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PubMed1975

[Quantitative determination of cyclophosphamide, ifosfamide, and trofosfamide and their stable metabolites on TLC-plates with the aid of 4-pyridine-aldehyde-2-benzothiazolyl-hydrazone (PBH) (author's transl)].

Cyclophosphamide, ifosfamide, and trofosfamide can be analysed quantitatively together with their stable alkylating urine metabolites on TL-plates by means of the PBH-reagent (4-pyridine-aldehyde-2-benzothiazolyl-hydrazone). The method requires only 0.01 ml urine, but a careful standardisation is necessary by using reference substances. The minimum measurable amounts are between 0.25 and 0.5 mug. In the urines of rat and man the carboxy derivatives and the dechloroethyl derivatives, respectively, resulting from side chain oxidation, are predominant next to cyclophosphamide, ifosfamide, or trofosfamide, respectively. Side chain oxidation can be prevalent, as we have found in some patients treated with ifosfamide. The method described allows not only the calculation of time functions for the excretion of PBH-reactive substances but also in vitro investigations of the chemokinetic properties of cyclophosphamide derivatives under physiological conditions.

Animals↗
PubMedDate not supplied

[Transfection of eucaryotic cells using cytochrome CYP450 2B6 gene: sensitivity to cyclophosphamide].

Sensitivity of 293 human epithelial kidney cells transfected by human cytochrome CYP450 gene to cyclophosphamide was investigated. Transfection was carried out by plasmid DNA containing CYP2B6 gene complexed with cationic liposomes. Liposomes were prepared from mixture of cationic lipids and cholesterol at different molar ratios. Experimental protocol included the following steps: transfection of epithelial kidney cells by complexes of plasmid DNA-cationic liposomes, clone selection in the medium with antibiotic Geneticin G418, selected clone harvesting and their treatment by cyclophosphamide as following cytotoxicity evaluation. It was shown that addition of 0.25 mM of cyclophosphamide resulted in death of 40-45% transfected cell population.

Antineoplastic Agents, Alkylating↗
PubMed2002

Does cyclophosphamide benefit relapsing thrombotic thrombocytopenic purpura?

Thrombotic thrombocytopenic purpura (TTP) is a rare disease. A high index of suspicion is required for early diagnosis and treatment. It can present in acute as well as chronic forms. Cyclophosphamide has been reported to be beneficial in relapsing TTP. Herein a case of acute TTP evolving into relapsing phase of the disease is presented. Cyclophosphamide in our case achieved partial remission without the need for plasma exchange therapy. The rationale of cyclophosphamide in management of relapsing TTP is discussed.

Adult↗
PubMed1976

[Ifosfamide in comparison with cyclophosphamide in advanced ovarian carcinomas (author's transl)].

Ifosfamide or cyclophosphamide was employed in an alternating series in 49 advanced ovarian carcinomas. The two cytostatic drugs were given in single massive doses. In primary inoperable ovarian carcinomas at stage III and IV a partial remission occurred in 8 of 19 cases (42%) after treatment with cyclophosphamide. Ifosfamide produced a partial or complete remission in 9 of 11 cases (82%). However, 3 patients treated by ifosfamide died within 3 weeks after the administration of the first massive dose. Regarding these cases as failures there was a remission in 9 of 14 cases (64%). Cyclophosphamide enabled a secondary radical operation in 7 of 19 (37%), ifosfamide in 6 of 14 cases (43%). The intervals between an exploratory laparotomy and the secondary radical operation were 5 months on the average for the two cytostatic drugs.

Cyclophosphamide↗
PubMed2002

[Effect of lysozyme on the growth of murine lymphoma and antineoplastic activity of cyclophosphamide].

