Cyclophosphamide

Cyclophosphamide is well adsorbed in the gastrointestinal tract, has minimal protein-binding capacity. Active and inactive metabolites of cyclophosphamide are eliminated by the kidneys. The half-life of the drug is about 7 hours, the peak concentration in the blood serum occurs 1 hour after administration.

Impaired renal function may lead to increased immunosuppressive and toxic activity of the drug.

Actin metabolites of cyclophosphamide affect all rapidly dividing cells, especially those in the S phase of the cell cycle. One of the important metabolites of cyclophosphamide is acrolein, the formation of which causes toxic damage to the urinary bladder.

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Cyclophosphamide treatment tactics

There are two basic treatment regimens for cyclophosphamide: oral administration at a dose of 1-2 mg/kg per day and bolus intermittent intravenous administration of high doses (pulse therapy) of the drug at a dose of 500-1000 mg/m2 ^during the first 3-6 months monthly, and then once every 3 months for 2 years or more. With both treatment regimens, it is necessary to maintain the white blood cell count in patients within 4000 mm3 ^. Cyclophosphamide treatment (except for rheumatoid arthritis) is usually combined with moderate or high doses of glucocorticosteroids, including pulse therapy.

Both treatment regimens are approximately equally effective, but with intermittent intravenous administration, the frequency of toxic reactions is lower than with continuous oral administration, but the latter fact has been proven only in lupus nephritis. At the same time, there is evidence that in patients with Wegener's granulomatosis, pulse therapy and oral cyclophosphamide are equally effective only in terms of short-term results, but long-term remission can only be achieved with long-term oral daily administration of the drug. Thus, pulse therapy differs from long-term administration of low doses of cyclophosphamide in its therapeutic profile. In some cases, oral administration of low doses of cyclophosphamide has advantages over intermittent administration of high doses. For example, in the induction phase, the risk of bone marrow suppression is higher in patients treated with pulse therapy compared to patients who receive low doses of cyclophosphamide. Since the true change in the peripheral blood leukocyte count after pulse therapy becomes apparent after 10-20 days, the cyclophosphamide dose can be modified only after a month, while with daily administration of the drug, the cyclophosphamide dose can be selected based on continuous monitoring of the peripheral blood leukocyte count and changes in renal function. The risk of toxic reactions in the early stages of treatment with high doses of cyclophosphamide is especially high in patients with dysfunction of many organs, rapid progression of renal failure, intestinal ischemia, and in patients receiving high doses of glucocorticosteroids.

During treatment with cyclophosphamide, it is extremely important to carefully monitor laboratory parameters. At the beginning of treatment, a complete blood count, determination of the level of platelets and urinary sediment should be carried out every 7-14 days, and when the process and the dose of the drug are stabilized - every 2-3 months.

How does cyclophosphamide work?

Cyclophosphamide has the ability to influence various stages of the cellular and humoral immune response. It causes:

• absolute T- and B-lymphopenia with predominant elimination of B-lymphocytes;
• suppression of lymphocyte blast transformation in response to antigenic, but not mitogenic, stimuli;
• inhibition of antibody synthesis and cutaneous delayed hypersensitivity;
• decreased levels of immunoglobulins, development of hypogammaglobulinemia;
• suppression of the functional activity of B-lymphocytes in vitro.

However, along with immunosuppression, an immunostimulating effect of cyclophosphamide has been described, which is believed to be associated with different sensitivities of T- and B-lymphocytes to the effects of the drug. The effects of cyclophosphamide on the immune system depend to a certain extent on the characteristics of the therapy. For example, there is evidence that long-term continuous administration of low doses of cyclophosphamide causes depression of cellular immunity to a greater extent, while intermittent administration of high doses is associated primarily with suppression of humoral immunity. Recent experimental studies on spontaneously developing autoimmune diseases performed on transgenic mice have shown that cyclophosphamide has an unequal effect on various subpopulations of T-lymphocytes that control the synthesis of antibodies and autoantibodies. It has been established that cyclophosphamide suppresses Th1-dependent immune reactions to a greater extent than Th2-dependent ones, which explains the reasons for the more pronounced suppression of autoantibody synthesis during cyclophosphamide treatment in autoimmune diseases.

Clinical application

Cyclophosphamide is widely used in the treatment of various rheumatic diseases:

• Systemic lupus erythematosus. glomerulonephritis, thrombocytopenia, pneumonitis, cerebrovasculitis, myositis.
• Systemic vasculitis: Wegener's granulomatosis, periarteritis nodosa, Takayasu's disease, Churg-Strauss syndrome, essential mixed cryolobulinemia, Behcet's disease, hemorrhagic vasculitis, rheumatoid vasculitis.
• Rheumatoid arthritis.
• Idiopathic inflammatory myopathies.
• Systemic scleroderma.

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Side effects

Potentially reversible:

• Suppression of bone marrow hematopoiesis (leukopenia, thrombocytopenia, pancytopenia).
• Bladder damage (hemorrhagic cystitis).
• Gastrointestinal tract damage (nausea, vomiting, diarrhea, abdominal pain).
• Intercurrent infections.
• Alopecia.

Potentially irreversible:

• Carcinogenesis.
• Infertility.
• Severe infectious complications.
• Cardiotoxic effects.
• Interstitial pulmonary fibrosis.
• Liver necrosis.

The most common complication that occurs during cyclophosphamide treatment is hemorrhagic cystitis, the development of which is described in almost 30% of patients. The frequency of hemorrhagic cystitis is somewhat lower with parenteral than oral administration of cyclophosphamide. Although hemorrhagic cystitis is considered a reversible complication, in some cases it precedes the development of fibrosis and even bladder cancer. To prevent hemorrhagic cystitis, it is recommended to take mesna, a detoxifying agent that reduces the risk of hemorrhagic cystitis caused by cyclophosphamide.

The active component of mesna is the synthetic sulfhydryl substance 2-mercaptoethanesulfonate. It is produced in the form of a sterile solution containing 100 mg/ml mesna and 0.025 mg/ml edetate (pH 6.6-8.5). After intravenous administration, mesna is very quickly oxidized to its main metabolite mesna disulfide (dimesna), which is eliminated by the kidneys. In the kidneys, mesna disulfide is reduced to free thiol groups (mesna), which have the ability to chemically react with urotoxic metabolites of cyclophosphamide - acrolein and 4-hydroxycyclophosphamide.

Mesna is administered intravenously at 20% of the cyclophosphamide dose (volume/volume) before and 4 and 8 hours after cyclophosphamide administration. The total mesna dose is 60% of the cyclophosphamide dose.