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PubMed1995

Effects of chronic low-dose cyclophosphamide exposure on the nuclei of rat spermatozoa.

Previous studies from our laboratory have shown that chronic exposure of the father to low doses of cyclophosphamide results in a significant increase in early embryonic death with little effect on the male reproductive system in rats. Such effects on progeny outcome are hypothesized to be mediated by an action of the drug on the nucleus of spermatozoa. The purpose of the present studies was to investigate the effects of cyclophosphamide treatment for 1 or 6 wk on the pattern of decondensation of sperm nuclei and on the sulfhydryl content of sperm nuclear proteins. Adult male rats were treated with cyclophosphamide (6.1 mg/kg/day) daily for 1 or 6 wk. Cauda epididymal spermatozoa were collected, demembranated, and then incubated with dithiothreitol (DTT) and proteinase K. The in vitro decondensation pattern of the nuclei of spermatozoa was divided into two phases: nuclear swelling and nuclear elongation. Spermatozoa from animals treated for 1 wk with cyclophosphamide showed the same decondensation pattern as those treated with vehicle (saline) alone. However, spermatozoa from animals treated for 6 wk with cyclophosphamide showed normal initial nuclear swelling but had a markedly affected nuclear elongation pattern. The changes with time in the decondensation pattern of these spermatozoa were quantitated by morphometric analysis of the head region of the spermatozoa. The nuclear area, curvature, and length of spermatozoa obtained from chronically drug-treated males were all significantly smaller than for those obtained from controls, while cell diameter was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Paternal exposure to cyclophosphamide alters cell-cell contacts and activation of embryonic transcription in the preimplantation rat embryo.

Paternal exposure to chronic low doses of cyclophosphamide, an anticancer agent, results in aberrant embryonic development of the progeny. We hypothesized that paternal exposure to cyclophosphamide disturbs zygotic gene activity regulating proper progression through preimplantation development and that this disturbance results in improper cell-cell interactions. To test this hypothesis, we analyzed cell-cell interactions and the expression of cytoskeletal elements in preimplantation embryos sired by male rats gavaged with saline or 6 mg kg(-1) day(-1) cyclophosphamide for 5 wk. Embryos from control litters had 4-12 cells on Day 2 of gestation; cell-cell contacts were observed consistently. Embryos from litters sired by cyclophosphamide-treated males were frequently abnormal and had lower cell numbers and decreased cell-cell contacts. Steady state concentrations of the mRNAs for cell adhesion molecules (cadherins and connexin 43) and structural proteins (beta-actin, collagen, and vimentin) were low in two- and four-cell control embryos; expression increased dramatically by the eight-cell stage. In contrast, embryos sired by cyclophosphamide-treated males displayed the highest expression of most trancripts at the two-cell stage. In parallel with the mRNA profiles, E-cadherin immmunoreactivity was nearly absent in two-cell control embryos and was strong by the eight-cell stage; immunoreactivity in embryos sired by drug-treated fathers was strong at the two-cell stage but absent at later stages. Thus, drug exposure of the paternal genome led to dysregulated expression of structural elements and decreased cell interactions during preimplantation embryonic development.

Animals↗

PubMed1994

Efficacy of oral ondansetron, a selective antagonist of 5-HT3 receptors, in the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapies. Ondansetron Study Group.