It was shown that hen egg-white lysozyme (LM) in the dose 100 mg/kg under the daily intragastral use slightly inhibited tumor grown or did not influence significantly upon it and did not change antitumor activity of cyclophosphamide. When used at mice C57Bl/6J with the transplanted ascitic or solid T-cell lymphoma EL4 (syngeneic system). On model of the same tumors in ascitic form at mice-hybrids (C57Bl/6J x DBA2)F1 (semisingeneic system) LM significantly potentiates antitumor activity of cyclophosphamide, though it had no effect on the rate of tumor growth. Potentiation of the effect of cyclophosphamide revealed itself in more slow development of ascite, increased mean life-span and the overall survival, appearance of completely cured animals. Our clinic-laboratory studies have revealed a sharp deficit of endogenic lysozyme in the blood serum of leukemic patients and extremely low lysozyme content in lavage liquid, from leukemic patients, with pneumonia. These data suggest that LM can be useful as a food additive in the complex treatment of oncological patients for enhancing antineoplastic chemotherapy efficacy.

Animals↗
PubMed1976

Acquired resistance to ticks. II. Effects of Cyclophosphamide on resistance.

Guinea-pig developed resistance to Dermacentor andersoni larvae after one infestation. Cyclophosphamide administered in one dose (300 mg/kg) 48 hr prior to an initial infestation with larvae blocked the acquisition of resistance. When cyclophosphamide was given in a similar regimen to guinea-pigs which had already acquired resistance, the expressin of resistance was partially blocked. It was proposed that the blockage of the acquisition of resistance further confirmed the immunological nature of tick resistance. Partial blockage of the expression of resistance by cyclophosphamide substantiated the presence of a humoral component to the resistance mechanism. The presence of a cell-mediated component was previously well established.

Animals↗
PubMedDate not supplied

Gonadal changes in nephrological patients treated with cyclophosphamide.

Therapeutic use of immunosupressive drugs in progressive renal diseases has increased during the last decade. Information concerned severe gonadal damage after such therapy, stresses the need for careful evaluation in each particular case before deciding to use these drugs. Gonadal lesions were investigated in 18 patients who were treated with cyclophosphamide and in one who received chlorambucil at variable doses and length of time; there were frequent relapses in patients with idiopathic nephrotic syndrome and with progressive forms of glomerulonephritis. Nine patients were females and received cyclophosphamide therapy at the ages of 11 a 16 years, being evaluated from 11 to 22 years of age with vaginal smears, gonadotropins and 17-ketosteroids. No alterations were found in these parameters and two of the girls became pregnant and had successful deliveries of healthy babies. Ten patients were males; one of them received chlorambucil and all the others received cyclophosphamide at the ages of 8 to 15 years; they were evaluated from 9 to 19 years of age. Because of their ages, gonadal function was not studied in 3 children, but the other 7 showed azoospermia, testicular atrophy was present in four out of these patients in whom testicular biopsy was performed. The patient who received chlorambucil was among this group. From these results and from the literature, we conclude: 1) immunosuppressive therapy is less risky in girls than in boys; 2) it is imperative to evaluate the risk/benefit ratio before deciding this therapy in any case and 3) doses not above 2 mg/kg/day and for periods no longer than 6 weeks may be considered safe.

Adolescent↗
PubMed2003

Static and ELF magnetic fields enhance the in vivo anti-tumor efficacy of cis-platin against lewis lung carcinoma, but not of cyclophosphamide against B16 melanotic melanoma.

Previous works showed that exposure to static and extremely low frequency (ELF) magnetic fields (MF) over 3 mT slows down the growth kinetics of human tumors engrafted s.c. in immunodeficient mice, reducing their metastatizing power and prolonging mouse survival. In the experiments reported here, immunocompetent mice bearing murine Lewis Lung carcinomas (LLCs) or B16 melanotic melanomas were exposed to MF and treated respectively with two commonly used anti-cancer drugs: cis-diamminedichloroplatinum (cis-platin) and N,N-bis (2-chloroethyl)tetra-hydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide (cyclophosphamide). The experiment endpoint was survival time. The survival time of mice treated with cis-platin (3mg/kg i.p.) and exposed to MF was significantly (P<0.01) longer than that of mice treated only with cis-platin or only exposed to MF, superimposing that of mice treated with 10mg/kg i.p. of the drug, showing that MF act synergically with the pharmacological treatment. On the contrary, when mice treated with cyclophosphamide (50mg/kg i.p.) were exposed to MF no synergic effects were observed, the survival curve being exactly the same as that of mice treated with the drug alone. No clinical signs or toxicity were seen in any of the mice exposed to MF alone or along with cis-platin or cyclophosphamide treatment, compared to mice given only the two known drugs.A possible explanation for the synergic effect of MF being found in mice treated with cis-platin could be that the platinum ion stimulates radical production and that MF enhance active oxygen production bringing about changes in tumor cell membrane permeability, influencing positively the drug uptake. Alternatively, or in addition to this, it has been demonstrated that the rate of conversion of cis-platin to reactive species able to bind to DNA, is increased by localized production of free radicals by MF.

