of the mother animals．
However，no influences of the drug were observed thereafter on the development of neonates，external differentiation，behavior and fertility，as well as on fetuses of the third generation at their terminal stages in their mothers wombs．
4．Local irritability tests
When Elcatonin is intramuscularly administered to rabbits，its effects on the site of injection are substantially the same as those of physiological saline solution．
5．Antigenicity tests
When Elcatonin，together with an adjuvant，is intramuscularly administered to guinea pigs in doses of 28 U／kg，83 U／kg and 250 U／kg Elcatonin units／kg，a systemic anaphylactic reaction is noted in the group of guinea pigs receiving 250 Elcatonin U／kg，and a passive cutaneous anaphylaxis reaction is noted in the groups of guinea pigs receiving not less than 83Elcatonin U／kg．However，these reactions are not observed when Elcatonin alone is administered．When Elcatonin is administered to mice and rats，no production of lgE antibodies is recognized，whether an adjuvant is used or not．
Absorption，Distribution，Metabolism and Excretion
1．Blood concentration
When125 I-Elcatonin is intramuscularly administered to a rat，its blood concentration rea-ches a peak after 10-30 minutes．
2．Distribution
When125I-Elcatonin is intramuscularly administered to a rat，it is predominantly distributed in the kidney，stomach and liver．Its concentration in these organs reaches a peak after 30-120 minutes and then decreases with time．
3．Metabolism
When Elcatonin is allowed to react with extracts from various organs of the rat，it is found that this drug is metabolized chiefly in the microsomal fraction of the kidney．
4．Excretion
When125I-Elcatonin is intramuscularlv administered to a rat， about 42% and 74% of this drug is excreted in the urine in the course of 4 hours and 48 hours，respectively．In addition，about 7% of the drug is excreted in the feces in the course of 48 hours．
General pharmacology
1．Effects on kidney
In rats，Elcatonin promotes the excretion of electrolyts(Na and K)in the urine and thereby increases the urinary volume．The urinary Na／K ratio is elevated．
2．Effects on gastrointestinal tract
Elcatonin inhibits the secretion of gastric juice in rats．It also inhibits the hypersecretion of gastric juice which is induced by pentagastrin，carbachol and histamine．
Description
(Description of preparation)
Elcitonin Inj．10 U．is a clear，colorless injectable solution．
The pH is 5．0-6．5，and osmotic pressure ratio(ratio per physiological saline solution)is approx．1．(Physicochemical findings on active ingredient)
Generic name：Elcatonin(r-INN)
Chemical name：1-butyric acid-7-(L-2-aminobutyric acid)-26-L-aspartic acid-27-L-valine-29-L-alanine calcitonin(salmon)
Molecular formula：C148H244N42O47
Molecular weight：3363．82
Description：Elcatonin is a hydroscopic white powder．It is odorless，very soluble in water，glacial acetic acid and formic acid，freely soluble in methanol and practically insoluble in ethanol，pyridine，acetone，n-butanol，ethyl acetate，ether，chloroform and benzene．
The pH of Elcatonin solution(1 in 100)ranges from 4．5-6．5．
Cautions in handling
As one-point ampoule(clean-cut ampoule)is used for this preparation，hold the ampoule with the circle-marked wall of its neck upward，and open the ampoule by snapping the neck in a direction opposite to the marked side(downward)．
1．Warning：This drug is a powerful drug．
2．Storage：Preserve at controlled room temperature．
3．Expiry date：As indicated on the package(use within 24 months)．
How supplied
Elcitonin Inj．10 U．(10 Elcatonin units)：10 ampoules
Manufacturer
Asahi Chemical Industry Co．，Ltd．
Head Office：2-6，Dojimahama 1-chome，Kita-ku，Osaka，Japan
Pharmaceutial Div．：5-13，Shibaura 4-chome，Minato-ku，Tokyo，Japan