Cyclophosphamide

Cyclophosphamide is a member of the nitrogen mustard agent family. Most of the orally ingested drug is resorbed (75 %) and readily distributed throughout the body. In the liver cyclo-phosphamide is metabolized into the cytotoxic agents phosphoramide mustard and hydroxy-

cyclophosphamide [9]. These metabolites crosslink DNA, RNA and cellular proteins, thus ultimately leading to cytotoxicity. Although primarily secreted unaltered through the kidney, the metabolite acrolein is considered to be involved in the development of bladder toxicity [10]. Therefore mesna (sodium 2-mercap-toethane sulphonate) should be given to reduce the risk of haemorrhagic cystitis [9]. Cyclophosphamide inhibits T- and B-cell functions, resulting in reduced delayed type hypersensi-tivity (DTH) reaction as well as reduced antibody responses [72].

Treatment indication for cyclophosphamide is the inflammatory involvement of retina and choroid in Behçet's disease. Cyclophosphamide has been shown to be effective and to be superior to corticosteroids or chlorambucil [33 60].

Serpiginous choroiditis is a sight-threatening disease when choriodal lesions develop in or close to the macula. Treatment with steroids is effective in controlling active inflammation and may reduce lesion size,but there is evidence that steroids fail to prevent relapses [12]; moreover, even cyclosporine may not completely avoid recurrences (summarized in [2]). Therefore more aggressive immunosuppression with low-dose cyclophosphamide (50-200 mg/day) for up to 53 months has been employed successfully for the prevention of relapses [3]. Current recommendations limit the duration of therapy to 3-6 months due to the increasing risk of developing neoplasia and bone marrow toxicity. Even after cessation of treatment, some of these patients did not experience recurrences.

The recommended use of cyclophosphamide is the oral treatment with 1-2 mg/kg/day, which may be increased to 3-4 mg/kg/day for several weeks in selected, severe cases only. Dose must be adjusted to renal and ocular function with close monitoring of leucopenia. For long-term treatment the dose is adapted to the therapeutic response as well as the leucocyte count, which should be maintained above 3,500 cells/ml. The patients are ordered to take their dose in the morning and to drink 2-31 of beverage daily to maintain frequent voiding. The intravenous administration is indicated in cases with severe inflammation, like patients with occlusive retinal vasculitis associated with Behçet's disease where a fast onset of therapeutic effect is important to preserve visual acuity. In addition, it reduces the exposure of acrolein to the bladder and induces only transient leucopenia. Every 3-4 weeks a bolus of 15-20 mg/kg (or 1 g/m2 body surface) is given, with concomitant application of mesna to protect the bladder from toxicity.

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