Animals↗
PubMed1976

Studies on 4-hydroperoxycyclophosphamide (NSC-181815): a simple preparation method and its application for the synthesis of a new class of "activated" sulfur-containing cyclophosphamide (NSC-26271) derivatives.

4-Hydroperoxycyclophosphamide was obtained in approximately 20% yield by ozonization of cyclophosphamide in acetone/water at 0 degrees C. It was reduced to 4-hydroxycyclophosphamide, which was treated with several mercaptans to yield compounds of the type 4-(S-R)-mercapto-cyclophosphamide. In the solid state these compounds are stable at room temperature; in aqueous solution they are hydrolyzed to 4-hydroxycyclophosphamide or its tautomer, aldophosphamide. One of the 4-(S-R)-mercapto-cyclophosphamide compounds was tested biologically in vitro against Yoshida ascites tumor cells and showed the same cytotoxic activity as 4-hydroxycyclophosphamide.

Alkylating Agents↗
PubMed1976

Aspects of the teratology of cyclophosphamide (NSC-26271).

Wistar-derived rat embryos were most sensitive to maternally administered cyclophosphamide on Days 9.5 and 10.5 of gestation and to chlorambucil on Day 9.5 of gestation. The spectrum of malformations and the dose-response behavior of both drugs were similar. Chlorambucil was three times more potent than cyclophosphamide on an mg/kg basis. The drugs showed additive behavior when administered in combination. The teratogenic effects of the individual or combined drugs were reduced by protective doses of cysteine or glutathione. Studies with analogs of cyclophosphamide have suggested that the whole molecule is involved in teratogenesis.

Abnormalities, Drug-Induced↗
PubMed2003

Efficacy of cisplatin and cyclophosphamide combination for recurrent and metastatic carcinoma of the uterine cervix.

The efficacy of a combination of cyclophosphamide and cisplatin in patients with metastatic and recurrent carcinoma of the cervix, was tested. Thirty patients were included in the study. Initially, 27 patients (90%) had received pelvic radiation and intracavitary boost and one patient was additionally given paraaortic radiation. Cisplatin was given at 75 mg/m2 followed by cyclophosphamide at 750 mg/m2 on day 1 with three weekly intervals for a maximum of six cycles. All patients received a median of four cycles of chemotherapy. The overall response rate for all eligible patients was 20% (continuous CR: 1, CR: 1, PR: 4 patients). Overall response rate and progressive response in patients with relapse within the previous radiation field were 9.5% and 66.7%, respectively; while for patients who had recurrent disease outside any irradiated area both were 44.4%. Eighteen patients (60%) had early withdrawal from the planned schedule, which was due to patient incompliance in seven patients (23.3%), disease progression in ten (33.3%) and early death after the first cycle in one patient (3.3%). Anemia was the most frequent toxicity, necessiating 24 transfusions in nine patients (30%). WHO grade 3 and 4 toxicity were anemia: 13 (43.3%), leucopenia: one (3.3%), thrombocytopenia: two (6.6%), renal: one, emesis: nine (30.0%) patients. The median survival duration for all eligible patients was 11 months. Univariate analysis revealed that progressive response to chemotherapy was the only prognostic factor for survival (7.1 vs 16.8 months, p = 0.003). The combination of cisplatin and cyclophosphamide did not appear to be more active than single agent cisplatin in this patient group with a relatively poor prognosis. Further studies are required to determine a better therapeutic approach for patients with relapsed carcinoma of the cervix.

Adenocarcinoma↗
PubMed2003

A Phase I study of docetaxel plus cyclophosphamide in solid tumors followed by a Phase II study as first-line therapy in metastatic breast cancer.

