The reasons for the unique selective effect of busulfan on granulocytopoiesis not been fully established. Although the drug does not allow to achieve cure, but it significantly reduces the total number of granulocytes and results in relief of symptoms and improvement of the general condition of patients. Therapy sustanon 250 cycle busulfan was more effective than irradiation spleen on such criteria as the survival and maintain the hemoglobin level; the effectiveness of both methods did not differ in their effect on spleen size.
The half-life was 3.4 hours after the first dose, and 2.3 hours after the last dose. These data suggest that the busulfan may increase the speed of its own metabolism with repeated use.
Stationary busulfan plasma concentration range from 0.5 to 2.0 micrograms / ml (8.2 mM). Sustanon 250 cycle plasma concentrations were 3,1-5,9 mg / ml in a patient who received a total dose of 16 mg / kg, and 3,8-9,7 mg / ml in two patients who received a total dose of 20 mg / kg.
Patients receiving high doses of busulfan and its metabolites were detected in urine 3-gidroksisulfolan, tetrahydrothiophene-1-oxide and sulfolane. A small amount of the drug (1-2%) is excreted in the urine in unchanged form.
When administered in high doses busulfan penetrates into the cerebrospinal fluid, where its concentration is comparable to plasma. Value busulfan concentrations in plasma and cerebrospinal fluid averaged 1.3: 1. Value for busulfan concentrations in saliva and plasma is 1.1:. 1
degree reversible binding to plasma proteins varies from negligible to 55%. The degree of irreversible binding to blood cells and plasma proteins is 47% and 32%.
busulfan is used for the palliative treatment of chronic myeloid leukemia in the chronic phase of the disease.
Busulfan cause long-term remission in polycythemia vera, especially occurring with marked thrombocytosis.
Busulfan may be effective in some cases in essential thrombocythemia and myelofibrosis.
- patients with previously identified resistance to busulfan;
- patients with hypersensitivity to any component of the formulation.
DOSAGE AND ADMINISTRATION
busulfan usually prescribed courses or permanently. Dose picked individually for each patient depending on the clinical condition and hematological parameters. If the patient requires the dose less than 2 mg / day (less than one tablet), a drug may be administered every day, and at intervals of one or more days. Share tablet into parts is impossible. Chronic myelogenous leukemia. The induction of remission in adults : Treatment is usually started immediately after diagnosis. The dose is 0.06 mg / kg / day; maximum starting dose is 4 mg / day, it can be administered in one step. Individual reaction to busulfan is variable; some patients can be high sensitivity of bone marrow cells to the drug. During remission induction control blood tests should be carried out at least once a week. The dose should only be increased in the absence of the desired effect after 3 weeks of treatment. The treatment should continue as long as the total number of cells decreases to 15-25h10 9 / L (typically within 12-20 weeks). Then treatment can be interrupted; then for a further 2 weeks further decrease the number of leukocytes can occur. Continued treatment in an induction dose after this point or after the platelet count of less than 100×10 9 / L accompanied by a significant risk of prolonged and possibly irreversible bone marrow aplasia. Maintenance therapy in adults . Long-term remission of leukemia can be achieved without further therapy busulfan; additional courses of treatment is usually carried out by increasing the number of leukocytes before 50h10 9 / L or when the symptoms of the disease. Some experts prefer to carry out continuous maintenance therapy. Continuous treatment is more grounded with a short duration of remission. The goal of treatment – to support the number sustanon 250 cycle of leukocytes at 10-15h10 9 / L; the number of blood cells should be monitored at least once every 4 weeks. Usually, a maintenance dose of 0.5-2 mg / day, but in individual cases it may be considerably lower. NOTE : busulfan should be administered at lower doses, if it is used in combination with other cytotoxic agents. Child . Chronic myeloid leukemia in children is rare. Busulfan may be used for the treatment of leukemia with the Philadelphia chromosome (Ph’-positive). Juvenile Ph’-negative variant on busulfan therapy responds poorly. Polycythemia vera . Generally, the dose is 4-6 mg / day; treatment is carried out for 4-6 weeks under careful control of blood cells especially platelets. With the development of relapses can be resumed course therapy or may alternatively be held in a maintenance therapy dose of about half of the induction dose. If the treatment is mainly carried polycythemia by venesection, is to monitor the number of platelets short courses. can be assigned Myelofibrosis . Typically, the initial dose is 2-4 mg / day. busulfan Careful monitoring of hematological parameters, given the very high sensitivity of bone marrow cells in myelofibrosis. Essential thrombocythemia . Generally, the dose is 2-4 mg / day. Treatment should be discontinued if the total number of white blood cells is reduced less than 5×10 9 / l or a platelet count of less than 500h10 9 / l.
