|Company Name:||J & K SCIENTIFIC LTD. |
|Cytarabine Chemical Properties|
|Cytarabine Usage And Synthesis|
|Antiviral drugs||Cytarabine is a kind of purine nucleoside-class antiviral chemical synthesis that initially extracted from the medium of streptomyces, and then produced from chemical synthesis. It is a white crystalline powder and is very slightly soluble in water. Its monophosphate ester is easily soluble in water. It has inhibitory effect on various kinds of DNA virus such as Herpes simplex virus HSV1 and HSV2, hepatitis B virus, varicella-zoster virus and cytomegalovirus however has no effect on the smallpox virus, adenovirus, and other kinds of DNA or RNA viruses, bacteria and fungi. The exact mechanism of the antiviral effect of cytarabine is currently not fully understood. The mechanism is primarily related to inhibition of viral replication. The drugs and their metabolites can inhibit the viral DNA synthesis through inhibiting viral DNA polymerase while only a very small amount of the drug itself is incorporated into the viral DNA molecule. In the human body, the antiviral effect of the drugs only partially depends on the host immune function with drugs having no immunosuppression effect. Upon intravenous administration in vivo, 75% to 87% of the drug quickly deaminized into arabinose hypoxanthine through the action of deadenylated deoxygenase, Arabinose hypoxanthine has a significant lower antiviral activity than the prototype, and is rapidly distributed in some parts of the tissues; administer 10 mg of drugs per kg of body weight; the peak value of the plasma concentration of arabinose hypoxanthine is 3 ~ 6μ/ml while the peak value of plasma concentration of vidarabine is 0.2 ~ 0.4μg/ml. Arabinose hypoxanthine can penetrate through the blood-brain barrier with the cerebrospinal fluid drug concentrations being approximately 1/3 of plasma drug concentration. 41% to 53% of the daily dosage is excreted through urinary in the form of arabinose hypoxanthine. 1% to 3% is excreted out in the form of prototype. Cytarabine is clinically mainly used for the treatment of herpes simplex virus encephalitis as well as being used for treating the herpes zoster and chicken pox of immunosuppressed patients but is invalid in treating cytomegalovirus. It also has certain pharmacological activity of inhibition of hepatitis B virus replication. Topical medication is applied to the treatment of herpes simplex virus keratitis and occasionally used for treating vaccinia virus keratitis. |
The above information is edited by the Chemicalbook of Dai Xiongfeng.
|Anti-tumor drug||Cytarabine is currently one of the most effective drugs in clinical treatment of acute non-lymphatic myeloid leukaemia. It was first successfully synthesized in 1959 f, and is also presented in the sponge. In 1961, it was found that it has inhibitor effect on in mice S180 sarcoma and leukemia L1210. Cross resistance phenomenon was not observed in animal experiments for cytarabine being used in combination with conventional antineoplastic agents such as 6-thioguanine, methotrexate, prednisone, vincristine, mechlorethamine, cyclophosphamide, daunorubicin, methyl cellosolve acetate gag, fluorouracil and mercaptopurine. This drug belongs to pyrimidine-type anti-metabolite class of anti-tumor agents and having cell cycle specificity with s-phase cells being most sensitive to it. It interferes with the cell proliferation through inhibiting the intracellular DNA synthesis. After entering into the human body, cytarabine is converted into cytarabine triphosphate and cytarabine diphosphate through the phosphorylation reaction catalyzed by kinase. The former one can strongly inhibits the synthesis of DNA polymerase while the later one is capable of inhibiting the conversion between cytidine diphosphate to deoxycytidine diphosphate and thereby inhibiting the synthesis and polymerization of cellular DNA. However, its Inhibitory effect on RNA and protein synthesis is very slight. |
It is clinically mainly applied to the treatment of the induction stage and maintenance and consolidation phase of acute lymphoblastic leukemia and non-lymphocytic leukemia, the acute transformation phase of chronic myeloid leukemia and malignant lymphoma. In ophthalmology, it is for the treatment of viral conjunctivitis and epidemic keratitis. It also has certain efficacy in the treatment of head and neck cancer, gastrointestinal cancer and lung cancer; In addition, the drug also has inhibitory effect on the proliferation of herpes simplex virus, smallpox virus, and vaccinia virus as well as the immune response of the body.
