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PubMed2003

[Analysis of cyclophosphamide in the urine of antineoplastic drugs handlers].

The first study in which amounts of cyclophosphamide were found in the urine of nurses handling cytotoxic drugs using gas chromatography was published in 1984. We carried out a similar investigation on six pharmacy technicians involved in the preparation of antineoplastic agents (25,000 doses per year) but the analysis was performed with a more sensitive method: gas chromatography-mass spectrometry (LOQ = 0.1 ng/ml). Cyclophosphamide was found in two urine samples (out of 104) from two different workers. The rates detected were just above the limit of quantification. No correlation was found between the amounts of cyclophosphamide handled and the urinary excretion. The mean urinary levels measured in this study are lower than those reported by other investigators. In addition, only 1.9% of the collected samples are positive to cyclophosphamide. The drug was detected for two different technicians during two different sampling periods, suggesting that pollution is not repeated. No relationship could be seen between urinary detection of cyclophosphamide and individual or general work in the cytotoxic preparation unit. As supported by recent datas, transdermal resorption seems to be the most important way of incorporation. Further investigations are necessary to prove this hypothesis if we want to prevent occupational exposure of people handling these drugs.

Antineoplastic Agents↗

PubMed2005

Accuracy, feasibility, and clinical impact of prospective Bayesian pharmacokinetically guided dosing of cyclophosphamide, thiotepa, and carboplatin in high-dose chemotherapy.

PURPOSE: Relationships between toxicity and pharmacokinetics have been shown for cyclophosphamide, thiotepa, and carboplatin (CTC) in high-dose chemotherapy. We prospectively evaluated whether variability in exposure to CTC and their activated metabolites can be decreased with pharmacokinetically guided dose administration and evaluated its clinical effect. EXPERIMENTAL DESIGN: Patients received multiple 4-day courses of cyclophosphamide (1,000-1,500 mg/m2/d), thiotepa (80-120 mg/m2/d), and carbop latin (area under the plasma concentration-time curve 3.3-5 mg x min/mL/d). Doses were adapted on day 3 based on pharmacokinetic analyses of cyclophosphamide, 4-hydroxycyclophosphamide, thiotepa, tepa, and carboplatin done on day 1 using a Bayesian algorithm. Doses were also adjusted before and during second and third courses. Observed toxicity was compared with that in patients receiving standard dose CTC (n = 43). RESULTS: A total of 46 patients (108 courses) were included. For cyclophosphamide, thiotepa, and carboplatin, a total of 39, 58, and 65 dose adaptations were done within courses and 17, 40, and 43 before courses. The precision within which the target exposure was reached improved compared with no adaptation, especially after within-course adaptations (precision for cyclophosphamide, thiotepa, and carboplatin is 19%, 16%, and 13%, respectively); >85% led to an exposure within +/-25% of the target compared with 60% without dose adjustments. Toxicity was similar to that in a reference population, although the incidence of veno-occlusive disease was reduced. CONCLUSIONS: Bayesian pharmacokinetically guided dosing for CTC was feasible and led to a marked reduction in variability of exposure.

Adolescent↗

PubMed2005

[Protective effect of Armillaria mellea polysaccharide on mice bone marrow cell damage caused by cyclophosphamide].

OBJECTIVE: To observe the effect of Armillaria mellea polysaccharide on mice bone marrow cells damage caused by Cyclophosphamide. METHOD: Kunming purebred mice were used and stochastic divided into 5 groups: normal control group, positive control group (rhG-CSF 20 microg x kg(-1) x d(-1)), damage group of Cyclophosphamide (150 mg x kg(-1) x d(-1)), the protective group with A. mellea polysaccharide, low dose (25.0 mg x kg(-1) x d(-1)) and high dose (50.0 mg x kg(-1) x d(-1)). Positive control was s.c. rhGCSF 6 d and i.p. Cyclophosphamide 3 d. A. mellea polysaccharide was i.p. 8 d. and Cyclophosphamide i.p. 3 d. WBC, RBC, PLT, BMNC were counted in peripheral blood and bone marrow cells. The myelogram were analyzed in bone marrow. RESULT: The WBC, RBC, PLT, BMNC of protective group and positive control group were higher than damage group (P < 0.01) significantly high dose group increaser than low dose group in protective group the numbed of Promyelocytic and lobulation nuclear of marrow. CONCLUSION: A. mellea polysaccharide has preferably protective effect on damaging mice bone marrow cell caused by Cyclophosphamide.

