18．柔红霉素

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67页（11895字）

【中文释文】：

柔红霉素(柔毛霉素或盐酸柔红霉素)是一种蒽环类抗肿瘤抗生素，由Farmirtalia Cario Erba研究实验室从一种波赛链霉菌(Str．Peucetius)培养液中分离而出。柔红霉素含盐酸柔红霉素，是一种含甘露醇的冻干粉剂，溶于水和生理盐水。

〔生物活性〕

柔红霉素一种强烈的抗白血病制剂。作用机制与该药可与DNA结合及抑制核酸合成有关。柔红霉素同样具有有限的抗菌活性及某些免疫抑制活性。细胞培养研究表明：它具有迅速穿透细胞膜的能力及抗生素主要集于核周染色质中。曾有报道，该药可迅速抑制核酸合成及有丝分裂，并致染色体畸变。体内实验表明，柔红霉素对小鼠和大鼠实验性实体瘤及腹水型肿瘤的生长都有抑制作用，明显地延长了这些动物的活存时间。

〔临床药理学〕

用同位素标记柔红霉素药代动力学研究显示：静脉注射后有一个快速血浆清除，抗生素迅速降低到某一血浆浓度水平，然后稳定维持一较长时间。柔红霉素迅速与各组织结合，特别是那些富于核酸的组织，如脾脏、淋巴结和骨髓，并从这些组织中释放进入血循环。正如荧光方法所测定，7d经泌尿系统排泄的量，约占摄入量的15%。经胆道排泄是最主要的排泄途径。肝功能受损后排泄将减慢，从而使该药聚积于血浆和组织中。柔红霉素不能通过血脑屏障。

〔适应证〕

1．急性粒细胞性白血病 无论是单一使用柔红霉素或者与其它抗肿瘤药物合用，柔红霉素均适用于治疗该病的各个分期。亦用于治疗早幼粒性白血病。

2．急性淋巴细胞性白血病 用柔红霉素治疗该病，缓解率很高，但由于其副作用大及尚有其它有效治疗方法，故柔红霉素只适用那些对其它药物已产生耐药的病例。在急性淋巴细胞性白血病急性期联合使用柔红霉素、强的松和长春新碱已证实十分成功。

3．其他肿瘤 已观察到柔红霉素对神经母细胞瘤及横纹肌肉瘤有肯定的疗效。

〔禁忌证〕

对于有心脏病的病人，柔红霉素能否增加其诱导心脏毒性，还未有现成的总结性资料。所以对有严重或潜在心脏病病人，不提倡用该药。对有严重感染病人亦不提倡用该药。

〔用量〕

单剂量：0．5～3mg／kg。

0．5～1mg／kg的剂量须间隔1d或以上，才可重复注射；而2mg／kg的剂量则须间隔4d或以上才可重复注射。虽然很少应用2．5～3mg／kg的剂量，但这个剂量须间隔7～14d才可重复注射。每个病人需要注射的次数可有不同。每个病人应根据各自对药物的反应和耐受性、各自的血象和骨髓象情况来调整剂量，与其它抗肿瘤药物合用时，亦应考虑调整剂量。无论成人或儿童，总剂量不能超过20mg／kg(见注意事项)。肝功能不良的病人须减量，以免药物毒性增强。

〔注意事项〕

在急性白血病诱导缓解期使用柔红霉素的病人须住院，并保持持续细致的监测。

柔红霉素可迅速溶解白血病细胞而致血尿和尿酸升高。所以在治疗的第一周，至少需监测3～4次血尿和尿酸水平。在严重的病例中，应给予充足的水分和别嘌呤醇，以避免尿酸性肾病。

柔红霉素对所有病人都有骨髓抑制作用，对某些病人甚至引起严重的骨髓再生障碍。所以在开始治疗之前，应时常注意药物的骨髓毒性，从而做好充分的支持疗法准备，如应用抗生素、输血、输血小板，最后也可输白细胞。治疗的第一周必须每日检查白细胞、红细胞及血小板数。

在治疗开始前及治疗期，提倡用一般实验室的检验如SGOT，SGPT、碱性磷酸酶，胆红素和BSP来评估病人的肝功能。

须特别注意，柔红霉素对心脏的毒性。如果柔红霉素的累积剂量在20mg／kg的限量以下，心力衰竭的危险性是很小的，约2%。但如果累积总量超20mg／kg，则发生率就明显增加。联合治疗(放疗及应用其他潜在心脏毒性的药物治疗)或有与症状相关的临床情况，如贫血、感染、心包炎或心肌炎都会加强柔红霉素对心脏毒性。心力衰竭有可能在完全缓解期发生或在停用柔红霉素治疗几周后发生，而且一般常用的内科治疗并不能改善心力衰竭。每一治疗周期之前及之后，都建议做基础心电图。心电图的改变，如T波低平或倒置，或S-T段下降，或心律失常发作，并不认为是停止用药的指征。现在认为QRS波低电压是心脏毒性较为特异的表现。如果发生QRS波低电压，须慎重权衡继续用药治疗的益处与发生不可逆心脏损害危险性两者间的利害关系。在累积总量很高时，心力衰竭可随时发生，而心电图预先无任何改变。

