mesna and trofosfamide

The development of the oxazaphosphorine cytostatics cyclophosphamide, ifosfamide, and trofosfamide was based on the idea of applying the transport form/active form principle to the highly reactive nitrogen mustard group. A critical analysis and synopsis of the available results and knowledge will include examination of the extent to which the hypotheses on which this concept is based have been confirmed by experimental and clinical findings: 1. Chemical synthesis succeeded in converting the reactive nitrogen mustard into an inactive transport form (latentiation). 2. The requirement that the transport form be enzymatically activated to the active form in the target organ (the cancer cell) has been achieved by a sequence of metabolic reactions. 3. The aim of considerably increasing the therapeutic index of alkylating agents has been achieved by the oxazaphosphorine cytostatics. The greater cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. 4. The cancerotoxic selectivity of oxazaphosphorines was further increased when mesna was introduced as a regional uroprotector. Mesna eliminates the risk of therapy-limiting urotoxic side effects of oxazaphosphorines. With mesna protection, these cytostatics can be given in higher doses with increased safety, and their therapeutic efficacy can be enhanced. 5. Stabilization of the primary oxazaphosphorines, e.g., by attaching 2-mercaptoethanesulfonic acid (mafosfamide), opens up new possibilities in preclinical investigations and in therapy, e.g., for the clonogenic stem cell assay, for in vitro purging in autologous bone marrow transplantation, for regional perfusion of tumors, and, in small doses, for immunomodulation, where appropriate, in conjunction with "biological response modifiers."

Topics: Cyclophosphamide; Humans; Ifosfamide; Mesna; Organ Specificity

The bioavailability of orally administered sodium 2-mercaptoethane sulfonate (mesna, Uromitexan drink ampoules) was tested in 18 healthy probands and in 5 tumor patients. Following single oral administration of 20 or 40 mg/kg mesna, 52.4% and 52.6%, respectively, of the dose were excreted in the urine as reactive thiol groups, the remainder as mesna disulfide (dimesna), the only metabolite of mesna; after i.v. injection of 20 mg/kg mesna, 48.7% of the dose administered appeared as thiol groups in the urine. Not until after 13.1 h (20 mg/kg p.o.) and 18.5 h (40 mg/kg p.o.), respectively, concentration drops below the minimum concentration of 100 micrograms/ml presumed to be still reliably protective. However, the elimination pattern and the time when the threshold concentration is reached are subject to marked individual variation. After i.v. administration of 20 mg/kg mesna and 9 times oral administration of 20 mg/kg mesna (the first dose concurrently with the i.v. injection, thereafter every 4 h), or 7 times oral administration of 20 mg/kg mesna (the first dose again concurrently with the i.v. injection, thereafter every 5 h), the percentage of the total dose administered appearing as thiol groups in the urine averaged 41.9% and 37.6%, respectively, up to 17 or 18 h after the last dose. Comparison of periods covering the same time of the day showed the total amount excreted to be higher on day 2 than on day 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Antineoplastic Agents; Biological Availability; Cyclophosphamide; Humans; Ifosfamide; Injections, Intravenous; Male; Mercaptoethanol; Mesna

Urotoxic side effects, especially hemorrhagic cystitis, have so far been a limiting factor in the therapeutic use of cyclophosphamide (Endoxan), ifosfamide (Holoxan), and trofosfamide (Ixoten). The uroprotective agent mesna (Uromitexan) allows regional detoxification in the kidney and the urinary tract, and thus clinical prevention of the urotoxic side effects of the above cytostatics. The uroprotective mechanism of mesna is based on the formation of nontoxic additive compounds with acrolein and 4-hydroxy-metabolites. In the body, mesna is rapidly transformed into its biologically inert disulfide. After glomerular filtration mesna disulfide is rapidly reduced by reacting with the glutathion system and elimination in the urine as a free thiol compound, further detoxifying the aggressive oxazaphosphorine metabolites.

Topics: Animals; Cyclophosphamide; Cystitis; Female; Ifosfamide; Kidney; Mercaptoethanol; Mesna; Rats; Urinary Bladder

Topics: Animals; Antidotes; Carcinosarcoma; Cyclophosphamide; Ifosfamide; Mercaptoethanol; Mesna; Phosphoramide Mustards; Rats; Urine