Animals↗

PubMed2005

Immune tolerance induced by donor antigen and cyclophosphamide in rat fetal small bowel transplantation.

BACKGROUND/PURPOSE: Donor specific immune tolerance is thought to be the ideal state for the recipient after organ transplantation. The administration of donor antigens and cyclophosphamide has been reported to induce donor specific immune tolerance in heart or liver transplantation. However, the effectiveness of this method for small bowel transplantation has not yet been studied. We assessed the cyclophosphamide induced immune tolerance on rat fetal small bowel transplantation. METHODS: Lewis rats (RT1(1), n=99) were used as recipients while either F344 (RT1(1), n=44) or WKAM (RT1(u), n=47) rats were used as donors. The combination of F344 and Lewis rats produces an immunologically low responder, while that of WKAM and Lewis rat produces a high responder. Bone marrow and spleen cells were harvested from the donor rats and 3x10(8)/kg of each were administrated to the recipient rats intravenously on day 0. Next, cyclophosphamide was given either divisionally or bolously. The fetal small bowel of the same strain as the donor was transplanted into the rectus muscle of the recipient abdominal wall on day 10. On day 17, all grafts were taken out and graft survival was thereafter evaluated. The body weight of recipient was also assessed. RESULTS: Most of the grafts (87.5%) survived in the F344-Lewis rat (low responder) combination using the divisional administration of 120 mg/kg of cyclophosphamide. Histologically, most of them showed the whole layers of the intestinal architectureto be well preserved. The weight loss of the recipient was minimal after divisional administration. In contrast, no graft survived in the WKAM-Lewis rat (high responder) combination. CONCLUSIONS: Immune tolerance is considered to be induced by the administration of donor specific antigen and cyclophosphamide in an immunologically low responder combination. Therefore, this method is expected to be useful as an adjuvant therapy and may also be able to reduce the dose of immunosuppressive agents in living-related clinical small intestinal transplantation.

Animals↗

PubMed1992

Depressed adjuvant arthritis in chronically Trypanosoma cruzi infected rats: reversal by cyclophosphamide.

Chronically Trypanosoma cruzi infected "I" rats and syngeneic naive recipients, transferred with a T cell enriched spleen cell population from infected donors, develop an attenuated arthritis when challenged with complete Freund's adjuvant. We report that cyclophosphamide, 40 mg/kg body weight, given 48 h before induction, was able to reestablish or exacerbate adjuvant arthritis in infected and control rats, respectively. Although the T cell enriched spleen cells from infected donors continued to down regulate adjuvant arthritis in syngeneic recipients given cyclophosphamide 48 h before cell transfer, treatment of infected donors with cyclophosphamide, 48 h before cell collection, prevented these cells from exerting such effect when transferred to healthy recipients receiving no cyclophosphamide. It is suggested that cyclophosphamide may primarily affect a suppressor cell population, present in the infected host, with regulatory activity on adjuvant arthritis.

Animals↗

PubMed2006

[Antagonistic effects of vitamin E on the testicular injury by cyclophosphamide in mice].