PURPOSE: In Phase I, the purpose was to determine the maximum tolerated dose and pharmacokinetics of docetaxel plus cyclophosphamide (DC) with and without granulocyte colony-stimulating factor in the treatment of patients with solid tumors. For Phase II, the purpose was to determine the safety and efficacy of this combination as first-line treatment in patients with metastatic breast cancer (MBC). EXPERIMENTAL DESIGN: In Phase I (45 patients), docetaxel was escalated from 60 mg/m(2) to 85 mg/m(2), and cyclophosphamide from 600 mg/m(2) to 800 mg/m(2). Pharmacokinetic evaluation of docetaxel was performed in 19 patients with MBC. In Phase II (34 patients), patients received cyclophosphamide (600 mg/m(2)) followed by docetaxel (75 mg/m(2)), i.v. RESULTS: In Phase I, the dose-limiting toxicity was neutropenia-related events. The maximum tolerated dose for DC was 75 mg/m(2)/700 mg/m(2) in solid tumor patients treated previously and 75 mg/m(2)/800 mg/m(2) for patients not treated previously for MBC. Dose escalation of docetaxel >75 mg/m(2) was not tolerated, despite prophylactic granulocyte colony-stimulating factor treatment. In Phase II, 71% of patients received prior anthracycline therapy. Neutropenic fever requiring i.v. antibiotics occurred in 6 patients (19%). One patient had grade 3 neuropathy. There was no cardiotoxicity. The overall Phase II intent-to-treat objective response rate was 65% (complete responses, 12%). The median overall survival was 22 months, and the median time to progression was 6 months. CONCLUSIONS: DC combination therapy is an active regimen with acceptable toxicity and is appropriate regardless of prior anthracycline therapy. In view of the high activity and lack of cardiotoxicity, this combination warrants additional investigation in early stage breast cancer and in combination with trastuzumab.

Adult↗
PubMed1992

Etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine for the treatment of metastatic, high-risk gestational trophoblastic disease.

OBJECTIVE: To evaluate the efficacy and toxicity of a regimen of etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine in patients with metastatic, high-risk gestational trophoblastic tumors. METHODS: Twelve women with metastatic gestational choriocarcinoma received 64 treatment cycles. All met the National Cancer Institute criteria for high-risk gestational trophoblastic tumors. Response was evaluated by monitoring serial serum beta-hCG levels. Toxicity was recorded using standard World Health Organization criteria. RESULTS: There was no life-threatening toxicity. Neutropenia necessitating a 1-week delay of treatment occurred with only eight treatment cycles (12.5%) and deferral of vincristine and cyclophosphamide with three cycles. Anemia requiring transfusion complicated only two cycles. Peripheral neuropathy in two patients was treated by discontinuing vincristine. Other toxicities included nausea and vomiting, diarrhea, stomatitis, alopecia, conjunctivitis, thrombocytopenia, and fever. Ten of the 12 subjects experienced a complete response. Two had partial responses and one with an initial complete response had relapse 4 months after completing therapy; all three were successfully salvaged with cisplatin-based chemotherapy. Overall survival was 100%, and all 12 patients are disease-free with a median follow-up of 26 months. CONCLUSIONS: Chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine is well tolerated and highly effective for metastatic, high-risk gestational trophoblastic disease.

Adult↗
PubMed1992

Depression of early protection against influenza virus infection by cyclophosphamide and its restoration by protein-bound polysaccharide.

Relationship between depression of early protection against influenza virus infection and the decrease in the number of peripheral polymorphonuclear leukocytes in cyclophosphamide-treated mice was investigated using protein-bound polysaccharide (PSK), which had been shown to exert a potent restorative effect on leukocytopenia in immunocompromised hosts. Following intranasal inoculation with influenza virus (1.5 x 10(3) PFU) into untreated mice, the pulmonary virus titer progressively increased during 3 days and decreased gradually from the day 7 after infection. The treatment of mice with cyclophosphamide (150 mg/kg) 2 days before infection markedly enhanced the pulmonary virus multiplication from the early phase of infection, and the higher virus titer was maintained thereafter. When mice were given cyclophosphamide after PSK-treatment, virus titers from the early to late phases of infection were lower than those in untreated mice.

Adjuvants, Immunologic↗
PubMed1992

[Bladder neoplasm in a patient with panarteritis nodosa treated with cyclophosphamide].