柔红霉素引起男性和女性不育、引起畸胎或对胎儿造成损害的可能性尚未得到足够评估。实验室资料显示柔红霉素可能引起胎儿生存力下降。故此，须慎重权衡孕妇用药的益处与药物对胎儿或胚胎潜在毒性两者间的利害关系。有报道指出，柔红霉素像其它抗肿瘤药物和免疫抑制药物一样在特定实验条件下对动物有致癌的可能。

注射柔红霉素1～2d后，尿液可呈桔红色。如果皮肤或粘膜意外接触到柔红霉素溶液，应立即彻底冲洗，虽然柔红霉素显示有部分抗菌活性，但决不能作抗菌素用。

〔副作用〕

骨髓抑制及心脏毒性是主要的副作用(见注意事项)。脱发是常见副作用，但治疗停止后可恢复正常。口腔炎如果不是由于肿瘤本身所表现的，会在注射药物5～10d后出现，其特点是溃烂区域的疼痛，特别是在舌两侧及舌下粘膜区域。可出现消化道症状如恶心、呕吐、腹泻。如果注射柔红霉素时发生药物外渗会导致组织严重的坏死。有报道，选用小静脉注射或一条静脉重复多次注射，可造成静脉硬化症(见给药途径)。

〔给药途径〕

柔红霉素口服无效。也不应行肌肉注射或鞘内注射，只能静脉注射给药。应先点滴生理盐水，以确保针头在静脉内，然后才在这一通畅的静脉输液管内注射柔红霉素。这项技术可减少药物外渗的危险性及保证在注射完毕后可冲洗静脉。柔红霉素切不可与肝素混合，因这类药物在化学性质上不相配伍，可产生沉淀物。柔红霉素可与其它抗白血病药物联合应用，但切不可用同一针筒来混合这些药物。

〔包装规格〕

每瓶含20mg盐酸柔红霉素冻干粉剂。药物溶液须避光保存，室温下24h或4～10℃温度下48h，药物保持稳定。

药物应远离儿童存放。

〔生产厂家〕

意大利爱宝药厂

(附本品别名：红比霉素13057R，Rubomycin，NSC-82151，DRB，DNR，Cerubidine)

【外文释文】：

Daunoblastina(daunomycin or daunorubicin hydrochloride)is an antiblastic anthracycline antibiotic isolated from cultures of Streptomyces peucetius in the Research Laboratories of Farmitalia Carlo Erba．Daunoblastina contains daunorubicin hydrochloride as a freeze-dried powder with mannitol．It is soluble in water and saline．

Biological activity

Daunoblastina is a potent antileukemic agent．The mechanism of action is related to its ability to bind to DNA and inhibit nucleic acid synthesis．Daunoblastina also shows modest antibacterial activity and some immunosuppressive activity．Cell culture studies have demonstrated rapid cell penetration and predominant localisation of the antibiotic in the perinucleolar chromatin．Rapid inhibition of nucleic acid synthesis，mitotic activity and chromosomal aberrations have also been reported．In vivo，Daunoblastina inhibits the growth of both solid and ascitic experimental tumours in the mouse and rat，extensively prolonging the survival of the animals．

Clinical pharmacology

Pharmacokinetic studies using radiolabelled Daunoblastina show that intravenous administration is followed by rapid plasma clearance of the antibiotic．Plasma concentrations remain steady for a long time after this rapid decline．Daunoblastina is rapidly bound to tissues，especially those rich in nucleic acids(spleen，lymph nodes and bone marrow)and is released from here into the circulating blood．Urinary excretion，as determined by fluorimetric methods，accounts for approximately 15% of the administered dose over seven days．Biliary excretion is the major route of elimination．Impaired liver function results in slower excretion，and consequently，accumulation in plasma and tissues．Daunoblastina does not cross the blood-brain barrier．

Indications-acute myeloblastic leukemia

Daunoblastina is indicated for the treatment of all stages of this disease，either as a single agent or in combination with other antiblastic drugs．It is also the treatment of choice for promyelocytic leukemia．

Acute lymphoblastic leukemia

Daunoblastina is very active in inducing remission in this disease．However，due to its side effects and the availability of other forms of therapy，Daunoblastina is only indicated in those cases that are resistant to other drugs．The combination chemotherapy regimen of Daunoblastina，Prednisolone and Vincristine in the acute phase of the disease has proved successful

Other tumours

Positive responses have been observed with Daunoblastina in neuroblastoma and rhabdomyosarcoma．