OBJECTIVE: To observe the protective effects of vitamin E on the testicular injury by cyclophosphamide in mice, and the correlative mechanism. METHODS: Fifty sexually mature male mice were randomly divided into five groups: the cyclophosphamide group (the CP group), the low-dose vitamin E group (the low-dose group), the middle-dose vitamin E group (the middle-dose group), the high-dose vitamin E group (the high-dose group), the matched control group (the control group). The first four groups were given cyclophosphamide by gavage at a dose of 5 mg/(kg x d). The low-dose group, the middle-dose group and the high-dose group were given vitamin E by subcutaneous injection at doses of 30 mg/(kg x d), 50 mg/(kg x d) , 70 mg/(kg x d) after 4 h of cyclophosphamide treatment. The control group was gavaged with equivalent normal saline. The treatment period for all groups was 28 days. The level of plasma FSH, LH, T and the activity of testicular SOD, GSHPx, CAT and the level of testicular MDA were detected. The histological structure and the ultrastructure of the testis were examined by light microscope and electron microscope. RESULTS: As compared with the CP group, the plasma FSH, LH, T level and the SOD, GSHPx, CAT activity in the middle-dose group and the high-dose group were higher (P< 0.05, P< 0.01), MDA level significantly lower(P<0.01). The histological structure and the ultrastructure of the testis were in the normal range. CONCLUSION: Vitamin E has protective effects on the testicular injury by cyclophosphamide in mice. The possible mechanism of vitamin E may be its scavenging free radical and antioxidant effects, as well as it may have some stimulatory effects on gonadotrophin releasing of pituitary anterior lobe.

Animals↗

PubMed1991

Protection by interleukin 1 against lung toxicity caused by cyclophosphamide and irradiation.

Interleukin 1 has been shown to provide protection against the toxic effects of cyclophosphamide given in combination with localized irradiation of the lung. A single dose of 15 micrograms/kg interleukin 1 was given 24 h before cyclophosphamide (25-125 mg/kg) which was followed 1 day later by five daily exposures of 4.5 or 5.0 Gy, localized to the lung. Interleukin 1 significantly reduced early measurements of breathing rate for mice treated with high cyclophosphamide doses and irradiation, and at cyclophosphamide doses above 50 mg/kg, there was a significant reduction in the lethality from the combined treatment. At lower levels of cyclophosphamide, however, there seemed to be no effect.

Animals↗

PubMed1991

Depression of early protection against influenza virus infection by cyclophosphamide and its restoration by Y-19995 [2,4'-bis(1-methyl-2-dimethyl-aminoethoxyl)-3-benzoylpyridine dimaleate].

The 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 by means of a novel synthetic compound, Y-19995 [2,4'-bis(1-methyl-2-dimethyl-aminoethoxyl)-3-benzoylpyridine dimaleate], 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) plaque-forming units) into untreated mice, the pulmonary virus titer progressively increased during 3 days and decreased gradually from day 7 after infection. The treatment with cyclophosphamide 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 Y-19995 after cyclophosphamide treatment, virus titers from the early to late phases of infection were lower than those in untreated mice. The number of peripheral polymorphonuclear leukocytes in cyclophosphamide-treated mice rapidly decreased and returned to normal levels only 9 days after the treatment, while such leukocytopenia was prevented to some extent and the leukocyte count was restored completely up to 7 days by postcyclophosphamide treatment with Y-19995. Furthermore, the treatment with Y-19995 augmented the inactivation of virus by the polymorphonuclear leukocytes. However, the virus inactivation by alveolar macrophages was modified only slightly by Y-19995 treatment. In addition, Y-19995 treatment could potentiate antibody-dependent cell-mediated cytotoxicity of polymorphonuclear leukocytes against the virus-infected target cells, and the production of serum neutralizing antibody to influenza virus in untreated and cyclophosphamide-treated mice. Y-19995 revealed neither antiviral nor interferon-inducing activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

[Delayed effect of cyclophosphamide on testicular function after treatment of nephrotic syndrome in childhood].