|Pharmacokinetics||The oral administration of drugs yield a low absorption amount, and is also extremely easy to get deaminated and lose function in the action of the cytosine deaminase in the gastrointestinal tract and liver. Therefore, it is not recommended to subject to oral administration. It can be absorbed through intravenous, subcutaneous, intramuscular or intrathecal injection. After intravenous injection, it can be widely distributed in the body fluids, tissues and cells. After intravenous infusion of the drug, there is a moderate amount of drugs which can penetrate through the blood - brain barrier with the cerebrospinal fluid drug concentration being about 40% of the plasma concentration. The drug is mainly metabolized in tissues such as liver and kidney. It is quickly deaminated by the cytosine deaminase to form the inactive uracil arabinoside. In the cerebrospinal fluid, due to relative low content of the deaminase, the domination reaction is very slow. For intravenous administration, the half-life of α-phase is 10 to 15 minutes, with beta phase being 2 to 2.5 hours; for intrathecal administration, the half-life can be extended to 11 hours. Within 24 hours, among the given drug, about 10% of drug is excreted through the kidney while the rest 90% is excreted in the form of uracil cytarabine.
|Dosing instructions||1. Upon administration of cytarabine, we should appropriately increase the fluid intake of the patient, so that the urine can be maintained basic. If necessary, the patient can also administer allopurinol in combination in order to prevent the increase of bleeding uric acid and uric acid nephropathy. |
2. Though it can cause severe adverse reactions such as nauseas and vomiting upon rapid intravenous injection, the drug has relative slight effect on bone marrow suppression which can be generally tolerated by the patients.
3. The intravenous infusion solution should be diluted to 0.5mg / ml.
4. The prepared injection solution can be stored on the at 4 ℃ (refrigerator) for about seven days. However, at room temperature, it can only be stored for 24 hours.
5. For intrathecal injection of drug, the diluted solution should be free of preservatives.
6. Upon adopting moderate dose or high-dose cytarabine for therapy, some patients may get severe adverse reaction in gastrointestinal and nervous system such as gastrointestinal ulcers, gastrointestinal cystic gas, necrotizing enterocolitis, peripheral neuropathy, brain or cerebellar dysfunction such as personality changes, hypotonia, epilepsy, lethargy, stupor, disorientation, nystagmus, dysarthria, and ataxia; Moreover, hemorrhagic conjunctivitis, skin rashes, hair loss, peeling, severe myocardial disease can also occur.
7. Upon the emergence of various kinds of serious adverse reactions, the drug administration should be discontinued immediately with taking effective measures immediately for treatment. Some patients can be given adrenocorticotropic hormone which may alleviate the adverse reactions caused by moderate-dose or high-dose cytarabine.
|Dosage||Adult Usage: |
1, the induction therapy of acute leukemia: often applied in combination with other chemotherapy drugs, 1 ~ 3mg / kg each time, intravenous infusion, q: 12h, continuously administer for 5 to 7 days. Repeat at a interval of 1 to 2 weeks.
2, Moderate, large reduction therapy: this is commonly used in the intensive treatment of refractory or relapsed acute leukemia or acute leukemia after remission. For moderate dose: administer 500 ~ 1000mg/m2 per time, intravenous infusion of 1 to 3 hours, q12h, 2 ~ 6 day as a course. Large doses means 1000 ~ 3000mg /m2 per time with similar usage as for moderate dosage. Owing to that the adverse reaction is enhanced with increased dose cytarabine, large doses mainly in turn negatively affect its efficacy, thereby it is now more in favor of moderate dosage protocol.
3, subcutaneous injection: 10mg/m2 per time, q12h, 14 ~ 21 as a course of treatment. If the symptom is not alleviated and the patient's condition allows, the treatment can be repeated for another course after 2 to 3 weeks. This protocol can be used for the treatment of myelodysplastic syndrome with increased amount of original cells, low proliferative leukemia, and acute non-lymphocytic leukemia of elderly patients.
