Cyclophosphamide

Cyclophosphamide is well adsorbed in the gastrointestinal tract, has a minimal protein-binding ability. 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.

Violation of kidney function can lead to an increase in immunosuppressive and toxic activity of the drug.

Actin metabolites of cyclophosphamide affect all fast-growing 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 bladder.

[1], [2], [3], [4], [5]

Treatment with cyclophosphamide

There are two principal 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 / m ² for the first 3-6 months on a monthly basis, and then 1 time in 3 months for 2 years or more. In both treatment regimens, it is necessary to maintain the leukocyte level in patients within 4000 mm ³. Typically, treatment with cyclophosphamide (with the exception of rheumatoid arthritis) is combined with the administration of moderate or high doses of glucocorticosteroids, including pulse therapy.

Both treatment schemes are approximately equally effective, but against the background of intermittent intravenous administration, the frequency of toxic reactions is less than with a constant oral intake, but the latter fact is proved only with lupus nephritis. At the same time, there is evidence that in patients with Wegener's granulomatosis, pulsic therapy and oral administration of cyclophosphamide are equally effective only for the immediate results, but prolonged remission can be achieved only with prolonged oral daily intake of the drug. Thus, pulse therapy is different from long-term administration of low doses of cyclophosphamide to the therapeutic profile. In some cases, oral administration of low doses of cyclophosphamide has advantages over intermittent administration of high doses. For example, during the induction phase, the risk of bone marrow suppression is higher in patients treated with Pulse therapy than in patients who receive low doses of cyclophosphamide. Since the true change in the number of leukocytes in the peripheral blood after pulse therapy becomes evident after 10-20 days, the dose of cyclophosphamide can be modified only after a month, whereas with daily administration of the drug the dose of cyclophosphamide can be selected on the basis of constant control of the level of leukocytes in peripheral blood and change in kidney function. The risk of toxic reactions in the early treatment with high doses of cyclophosphamide is especially great in patients with impaired functions of many organs, rapid progression of renal failure, intestinal ischemia, and also in patients receiving high doses of glucocorticosteroids.

In the process of treatment with cyclophosphamide, it is extremely important to carefully monitor laboratory parameters. At the beginning of the treatment, a general blood test, determination of platelet and urinary sediment level should be performed every 7-14 days, and with stabilization of the process and dose of the drug - every 2 3 months.

How does cyclophosphamide work?

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

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

However, along with immunosuppression, the immunostimulating effect of cyclophosphamide has been described, which is thought to be associated with different sensitivity of T and B lymphocytes to the effect of the drug. The effects of cyclophosphamide on the immunity system and to a certain extent depend on the characteristics of therapy. For example, there is evidence that a long continuous intake of low doses of cyclophosphamide causes a greater degree of depression of cellular immunity, intermittent administration of high doses is associated, first of all, with suppression of humoral immunity. In recent experimental studies on spontaneously developing autoimmune diseases performed on transgenic mice, cyclophosphamide has been shown to affect, in varying degrees, different subpopulations of T lymphocytes that control the synthesis of antibodies and autoantibodies. It was found that cyclophosphamide more strongly suppresses Th1-dependent Th2-dependent immune responses, which explains the reasons for more pronounced suppression of the synthesis of autoantibodies against the background of cyclophosphamide treatment in autoimmune diseases.

Clinical use

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

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

[6], [7], [8], [9], [10], [11], [12]

Side effects

Potentially reversible:

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

Potentially irreversible:

• Carcinogenesis.
• Infertility.
• Severe infectious complications.
• Cardiotoxic effects.
• Interstitial pulmonary fibrosis.
• Necrosis of the liver.

The most common complication arising from the treatment of cyclophosphamide is hemorrhagic cystitis, the development of which has been described in almost 30% of patients. The frequency of hemorrhagic cystitis is somewhat less on the background of parenteral than oral administration of cyclophosphamide. Although hemorrhagic cystitis is referred to as reversible complications, in some cases it precedes the development of fibrosis and even cancer of the bladder. For the prevention of hemorrhagic cystitis, the use of mesna, a detoxifying agent, is recommended that reduces the risk of hemorrhagic cystitis caused by cyclophosphamide.

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

Mesna is administered intravenously in an amount equal to 20% of the dose of cyclophosphamide (volume / volume), before and after 4 and 8 hours after taking cyclophosphamide. The total dose of mesna is 60% of the dose of cyclophosphamide.