The authors present the results of study of testicular spermatogenetic and endocrine function in adult males treated with high doses of cyclophosphamide for nephrotic syndrome during childhood and/or adolescence. Seventeen males, mean age of 22.5 years (range, 17-30) were examined after mean follow-up of 11.8 (5-17.3) years. Mean age at the time of treatment was 10.8 (3.6-17.6) years; mean duration of cyclophosphamide treatment was 240 (39-701) days, and mean total cumulative doses were 641 mg/kg body weight (103-1999) or 16.4 (3.9-55.7) grams. All the patients undergone normal pubertal development and had normal sexual characteristics. Eleven were normospermic (more than 20 x 10(6)/ml spermatozoa), one oligospermic and five azoospermic. There was a significant inverse correlations of sperm density with cyclophosphamide dosage and duration of treatment. These variables seem to be more important for cyclophosphamide toxicity, than stage of sexual development at time of treatment. Raised basal and stimulated FSH concentrations in oligoazoospermic patients were in keeping with impaired spermatogenesis. These patients had also raised basal and stimulated LH concentrations suggesting compensated Leydig cell failure. Subgroup of normospermic patients with lower spermatozoa concentrations (20-40 x 10(6)/ml) had significantly raised FSH and LH responses on stimulation with gonadotropin releasing hormone, suggesting dysfunction both tubular and interstitial cell component of the testis. In other normospermic patients gonadotropin responses were not different from controls. Basal and HCG stimulated testosterone concentrations showed no differences between patients and controls. These results confirmed significant inverse correlations of cyclophosphamide dosage with its effect on spermatogenesis, and documented the long-term effect on the Leydig cell function requiring further follow-up.

Adolescent↗

PubMed1990

Glutathione protects cardiac and skeletal muscle from cyclophosphamide-induced toxicity.

Administration of cyclophosphamide at a dose which is lethal to 10% of control athymic nude mice resulted in sudden death within 3 h in all mice that had been pretreated with the glutathione synthesis inhibitor L-buthionine-SR-sulfoximine. In Fischer 344 rats pretreated with L-buthionine-SR-sulfoximine, the cyclophosphamide dose producing 100% acute toxicity was lowered from 500-150 mg/kg; cardiac monitoring revealed ventricular fibrillation to be the cause of death. These and additional studies reported demonstrate that cytoplasmic glutathione is an important protectant against the cardiac and skeletal muscle toxicity of cyclophosphamide and indicate that such toxicity may be substantially increased by glutathione depletion. Since diet and many drugs (including cyclophosphamide itself) are known to affect glutathione levels, the present studies suggest that cardiac and skeletal muscle glutathione content is likely to be a clinically significant determinant of the frequency and severity of the adverse drug interactions and systemic toxicity sometimes observed during cyclophosphamide therapy.

Animals↗

PubMed1985

Mechanism of depressed immunity in chronic renal failure: effect of cyclophosphamide pretreatment on delayed-type hypersensitivity skin reaction.

An imbalance in immunoregulatory mechanisms resulting in a relative increase in suppressor cell activity has been implicated in the development of the immunological deficit observed in chronic uremia. The present study was designed to assess whether cyclophosphamide pretreatment would preferentially enhance immune responses of chronically uremic animals. Delayed-type hypersensitivity (DTH) skin responses to oxazolone were found significantly decreased in chronically uremic mice as compared with sham-operated and normal controls. The administration of a single high dose (250 mg/kg) of cyclophosphamide 3 days prior to skin sensitization with oxazolone resulted in enhancement of DTH responses in all mice groups. Maximal increases in DTH responses following cyclophosphamide treatment was 61.6% in chronically uremic mice, and 100.5 and 86.2% in sham-operated and normal controls, respectively. The levels of active metabolites of cyclophosphamide, as estimated indirectly by the degree of myelosuppression achieved, were comparable across the 3 mice groups. These results thus fail to provide evidence for excessive numbers of cyclophosphamide-sensitive suppressor cells in chronic experimental uremia.

Animals↗

PubMed1988

Comparison of cyclophosphamide, cytarabine, and etoposide as immunosuppressive agents before allogeneic bone marrow transplantation.