Cyclophosphamide is used both in the treatment of malignant and non-malignant diseases. Urinary neoplasms secondary to its use have been described. We discuss the case of a patient with panarteritis nodosa treated with cyclophosphamide during 63 months, with a total dose of 210 grams, and that showed a bladder neoplasm 8 years after beginning of the treatment. In patients receiving a total dose of cyclophosphamide over 85 grams, a follow-up of ten years minimum should be performed aimed to the early detection of secondary neoplasms.

Adrenal Cortex Hormones↗
PubMed1976

[Reversal of the depressive power of cyclophosphamide on the anti-infectious defense of the mouse by means of a somatic antigen from Bacillus subtilis].

In the experimental conditions reported the cyclophosphamide increases the pathogenic effect of Escherichia coli in mice. Treating the animals with a somatic antigen of Bacillus subtilis, reverses the aggravating effect of cyclophosphamide on the experimental infection. Similar results are obtained through the parenteral and the rectal routes. This antigen does not limit either the leucopenient effect of cyclophosphamide nor its blocking effect on the synthesis of sheep red blood cells antibody in mice.

Animals↗
PubMed1992

Intermittent intravenous pulse cyclophosphamide treatment in systemic lupus erythematosus.

To determine the efficacy and safety of intermittent intravenous pulse cyclophosphamide in patients of severe systemic lupus erythematosus (SLE), 50 patients having severe/refractory lupus nephritis, vasculitis or neuropsychiatric manifestations were treated with 3 weekly pulses of cyclophosphamide for 6 such pulses. This treatment was found to be associated with significant and sustained improvement during a 2 yr follow up with respect to the mean renal activity score, individual renal parameters (proteinuria, erythrocyturia, and serum creatinine levels), focal neurological manifestations, vasculitic lesions, antinuclear antibody titers, complement component C3, anti-dsDNA antibodies levels and ESR. There was a sustained decrease in the overall mean disease activity score, and the mean daily dose of prednisolone (pretreatment 32.62 mg daily to 3.75 mg daily after 24 months). There was a significant decline in the percentage and absolute B cell count after 7, 14 and 21 days of this treatment. Effect on other lymphocyte subsets (CD3+, CD4+ and CD8+) was not marked. Pulse cyclophosphamide could therefore be an effective and less toxic form of treatment in patients with SLE having severe lupus nephritis, focal neurological lesions or vasculitis.

Adolescent↗
PubMedDate not supplied

Chemical stability of two sterile, parenteral formulations of cyclophosphamide (Endoxan) after reconstitution and dilution in commonly used infusion fluids.

The commercially available parenteral dosage forms of cyclophosphamide (Endoxan, Cycloblastine) are manufactured by an aseptic dry-filling technique and exhibit a slow dissolution rate. A novel dosage form has been developed by one of the manufacturers based on the technique of freeze drying. Dissolution rates of both types of formulations were determined and it was shown that the freeze-dried formulation dissolves more rapidly, within 20 seconds, while it takes at least three minutes to dissolve the dry-filled formulation. The chemical stabilities of the cyclophosphamide solutions, obtained after reconstitution and/or dilution of both formulations, have been investigated and tested as a function of drug concentration (20 and 1 mg/mL), solvent (water, 0.9% sodium chloride, 5% dextrose), container material (glass and polyvinyl chloride (PVC)), light conditions (normal room fluorescent light/dark) and temperature (4 degrees, 20-22 degrees and 37 degrees C). The test solutions were analyzed by a stability-indicating reverse phase high performance liquid chromatographic method with ultraviolet detection at 214 nm. Cyclophosphamide solutions (solvent: water; drug concentration; 20 mg/mL) are stable when stored for seven days at 4 degrees C in the dark. At higher temperatures degradation occurred during the test period with 10% loss after seven days at ambient temperature and 50% loss after seven days storage at 37 degrees C. Similar data were found in admixtures with 5% dextrose and 0.9% sodium chloride and initial drug concentration of 1 mg/mL. There are no significant differences in chemical stability between the solutions obtained from reconstitution and dilution of the dry-filled and lyophilized formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemistry, Pharmaceutical↗