Daunorubicin ( Lat. Daunorubicinum , Eng. Daunorubicin ) is one of the anthracycline antibiotics , a cytostatic drug , known since the early 1960s.
| Daunorubicin | |
|---|---|
| Daunorubicinum | |
 | |
| Chemical compound | |
| IUPAC | (8S-cis) -8-acetyl-10 - [(3-amino 2,3,6-tridesoxy-alpha-L-dioxohexopyranosyl) oxy] - 7,8,9,10-tetrahydro-6.8,11-trihydroxy- 1-methoxy-5,12-naphthacenedione (including hydrochloride ) [1] |
| Gross formula | C 27 H 29 NO 10 |
| Cas | |
| PubChem | |
| Drugbank | |
| Classification | |
| Farmakol. Group | antitumor antibiotics [2] |
| ATX | |
| ICD-10 | |
| Dosage Forms | |
| • hydrochloride or citrate encapsulated in liposomes (average diameter 45 nm , consisting of a lipid bilayer: distearoylphosphatidylcholine and cholesterol in a molar ratio of 2: 1) [3] ; • lyophilisate for the preparation of a solution for intravenous administration of 20 mg , 40 mg ; • solution for intravenous administration of 5 mg / ml [1] | |
| Other names | |
| rubomycin hydrochloride [1] | |
It is produced by the microorganisms Streptomyces coeruleorubidus or Streptomyces peucetius . It inhibits the growth of gram-positive bacteria and mycobacteria , but exhibits low activity against gram-negative bacteria . It is used in cancer chemotherapy and as a starting material in the production of a number of other anthracycline antibiotics ( doxorubicin , epirubicin , idarubicin , etc.). The daunorubicin molecule consists of a tetracyclic anthraquinoid aglycone daunorubicinone linked by a glycosidic bond with the amino sugar daunosamine . Synonyms: rubomycin, rubidomycin, daunomycin [4] [5] .
According to the physical characteristics, daunorubicin is a powder or a porous mass of red color. Soluble in aqueous solutions of acids , butanol . Commercially available as daunorubicin hydrochloride .
Daunorubicin hydrochloride is a crystalline powder of orange-red or red color, CAS code 23541-50-6, gross formula C 27 H 29 NO 10 HCl , molecular weight 563.98, melts at 177 ° C with decomposition. It is soluble in water and methanol , slightly soluble in ethanol , practically insoluble in acetone . The pH of the aqueous solution is 4.5-6.5 (at a concentration of 5 mg / ml ). Hygroscopicity of daunorubicin hydrochloride has been reported, but a well-purified material is non-hygroscopic.
Daunorubicin is included in the list of essential drugs .
Content
Pharmacological action
Antitumor anthracycline antibiotic produced by Streptomyces coeruleorubidis or Streptomyces peucetius , with a cytostatic effect. Acts on the S-phase of mitosis . Blocks the matrix function of DNA , disrupting the synthesis of nucleic acids and protein. Antitumor activity is also realized through interaction with membranes and the formation of free radicals of the semiquinone type.
It is characterized by high antimitotic activity and low selectivity.
The therapeutic effect in acute leukemia develops after 2-3 injections (the number of blast cells in the blood and bone marrow is significantly reduced). The decrease in the total number of leukocytes continues for 2 weeks after the end of the course. Toxicity is highest with the intraperitoneal route of administration.
Pharmacokinetics
After intravenous administration, it circulates in the blood for several minutes. After 30 minutes after injection, the highest concentrations are recorded in the spleen, lungs, heart muscle and kidneys. The blood-brain barrier does not pass. Unevenly distributed in the organelles of the cell, the main part accumulates in the nucleus. The decrease in blood concentration is biphasic - with T 1/2 from 35–45 min. up to 46-54 hours , on average - 26.7 hours
It is rapidly (within an hour) metabolized in the liver by reduction and conjugation reactions with glucuronic acid to form the active metabolite of daunorubicinol. It is excreted by the kidneys: 10% - in 24 hours , 2 5% - in 5 days ; with bile - 40%. It has pronounced cumulative properties [1] .