4, intrathecal injection: for treating meningeal leukemia, administer 25 ~ 75 mg per time; together with 5 mg of dexamethasone; subject to intrathecal injection after using NS for dissolving; administer 1 or 2 times per week until the cerebrospinal fluid (CSF) examination becomes normal. For preventive medicine purpose, administer 1 time in every 4 to 8 weeks.
For children usage: acute leukemia induction therapy, 100mg / (m2 • d), continuously administer for 5 to 7 days.
|Adverse reactions||Digestive System: common adverse reactions include loss of appetite, nausea, vomiting, diarrhea, gastritis, stomatitis and gastrointestinal ulcers. Some patients get abnormal liver function, elevated level of bilirubin and aminotransferase. Large-dose treatment can cause significant liver dysfunction and jaundice; it can cause the occlusion of central vein of liver and vein of liver lobule, resulting in jaundice, hepatomegaly, ascites and hepatic encephalopathy. |
Blood system: bone marrow suppression increases with increased dose; exhibit as the decrease of leukopenia and thrombocytopenia.
Local reactions: pain at the infusion site and thrombophlebitis mostly disappear after stopping; there are still occasionally reactions such as itching and rashes; treatment of topical ophthalmic drugs can often cause temporary burning, itching and other mild irritation and can also cause tears, foreign body sensation, conjunctival hyperemia, superficial punctate keratitis, pain, photophobia and other reactions.
Central nervous system: occasional discomfort, fatigue, tremors, dizziness, hallucinations, psychotic symptoms and fuzzy sense. These adverse reactions are dose-related and usually disappear after stopping drug. Cases of headache and encephalopathy have also been reported with the later often being difficult for distinguish from protopathy disease can often occurs in the patients with liver and kidney dysfunction.
Overdose performance: when the daily administered cytarabine dose is higher than 20mg/kg, bone marrow suppression can occur; once overdose occur, the patients need to subject to close monitor of the blood system and changes in liver and kidney function .
Other adverse reactions: transient increase in alanine aminotransferase is often observed. Increase of serum total bilirubin also occurs occasionally. Dizziness, fever, hair loss, rash, etc., can also occur. Moreover, it can result in male reproductive dysfunction. Patients of allergy, pregnant women and lactating women should be disabled. Patients with decreased white blood cell count and decreased platelet counts decreased significantly, biliary tract disease, history of gout or urate kidney stones, and who have recently received cytotoxic drugs or radiation therapy, as well as with liver and kidney dysfunction should take with caution.
|Function||Ara-C inserts into DNA, and forms complex with topoisomerase I (topoisomerase I) to inhibit DNA replication, causing DNA cleavage. It can’t inhibit RNA synthesis. It can be used as anti-leukemia substance for being used in various types of acute leukemia.
|Acute toxicity||Oral - rat: LD50> 5000 mg / kg; Oral - Mouse LD50: 3150 mg / kg
|Stimulus data||Skin - people 45 mg/3 weeks, moderate, three weeks; eyes - people 105 mg / 7 days
Skin allergy agent
|Flammability hazard characteristics||Combustible; combustion produces toxic fumes of nitrogen oxides
|Usage||Used as an antineoplastic and antiviral. A selective inhibitro of DNA synthesis. Does not inhibit RNA synthesis|
|Usage||antineoplastic, antiviral, antimetabolite|
|Storage Characteristics||Treasury: ventilation, low-temperature and drying; store it separately from food raw materials
|Extinguishing agent||Dry powder, foam, sand, carbon dioxide, water spray
|General Description||Colorless crystals. Used as an antiviral agent.|
|Air & Water Reactions||Water soluble.|
|Health Hazard||ACUTE/CHRONIC HAZARDS: Very toxic. Hazardous decomposition products. May cause irritation on contact. Teratogen. Mutagen. Central nervous system effects.|
|Cytarabine Preparation Products And Raw materials|