We evaluated the efficacy and safety of oral ondansetron, a selective antagonist of 5-HT3 receptors, for the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapy (> 500 mg/m2). In this trial 324 chemotherapy-naive cancer patients, mostly females with breast cancer, were randomized to receive either placebo or ondansetron 1 mg, 4 mg, or 8 mg three times per day for 3 days. There were no differences in the doses of cyclophosphamide, doxorubicin, and methotrexate between the study groups. All ondansetron dose groups were superior to the placebo control group (p < .001) for all measured efficacy parameters (complete response, number of emetic episodes, therapeutic failures, need of rescue antiemetics). No emetic episodes were reported by 9 (12%), 29 (37%), 48 (64%), and 47 (66%) of the placebo patients and the 1-mg, 4-mg, and 8-mg dose of ondansetron patients, respectively. Nausea was reduced and food intake was improved for all the ondansetron groups. A more severe emetic response was observed in patients receiving cyclophosphamide and doxorubicin combination chemotherapy. In this subgroup of patients, 66%, 38%, 25%, and 16% of the placebo group and 1-mg, 4-mg, and 8-mg ondansetron patients, respectively, required rescue antiemetics. No significant toxic effects were observed in this study. A higher incidence of headaches and gastrointestinal complaints (constipation, abdominal pain) were observed in the three ondansetron groups. In conclusion, oral ondansetron is an effective and well-tolerated antiemetic treatment in the management of cancer patients receiving ambulatory cyclophosphamide-based chemotherapy. These results support the view that serotonin and 5-HT3 receptors play an important role in cyclophosphamide-induced nausea and vomiting.

Administration, Oral↗

PubMed1998

Dose escalation study of carboplatin and cyclophosphamide with filgrastim support: a phase I study.

This clinical trial was designed to explore dose escalation of carboplatin and cyclophosphamide when supported with filgrastim. Twenty-seven patients who had advanced solid tumors received up to six cycles of treatment; a total of 92 cycles of chemotherapy were delivered. Two control groups received standard-dose carboplatin (300 mg/m2) and cyclophosphamide (600 mg/m2), with and without filgrastim. Subsequently, the doses of both carboplatin and cyclophosphamide were increased simultaneously by 50% of the standard dose in sequential cohorts. Doses of up to 2.5 times the standard dose were explored. A final dose of carboplatin, 600 mg/m2, and cyclophosphamide, 1,500 mg/m2, was tested in 4 patients. The duration of neutropenia was brief, even at the highest dose levels. The mean duration of grade 3 or 4 neutropenia was 5.8 days at standard dose without filgrastim and 5.4 days at 2.5 times standard dose with filgrastim. More severe neutropenia was more prolonged at higher doses but remained brief in duration. The mean duration of neutropenia of less than 100 x 10(6)/l was 0.4 days at standard dose without filgrastim and 1.3 days at 2.5 times standard dose. There was no evidence of cumulative neutropenia over repeated cycles of treatment. In contrast, thrombocytopenia was both dose limiting and cumulative. The mean duration of grade 3 or 4 thrombocytopenia was 1.6 days at standard dose and 9.6 days at 2.5 times standard dose. An average of 2.3 platelet transfusions per cycle of treatment was required at the highest dose. Thrombocytopenia was worse with repetitive cycles of therapy. The mean duration of grade 3 or 4 thrombocytopenia was 2.2 days after the first cycle of chemotherapy and 7.8 days after cycle four. The maximum tolerated dose, as defined prospectively, was not reached but further dose escalation was not thought to be warranted because of the severity of thrombocytopenia. When supported with filgrastim, carboplatin and cyclophosphamide can be administered safely with substantially increased dose and acceptable toxicity.

Adolescent↗

PubMed2001

Automated noninvasive measurement of cyclophosphamide-induced changes in murine voiding frequency and volume.