Application
- Indications
Acute lymphoblastic and non-lymphoblastic (myeloblastic, monoblastic, erythroblastic) leukemia , non-Hodgkin 's lymphomas , Ewing 's tumor, Wilms tumor [1] . Blast crisis of chronic myeloid leukemia , lymphosarcoma , uterine chorionepithelioma , malignant histocytosis (in adults and children), soft tissue sarcoma , neuroblastoma (in children). Used in combination with other antitumor agents as part of remission induction programs [2] .
- Contraindications
Hypersensitivity (including to other anthracyclines or anthracenediones ), severe inhibition of bone marrow hematopoiesis, severe renal / hepatic insufficiency, decompensated diseases of the cardiovascular system, prior chemotherapy with other anthracyclines or anthracendion in limiting total doses [1] . Cachexia , terminal stages of the tumor process, bone marrow metastases , leukopenia , thrombocytopenia , organic heart lesions, gastric and duodenal ulcer in the acute stage [2] .
- Pregnancy and lactation
Contraindicated. Women of childbearing age should use reliable methods of contraception during the period of daunorubicin therapy. In experimental studies, the teratogenic, embryotoxic effect of daunorubicin was established.
Breastfeeding is not recommended because of the possible risk for infants (adverse effects, mutagenic and carcinogenic effects) [2] .
- Carefully
Inhibition of bone marrow hematopoiesis (including against concomitant radiation or chemotherapy, bone marrow infiltration by tumor cells), acute infectious viral diseases (including chicken pox, herpes zoster), fungal or bacterial nature (risk of serious complications and generalization of the process ), an increased risk of hyperuricemia (including gout, urate nephrolithiasis), elderly patients, and children [1] .
Dosage
Installed individually, depending on the indications and stage of the disease, the state of the hematopoietic system, anti-tumor therapy regimen.
Only intravenously. The daily dose for adults is 30-60 mg / m² every 2-3 weeks for 3 days or 20-40 mg / m² for 5 days . For children - 25 mg / m² 1 time in 5-7 days . The course dose for adults is 600 mg / m² , in the case of previous radiation therapy - 450 mg / m² , the previous treatment with doxorubicin - 550 mg / m² ; for children - 300 mg / m² . It is possible once in a dose of 0.18 g / cm² with an interval of at least a month.
In patients with impaired renal function, the dose is reduced - with a serum creatinine concentration above 0.3 mmol / L, it is recommended to use half the usual dose.
In case of impaired liver function and a concentration of bilirubin in the blood serum of 20.5-51.3 μmol / L , 3/4 of the usual dose should be used, and with a bilirubin concentration above 51.3 μmol / L , half the usual dose of the drug [1] .
Side effect
Hematopoietic organs: inhibition of bone marrow hematopoiesis (anemia, leukopenia, neutropenia, thrombocytopenia). The lowest white blood cell count is 10-14 days after administration; recovery usually occurs within 21 days after administration.
From the cardiovascular system: the development or worsening of heart failure (arrhythmia, shortness of breath, swelling in the ankle joints) - usually observed with a total dose of more than 550 mg / m² , 450 mg / m² - with previous radiation therapy, in the elderly, with diseases heart myocarditis, pericarditis.
From the digestive system: nausea , decreased appetite, vomiting , diarrhea, ulceration of the gastrointestinal mucosa (ulcerative stomatitis, esophagitis ).
From the genitourinary system: hyperuricemia (painful or difficult urination, cystitis), reddish color of urine, amenorrhea, azoospermia.
Local reactions: at the injection site - phlebitis; with extravasation - soreness, inflammation of the subcutaneous fat, necrosis of surrounding tissues.
Other: allergic reactions, headache, alopecia, discoloration of the skin (hyperpigmentation or hyperemia of previously irradiated skin areas), the development of opportunistic infections , fever, pain in the lower back or side [1] .