In relation to this drug is no modern clinical data that could be used to determine the frequency of side effects. The incidence of side effects may vary depending on the dose received by the patient busulfan, as well as used in combination with the other preparations.
Histological features include atypical changes in the epithelium of the alveoli and bronchioles and the presence of giant cells with large nuclei giperhromaticheskimi. In case of a toxic lung disease prognosis despite the abolition of busulfan unfavorable, in this situation, use of corticosteroids is not enough.Interstitial pulmonary fibrosis usually develops gradually, but may have a sharp current. This pathology may be complicated by pulmonary infection. Described as ossification and dystrophic calcification of the lungs. It is possible that subsequent radiotherapy can enhance subclinical lung damage caused by busulfan. Other cytotoxic agents may cause additive lung toxicity defeat. On the part of the gastrointestinal tract : Very common: nausea, vomiting, diarrhea and ulceration of the oral mucosa when using high doses of busulfan. Probably the symptoms can be alleviated by the use of fractional doses. Hepatobiliary disorders : Very frequent: hyperbilirubinemia, jaundice, hepatic vein occlusion and tsentrolobulyarny sinusoidal fibrosis with hepatocellular atrophy and necrosis at high doses; Rare:. cholestatic jaundice and abnormal liver function with conventional doses tsentrolobulyarny sinusoidal fibrosis is believed that in the usual therapeutic doses of busulfan has no significant toxic effect on the liver. However, a retrospective analysis of pathological data of patients who received low-dose sustanon 250 cycle busulfan for at least two years for chronic granulocytic leukemia, revealed the presence of tsentrolobulyarnogo sinusoidal fibrosis. The combination of busulfan and thioguanine has a strong toxic effect on the liver. Skin and subcutaneous tissue disorders : frequent: alopecia at high-dose treatment, hyperpigmentation;Rare: Alopecia at conventional dose, skin reactions including urticaria, multiforme erythema, erythema nodosum, porphyria cutanea tarda, rash allopurinolovogo type, as well as excessive dryness and skin fragility full anhidrosis, dryness of the oral mucous membranes and cheilosis, Sjogren’s syndrome. More pronounced ray skin changes in patients receiving radiotherapy soon after high-dose busulfan treatment. There are cases of hyperpigmentation, particularly in dark-skinned patients. Often, it is most pronounced in the neck, upper trunk, nipples, abdomen and on the palmar creases. Hyperpigmentation can be part of a clinical syndrome. On the part of the kidney and urinary tract infections : Frequent: hemorrhagic cystitis in the treatment of high dose in combination with cyclophosphamide. Reproductive system and breast : very common: inhibition of ovarian function and amenorrhea with the symptoms of menopause in patients premenopausal in the treatment of high doses; severe and persistent ovarian failure, including the lack of puberty after administration of high doses of young women and girls who have not reached adolescence. Sterility, azoospermia and testicular atrophy in men receiving busulfan;infrequent: inhibition of ovarian function and amenorrhoea with menopausal symptoms in pre-menopausal patients at conventional dose treatment. In very rare cases, recovery of ovarian function were observed with continued treatment; very rare: gynecomastia Research busulfan in animal studies revealed its toxic effects on the reproductive system. Violations of the general : very rare: Clinical syndrome (weakness, severe fatigue, anorexia, weight loss, nausea and vomiting, skin hyperpigmentation) resembling adrenal insufficiency (Addison’s disease) but without biochemical evidence of adrenal suppression, mucous membrane hyperpigmentation and hair loss; rare: common epithelial dysplasia. (observed in rare cases after prolonged busulfan therapy). This syndrome is sometimes disappearing after the abolition of busulfan. In patients treated with busulfan, found numerous histological and cytological changes, including widespread dysplasia of cervical epithelium, the epithelium of bronchi and other sites. In most cases such changes occur in the results of long-term therapy, however transient anomaly described epithelium and after short-term treatment with high doses.