Contraindications

Conclusive data are not available on pre-existing heart disease as a factor of increased risk of Daunoblastina-induced cardiotoxicity，it is therefore not recommended in patients with severe or pre-existing heart disease．

It is also inadvisable to administer the drug to patients with severe infections．

Dosage

The single dose may vary from 0．5-3 mg／kg．

Doses of(0．5-1 mg／kg)may be repeated at intervals of one or more days；doses of 2 mg／kg should be given at intervals of 4 or more days．Doses of 2．5-3mg／kg，although rarely used，should be given at intervals of 7-14 days．

The number of injections required may vary from patient to patient and the dose should be adjusted for each patient according to response and tolerance and according to the haematological and bone marrow status．Combination chemotherapy with other anti-blastic compounds should also be taken into account．In both adults and children a total dose of 20 mg／kg should not be exceeded(see Warnings)．Dosage should be reduced in patients with impaired hepatic function to avoid an increase in toxicity．

Warnings

The patient should be kept under constant supervision and hospitalised during induction or remission of acute leukemia with Daunoblastina．Since an increase in biood urea and uric acid，scondary to rapid lysis of leukemic cells，may be induced by Daunoblastina，these levels should be monitored at least 3 or 4 times a week during the first week of treatment．In severe cases it is advisable to give abundant fluids and allopurinol to avoid the onset of uric acid nephropathy．Daunoblastina causes myelosuppression in all patients and severe aplasia in some cases．This must be borne in mind before starting therapy so that adequate supportive measures(antibiotics，transfusions，packed platelets and eventually also leukocytes)are available．WBC，RBC and platelet counts are necessary daily during the first week of treatment．

Before and during treatment，evaluation of hepatic function is recommended using conventional laboratory tests such as SGOT，SGPT，alkaline phosphatase，bilirubin and BSP．Special attention must be given to cardiac toxicity induced by Daunoblastina．The risk of cardiac failure is extremely low(about 2%)below the cumulative dose limit of 20 mg／kg，but increases considerably if this dose in exceeded．Concomitant treatment(radiotherapy and other potentially cardiotoxic agents)or disease-related clinical conditions(anemia，infections，peri-and／or myocardial infiltrates)may enhance Daunoblastina-induced cardiotoxicity．Cardiac failure may，however，be encountered during complete remission and several weeks after discontinuation of Daunoblastina therapy and is often not improved by known medical or physical therapy．Baseline ECG before and after each treatment cycle is recommended．ECG changs such as T-wave flattening or inversion，or ST segment depression，or the onset of arrhythmias，are not considered indications for suspension of treatment．A reduction in the voltage of the QRS wave is currently considered more specifically predictive for cardiotoxicity．If this occurs，the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage．Cardiac failure may occur after a high cumulative dose even without preceeding ECG changes．The possible adverse effects on fertility in males and females and teratogenic or harmful effects on the foetus have still not been adequately evaluated．Experimental data show，however，that foetal viability may be reduced by Daunoblastina，Therefore，the benefits to the pregnant patient should be carefully weighed against the potential toxicity to the foetus or embryo．Daunoblastina like other antitumour and immunosuppressive drugs has also been shown to have carcinogenic potential in animals under particular experimental conditions．Daunoblastina imparts a red colour to the urine for 1-2 days after administration．If the solution of the drug comes into contact with the skin or mucosa，wash immediately and thoroughly．Daunoblastina should not be used as an antimicrobial agent although it does show some antibiotic activity．

Side effects

Myelosuppression and cardiotoxicity are the major side effects(see Warnings)．Alopecia is a frequent side effect but is often reversible at the end of treatment．Stomatitis，if not already present due to the underlying disease，may occur 5-10 days after administration．It is characterized by painful areas of erosion particularly along the lateral borders of the tongue and sublingual mucosa．Gastrointestinal disorders such as nausea，vomiting and diarrhea may occur．Severe necrosis will occur if Daunoblastina is extravasated during administration．Phlebosclerosis has been reported especially when small veins are used or if a single vein is used for repeated administration．(see Administration)．

Administration

Daunoblastina is not active orally and intramuscular or intrathecal administration should be avoided．It should be administered only intravenously and it is recommended that Daunoblastina be administered into the tubing of a freely running intravenous infusion of physiological saline making sure that the needle is inserted properly into the vein．This technique reduces the risk of drug extravasation and ensures that the vein is washed after administration．Daunoblastina should not be mixed with heparin as these drugs are chemically incompatible and a precipitate may form．Daunoblastina has been used in combination with other antiteukemic drugs，but it should not be mixed with other drugs in the same syringe．

Presentation

A vial containing 20 mg daunorubicin hydrochloride as a freeze-dried powder．Solutions of the drug should be protected from exposure to sunlight and are stable for 24 hours at room temperature or for 48 hours between 4-10℃。

Keep out of the reach of children．

Manufacturer

Erba Ltd．，Italy