PURPOSE: We developed an automated noninvasive method for studying bladder function in mice. Changes in voided volume and frequency accompanying cyclophosphamide-induced cystitis were measured using computerized digital balances. MATERIALS AND METHODS: Eight CRL CD-1 mice were given a solution of glucose and saccharin to increase urine output and studied during the dark cycle, when most voiding occurs. Urine fell directly onto electronic balance pans. The time and weight of each void was recorded. Computer programs adjusted for evaporative loss analyzed voiding data within and across sessions. After establishing stable voiding patterns 300 mg./kg. cyclophosphamide were administered intraperitoneally. The Wilcoxon signed rank test was done to compare median voided volumes, frequency and gm. per hour of urine produced before and after cyclophosphamide. RESULTS: We implemented an automated method for voiding studies in mice. After cyclophosphamide administration the number of voids per hour increased and voided volume decreased. Some mice had as much as a 70% decrease in bladder volume and a tripling of urinary frequency. Mice responded by a sustained elevation in frequency and decreased voided volume as early as 24 hours after cyclophosphamide administration or by a pattern of delayed toxicity. CONCLUSIONS: This noninvasive technique measures changes in mouse voiding patterns with great sensitivity and minimal effort. The method is applicable to murine models of interstitial cystitis, detrusor instability and other abnormal voiding states. It may be used for evaluating potential therapies for such conditions.

Animals↗

PubMed1983

Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation.

One hundred thirty-seven patients had gonadal function evaluated 1-11 years after marrow transplantation. All 15 women less than age 26 and three of nine older than age 26 who were treated with 200 mg/kg cyclophosphamide recovered normal gonadotropin levels and menstruation. Five have had five pregnancies resulting in three live births, one spontaneous abortion, and one elective abortion. Three of 38 women who were prepared with 120 mg/kg cyclophosphamide and 920-1200 rad total-body irradiation had normal gonadotropin levels and menstruation. Two had pregnancies resulting in one spontaneous and one elective abortion. Of 31 men prepared with 200 mg/kg cyclophosphamide, 30 had normal luteinizing hormone levels, 20 had normal follicle-stimulating hormone levels, and 10 of 15 had spermatogenesis. Four have fathered five normal children. Thirty-six of 41 men prepared with 120 mg/kg cyclophosphamide and 920-1750 rad total-body irradiation had normal luteinizing hormone levels, ten had normal follicle-stimulating hormone levels, and 2 of 32 studied had spermatogenesis. One has fathered two normal children. It was concluded that cyclophosphamide does not prevent return of normal gonadal function in younger women and in most men. Total-body irradiation prevents return of normal gonadal function in the majority of patients.

Acute Disease↗

PubMed1995

A phase I and II trial of dose-intensified cyclophosphamide and GM-CSF in pediatric malignant brain tumors.

PURPOSE: Cyclophosphamide is commonly used in the treatment of children with malignant brain tumors. The purpose of this study was to develop a multicycle, high-dose intensity cyclophosphamide regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) and to assess its activity against malignant glioma and primitive neuroectodermal tumor (PNET). METHODS: Twenty-three patients with brain tumors, including 15 with malignant glioma and six with PNET, were enrolled. Cyclophosphamide (1.8-2.25 g/m2/day for 2 days i.v.; total dose 3.6-4.5 g/m2) was administered and was followed by recombinant human GM-CSF (5 micrograms/kg/day s.c.) on days 3-11 or until the absolute granulocyte count reached 1.5 x 10(9)/L. RESULTS: With a total of 83 cycles administered, the mean dose intensity of cyclophosphamide ranged from 1.5 g/m2/week through cycle 2 (22 patients) to 0.8 g/m2/week through cycle 8 (two patients). No activity was seen against malignant glioma, and five of six patients with PNET had partial responses. The mean duration of a neutrophil count of < 0.5 x 10(9)/L was only 8 days; the platelet recovery was substantially longer. Fever during neutropenia occurred in 54 of 83 cycles. One patient died from transfusion-related graft-versus-host disease. CONCLUSIONS: A cyclophosphamide regimen equal to twice the dose intensity of that used in conventional therapy was administered. The regimen was active against PNET but inactive against malignant glioma.

Adolescent↗

PubMed2002

High dose cyclophosphamide treatment for autoimmune disorders.