Etoposide and cytarabine have been shown to exert high antileukemic activity and are currently under study as preparatory agents before allogeneic bone marrow transplantation. However, data concerning their engraftment-promoting potency are scarce. Therefore, we tested these agents in LEW rats receiving a myeloablative dose of busulfan followed by transfer of F1 (CAP X LEW) marrow, which is unable to induce a graft-v-host reaction (GVHR). Since busulfan by itself has only minor immunosuppressive potency, graft rejection ensues unless etoposide, cytarabine, or cyclophosphamide provide additional immunosuppression to facilitate durable engraftment. Before allogeneic bone marrow transplantation in humans, 120 mg/kg of cyclophosphamide, 60 mg/kg of etoposide, or 900 mg/kg of cytarabine are the standard doses given in conjunction with total body irradiation. Seventy-five percent of these doses administered in addition to busulfan resulted in rejection rates of 75% for cytarabine and 58% for etoposide, respectively, whereas no rejections were observed with cyclophosphamide. These data indicate that etoposide and cytarabine are inferior to cyclophosphamide in their rejection-preventing potential. Using either of these agents as substitutes for cyclophosphamide before allogeneic bone marrow transplantation may increase the risk of graft rejection in HLA-mismatched bone marrow transplantation and, in case of HLA identity, if T-depleted marrow is administered.

Animals↗

PubMed1988

[Immunomodulating therapy of adjuvant disease in rats using cyclophosphamide in combination with prodigiozan--its effect on anti-infectious resistance].

The effect of immunomodulating therapy of adjuvant disease in rats with cyclophosphamide, prodigiozan and their combinations on infection resistance, weight of the lymphoid organs and leukocyte counts in peripheral blood, as well as the effect of prodigiozan on acute toxicity of cyclophosphamide in intact mice and mice exposed to the Freund's complete adjuvant (FCA) was studied. Prodigiozan did not increase acute toxicity of cyclophosphamide in the intact mice. It lowered the cyclophosphamide toxicity at the background of the FCA and decreased the levels of leukopenia induced by the immunosuppressor in the rats with adjuvant arthritis. It was shown on the models of local infectious inflammation caused by Proteus and lethal sepsis due to P. aeruginosa that the combined use of prodigiozan and cyclophosphamide resulted in correction of the infection resistance impairment induced by both the arthritis development and the immunosuppressor administration.

Adjuvants, Immunologic↗

PubMed1987

Combinations of mesna with cyclophosphamide or adriamycin in the treatment of mice with tumors.

Following therapeutic administration, cyclophosphamide and Adriamycin are biotransformed to reactive metabolites, some of which are responsible for undesirable systemic toxicities of these chemicals, whereas others are responsible for their chemotherapeutic effectiveness. Microsomal mixed function oxidases activate cyclophosphamide to produce phosphoramide mustard and acrolein, while cytochrome reductase and xanthine oxidase are capable of transforming Adriamycin and forming free radicals. These reactive metabolites produce unwanted toxic side effects; however, their action may be partially ameliorated by the concomitant administration of thiols. In this study we evaluated the therapeutic activity of combinations of mesna (2-mercaptoethanesulfonate) with cyclophosphamide or Adriamycin in mice with a variety of transplantable tumors (L1210 and P-388 leukemia, Lewis lung and colon 26 carcinoma, B16 melanoma, and M5076 sarcoma). In all cases the administration of mesna prior to cyclophosphamide or Adriamycin treatment did not reduce the antitumor effectiveness of these agents and in some instances (C57BL/6 mice with B16 melanoma or M5076 sarcoma) small improvements were observed. Therefore, the addition of thiols, to reduce effectively the buildup of toxic metabolites of cyclophosphamide or Adriamycin may result in the improved therapeutic effectiveness for these agents in the treatment of cancer.

Animals↗

PubMed1987

Effect of methylprednisolone and cyclophosphamide in mercury-induced autoimmune glomerulonephritis.