Overdose Symptoms : the manifestation of acute dose-limiting toxicity of busulfan in man is myelosuppression. If busulfan used at the high dose in combination with bone marrow transplantation, the dose-limiting factor is the toxic effect on the gastrointestinal tract with lesions of the mucous membranes, nausea, vomiting, diarrhea and anorexia. The main manifestation of chronic drug overdose – inhibition of bone marrow function and pancytopenia. Treatment : antidote is unknown. Information on the possible effectiveness of dialysis there. In the presence of signs of toxic effects on hematopoiesis conduct appropriate symptomatic therapy.
INTERACTION WITH OTHER DRUGS
A combination of busulfan with other cytotoxic drugs pulmonotoksichnymi may enhance toxic sustanon 250 cycle effects on lung tissue.
The appointment of phenytoin to patients receiving high-dose busulfan may result in a reduction of the effect of the latter.
The simultaneous use of busulfan and itraconazole may reduce the clearance of busulfan.
Cautions busulfan is a cytotoxic agent which should only be used under the supervision of physicians experienced in the use of these drugs. In the intact outer shell of the use of busulfan tablets do not pose a risk. Tablets should not be divided into parts. When using busulfan tablets should comply with the recommendations for the use of cytotoxic drugs. Busulfan should abolish the appearance of signs of toxic effects on lung tissue. Typically, busulfan not used in combination with radiotherapy or shortly after a course of radiotherapy. Busulfan is not effective under blast transformation. If patients with possible toxic lesions of the lungs in need of general anesthesia, the concentration of inspired oxygen should be kept at the lowest safe level; in the postoperative period is necessary to carefully monitor and maintain respiratory function. In patients with CML often marked hyperuricemia and / or hyperuricosuria that should be removed prior to administration of busulfan. During treatment with busulfan necessary prevention of hyperuricemia and Uric acid nephropathy, including adequate fluid intake and the use of allopurinol. It should be very careful when using busulfan for the treatment of polycythemia vera and essential thrombocythemia, considering the carcinogenic properties of the drug. If these diseases are not recommended for busulfan in young patients or in the absence of symptoms. If the appointment of busulfan necessary, treatment courses should be as short as possible. In the treatment of patients with high doses of busulfan should take anticonvulsant drugs for prophylactic purposes; preferable to prescribe benzodiazepine than phenytoin. At the same time taking busulfan and itraconazole should carefully monitor the condition of a patient for the purpose of early detection of signs of busulfan toxicity. Monitoring the . During treatment with busulfan should be regularly monitoring blood count in order to avoid severe myelosuppression and irreversible bone marrow aplasia. Mutagenic and carcinogenic properties . In patients treated with busulfan, a variety of chromosomal aberrations were observed. According to the WHO concluded there is a causal relationship between busulfan exposure and cancer development. In patients treated with busulfan for a long time, revealed widespread epithelial dysplasia; Some changes were similar to precancerous. Several patients receiving busulfan, cases of malignant tumors are described. There is evidence that the busulfan as other alkylating agents has leykozogennoe action. Although acute leukemia is probably a component of the natural history of polycythemia vera, prolonged alkylating agent therapy may increase the risk of its development. Teratogenic properties . Busulfan is teratogenic in animal studies, and has the potential teratogenic in humans. It described several cases of birth defects, which were not necessarily associated with busulfan; use of the drug in the third trimester of pregnancy may be associated with violation of fetal growth. At the same time, we know many cases of the birth of healthy children after exposure to busulfan in vivo, even during the first trimester of pregnancy. Fertility . In premenopausal women frequently observed the suppression of ovarian function and amenorrhoea with menopausal symptoms. In rare cases, recovery of ovarian function was noted in the continuation of treatment. Treatment with high-dose busulfan girls during childhood and adolescence, leading to ovarian failure, including the lack of puberty. Busulfan violates spermatogenesis in experimental animals; male sterility described cases, azoospermia, and testicular atrophy.
Pregnancy and lactation
As with any treatment with cytotoxic drugs, while taking busulfan any of the partners is necessary to comply with measures to prevent pregnancy.
It is possible to avoid the appointment of busulfan during pregnancy, especially during the first trimester. In each case it is necessary to assess the potential risk to the fetus and the expected benefit to the mother.
Women taking busulfan sustanon 250 cycle is not recommended to breastfeed.