High-dose cyclophosphamide (200 mg/kg) was initially developed as a conditioning regimen for allogeneic bone marrow transplantation. Recently, high-dose cyclophosphamide without bone marrow transplantation has been employed as a method to induce durable treatment-free remissions in severe aplastic anemia and a variety of other severe autoimmune disorders. The premise underlying this approach is that high-dose cyclophosphamide is maximally immunosuppressive, but not myeloablative. Early hematopoietic stem cells are spared the cytotoxicity of cyclophosphamide because of their high levels of aldehyde dehydrogenase, an enzyme that confers resistance to the drug. Conversely, autoimmune effector cells (T cells, B cells, and NK cells) are exquisitely sensitive to high-dose cyclophosphamide because of their relatively low levels of aldehyde dehydrogenase. Intensive investigation is underway to determine which autoimmune disorders will most benefit and where in the natural history of these diseases to employ this rapidly developing therapy.

Anemia, Aplastic↗

PubMed1988

Effect of a rice-rich diet on the therapeutic efficacy of cyclophosphamide with special reference to the enhancement of transplantation immunity.

The present study investigated the problem of whether the therapeutic efficacy of cyclophosphamide in the in vivo Ehrlich ascites tumor system can be improved by adjuvant use of hydrocortisone or of dietary hydrocortisone mobilizers. In the chemotherapy experiment, female ICR mice each received an inoculum of 1 x 10(6) cells of Ehrlich ascites tumor ip followed by 2 ip injections of cyclophosphamide 36 and 37 hr later (2.4 mg/mouse for the 1st injection, and 1.0 mg/mouse for the 2nd injection). The effects of both cyclophosphamide and adjuvant treatments were assessed in terms of either survival rate or cure rate in the 1-month experiment. The results obtained were as follows. 1) Prolonged use of hydrocortisone as an adjuvant can improve the survival of cyclophosphamide-treated mice. 2) Adjuvant use of a rice-rich diet for maintenance increased the rates of both survival and cure in the cyclophosphamide-treated mice. 3) The same maintenance of mice on a rice-rich diet increased transplantation immunity on the one hand, and induced a set of steroidal changes including hydrocortisone excess on the other hand. 4) Evidence is presented to indicate that the beneficial influence of a rice-rich diet on the drug effect is related to an increase of transplantation immunity in the host, and that there could be a causal relationship between hormonal and immunological changes in rice-saturated mice.

Animals↗

PubMed1996

Cyclophosphamide pharmacokinetics in children.

1. Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2. A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-1 m-2 and volume of distribution varied between 0.26 and 1.48 1 kg-1. 3. The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4. Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.51 h-1 m-2 (P = 0.001) presumably as a result of CYP450 enzyme induction. 5. Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6. Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.

Adolescent↗

PubMed1988

Intermittent high-dose dexamethasone-cyclophosphamide therapy for pemphigus.

Since 1982, we have treated 79 pemphigus patients with an arbitrarily designed regimen of 100 mg dexamethasone dissolved in 5% glucose given by an intravenous infusion over 1 h, daily on 3 consecutive days and in addition, 500 mg cyclophosphamide on day 1 only. The intermittent high doses (IHD) of dexamethasone are repeated every 2-4 weeks, and the patient continues to take 50 mg/day oral cyclophosphamide. This treatment is divided into four phases. During Phase I, the patient continues to develop relapses of pemphigus a variable number of days after IHD, but the lesions heal up quickly after IHD. These relapses become progressively milder and stop after a few months, but the IHD are continued once a month for 6-9 months (Phase II). In the next phase (Phase III), the monthly IHD are stopped, and the patient continues to take 50 mg/day cyclophosphamide orally. After approximately 1 year this maintenance treatment is withdrawn and the patient is observed for any relapses (Phase IV). Of the 79 patients treated, 10 patients have been lost to follow-up and two have died, one due to leukopaenia caused by inadvertent additional administration of methotrexate, and the other of an unknown cause. Of the remaining 67 patients, 25 are off treatment (Phase IV), 25 are taking only 50 mg cyclophosphamide daily (Phase III), ten are also in remission, but still receiving intermittent high doses of dexamethasone-cyclophosphamide (Phase II), and seven still have active disease (Phase I).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1997

Interstitial pneumonitis probably induced by cyclophosphamide in nephrosis.