Interaction
Compatible with vincristine, cyclophosphamide, 6-mercaptopurine, prednisone, L-asparaginase, methotrexate.
Hepatotoxic drugs (including methotrexate) increase the risk of impaired liver function.
Pharmaceutically incompatible with heparin and dexamethasone phosphate precipitate; strongly alkaline solutions (pH greater than 8) - the destruction of the daunorubicin molecule; Drugs containing bacteriostatic agents (benzyl alcohol) - premature release of the active drug.
Dr. antitumor drugs enhance the effect and additively inhibit bone marrow function.
Cyclophosphamide or irradiation of the mediastinum enhances cardiotoxicity.
With the introduction of live viral vaccines, replication of the vaccine virus and the increase in side effects of inactivated vaccines — a decrease in the production of antiviral antibodies [1], is possible.
Reduces the antigout effect of allopurinol, colchicine and sulfinpyrazone.
The liposomal form of daunorubicin citrate can only be mixed with 5% glucose solution. Do not mix with saline, bacteriostatic agents (benzyl alcohol) and any other solutions. The solution cannot be used if it becomes opaque, or if there is a precipitate or foreign particles in it. There are no data on the interaction of the liposomal form of daunorubicin citrate with other drugs [2] .
Special instructions
Treatment should be carried out in a specialized department by a specialist with experience in antitumor chemotherapy. Only a freshly prepared solution of the drug is used.
Before and during treatment, it is necessary to control the picture of peripheral blood, the functional state of the kidneys, liver, CVS (echocardiography, ECG).
In the first few days of using the drug, a reddish color of urine may appear, which disappears within 48 hours.
During treatment, most patients may experience alopecia, which disappears after 5 weeks or more after completion of the course of therapy.
If there are signs of extravasation (burning or pain at the injection site), the drug should be stopped immediately. The remaining drug is injected into another vein.
A rush of blood to the skin of the face or the appearance of erythematous bands on the skin along the vein indicate a high rate of administration.
To prevent hyperuricemia, heavy drinking is recommended, if necessary, allopurinol, alkalization of urine.
During the treatment of any of the sexual partners, it is recommended to use reliable methods of contraception.
Violation of myocardial contractility, symptoms of heart failure and other cardiotoxic effects can occur several months and years after the end of treatment (especially in children), therefore, the monitoring of CVS should be carried out for a long time.
During treatment, vaccination with viral vaccines is not recommended, it is also necessary to avoid contact with bacterial infections and contact sports, in which hemorrhages and injuries are possible (especially with bone marrow depression) [1] .
Notes
- ↑ 1 2 3 4 5 6 7 8 9 10 11 Search the database of drugs, search options: INN - Daunorubicin , the flags “Search in the register of registered drugs” , “Search TKFS” , “Show drug forms” unspecified . Circulation of drugs . Federal State Institution “Scientific Center for Expertise of Medical Devices” of the Russian Healthcare Supervision Authority of the Russian Federation (03/27/2008). - A typical clinical and pharmacological article is a by-law and is not protected by copyright in accordance with part four of the Civil Code of the Russian Federation No. 230-FZ of December 18, 2006. Date of treatment May 20, 2008. Archived on August 22, 2011.
- ↑ 1 2 3 4 5 6 Daunorubicin . Register of medicines . ReLeS.ru (04.24.2002). Date of treatment May 20, 2008. Archived on August 25, 2011.
- ↑ Daunorubicin . Encyclopedia of medicines and pharmaceutical products . Radar Patent. - Instruction, application and formula.
- ↑ Arcamone, F. Doxorubicin = Doxorubicin. - London: Academic Press, 1981. - ISBN 0-12-059280-0 .
- ↑ Daunorubicin hydrochloride = Daunorubicin hydrochloride // European Pharmacopoeia. Fifth Edition: Monograph. - 2005 .-- S. 1389-1390 . (inaccessible link)