The effects of methylprednisolone and of cyclophosphamide were tested in mercury-induced autoimmune disease in Brown-Norway rats. Survival, proteinuria, presence of antiglomerular basement membrane bound antibodies and of immune complex type deposits, amounts of circulating immune complexes, and total serum IgE were studied. Serum IgE represents the most sensitive marker in this drug-induced autoimmune disease. Methylprednisolone alone (1.5 mg/kg per day) affected the course of the disease only slightly. Cyclophosphamide (20 mg/kg every other day) given from day 0 completely prevented all the autoimmune manifestations, but the rats were profoundly immunosuppressed. The same protective effect was obtained with lower cyclophosphamide dosage (15 mg/kg on day 0 and then 2 mg/kg per day). More interestingly, cyclophosphamide given from day 10 or 15 (20 mg/kg twice a week or every other day), at a time when the disease was already expressed, resulted in partial or complete recovery, provided that the rats had not exhibited heavy proteinuria before initiation of treatment. Cyclophosphamide is therefore a powerful agent, able to prevent and even to reduce the consequences of polyclonal activation in this model.

Animals↗

PubMed1986

The effect of cyclophosphamide and vincristine on glucose absorption in rats using in vivo perfusion experiments.

The effect in rats of cyclophosphamide and vincristine on glucose absorption was studied by the in vivo perfusion method. On testing the local effect of cytostatics, the drugs were dissolved in the perfusion solution, cyclophosphamide at a concentration of 10(-4) M and vincristine at 10(-6) M. Glucose absorption was not reduced by cyclophosphamide, while it was significantly reduced by vincristine. On testing the systemic effect of cytostatics, the drugs were administered intraperitoneally 24 hours prior to perfusion, i.e. in doses of 80 mg/kg in the case of cyclophosphamide, and of 0.05 mg/kg of vincristine. In that case, both cytostatics decreased glucose absorption significantly. Based on the results it was found that, being administered locally, cyclophosphamide did not have a damaging effect on the intestinal wall, and did not reduce absorption either. On the contrary, vincristine impaired the mucosa locally, thereby reducing glucose absorption. On systemic administration, both cytostatics decreased absorption from the small intestine.

Animals↗

PubMed1987

Interactions of methotrexate and cyclophosphamide with the pharmacokinetics of 5-fluorouracil in an animal model.

The interaction of methotrexate and/or cyclophosphamide with the pharmacokinetics of 5-fluorouracil (5-FU) was studied in tumor-bearing WAG/Rij rats. Four groups were formed including treatment with single-agent 5-FU (eight rats); 5-FU plus methotrexate (11 rats); 5-FU plus cyclophosphamide (12 rats); and 5-FU, cyclophosphamide, and methotrexate (13 rats). The area-under-the-plasma-concentration/time curve, total-body clearance, elimination half-life, mean residence time, and steady-state volume of distribution were computed and compared. The mean residence time and elimination half-life of 5-FU increased when methotrexate was included in the combination. The increase was significant (P less than 0.05) for 5-FU, cyclophosphamide, and methotrexate versus 5-FU and cyclophosphamide.

Animals↗

PubMed1986

I.v. melphalan in carcinoma of the lung: effect of cyclophosphamide priming on hematopoietic toxicity.

Thirty-six patients with lung cancer, 24 with prior chemotherapy and 12 without prior chemotherapy, received iv melphalan at doses ranging from 20 to 40 mg/m2 of body surface area. Patients who showed moderate myelosuppression and remained in the study were also investigated to determine if cyclophosphamide (300 mg/m2) administered 1 week before the identical dose of i.v. melphalan modified the hematopoietic toxicity of melphalan (cyclophosphamide priming). In this study, the activity of melphalan was minimal, four minor responses with no partial or complete responses. Three of these minor responses were in previously untreated patients. The major toxicity was hematopoietic and the maximum tolerated i.v. dose was 20 mg/m2 in the patients previously treated with chemotherapy and 30 mg/m2 in those without prior chemotherapy. Cyclophosphamide priming did not reduce the myeloid toxicity. Myelosuppression was more severe in the course that included cyclophosphamide. Recovery, however, appeared to be similar in both courses. I.v. melphalan at these doses has minimal activity in lung cancer. Cyclophosphamide administered 1 week before i.v. melphalan does not decrease the myelosuppression but should be investigated further for its effect on the rate of wbc and neutrophil count recovery.

Adult↗