A case of interstitial shadows associated with oral cyclophosphamide therapy in a 32-month-old girl with steroid-resistant nephrotic syndrome, who was admitted to the Nishi-Kobe Medical Center with systemic edema, is reported. Due to the lack of response to prednisolone, cyclophosphamide was also administered orally at a dose of 3 mg/kg per day, 4 weeks after the start of steroid therapy. Approximately 3 weeks after the combination treatment she developed a fever, dry cough and cyanosis. Radiographic examination showed diffuse ground-glass shadow in both lungs, presumably indicating that she had interstitial pneumonitis. Her pulmonary signs and symptoms deteriorated despite various antimicrobial treatments. A discontinuation of cyclophosphamide and the administration of high-dose methylprednisolone yielded a dramatic improvement. These findings suggest that the diffuse pulmonary disease in this case was induced by cyclophosphamide. Since interstitial pneumonitis may be fatal and irreversible, attention should be paid to this rare complication even in patients undergoing low-dose oral cyclophosphamide treatment.

Alkylating Agents↗

PubMed1993

Studies of new short-period method for delayed contact hypersensitivity assay in the guinea pig. (2). Studies of the enhancement effect of cyclophosphamide.

The enhancement effect of cyclophosphamide on the delayed contact hypersensitivity reaction of chemical compounds was studied in Hartley albino guinea pigs. A series of assay procedures, combining the AP2 test (adjuvant and 24-h occlusive patch 2x test, as previously reported) with intraperitoneal cyclophosphamide administration, were examined. The newly developed method was as follows; cyclophosphamide 200 mg/kg intraperitoneal administration 3 days before the 1st sensitization of the AP2 test (cyclophosphamide, adjuvant and 24-h occlusive patch 2x test: CAP2 test). Comparing the CAP2 test with the AP2 test, the cumulative contact enhancement test (CCET) and the guinea pig maximization test (GPMT), the CAP2 test equally and/or better enabled the detection of allergenicities not only of strong allergens such as bromostyrol, citronellal, p-phenylenediamine and formaldehyde, but also of weak allergens such as benzyl salicylate and p-aminobenzoic acid ethyl ester. Acanthosis and spongiosis in the epidermis and mononuclear cell infiltration into the dermis at the skin reaction site were histopathologically observed. Cyclophosphamide effectively enhanced the delayed contact hypersensitivity reaction of weak allergens.

Allergens↗

PubMed2005

Activity of d,l-alpha-tocopherol (vitamin E) against cardiotoxicity induced by doxorubicin and doxorubicin with cyclophosphamide in mice.

The aim of this study was to investigate the cardioprotective activity of vitamin E against doxorubicin alone and doxorubicin in combination with cyclophosphamide in mice. Female BalbC/NIH mice were treated with vitamin E (100 IU/kg, orally) 24 hr before single bolus doses of doxorubicin (10 mg/kg, intravenously), or doxorubicin and cyclophosphamide (150 mg/kg, intraperitoneally). Non-treated animals served as negative controls, while positive control groups received doxorubicin or doxorubicin and cyclophosphamide. For evaluation, serum enzyme activity of aspartate aminotransferase (AST), lactate dehidrogenase (LDH), alpha-hydroxybutirate dehydrogenase (alpha-HBDH), and creatine kinase (CK) at 48 hr and histopathology examination of the heart tissue (Billigham rules) at 1.5 and 3 months followed to treatments were used. In sera of mice treated with vitamin E prior to doxorubicin, the creatine kinase and % alpha-HBDH activity were significantly reduced, compared to positive control. Histopathology changes (scored as 1.5 at 1.5 and 3 months respectively) were not significant compared to negative control at both time points of examination. In animals which received vitamin E before doxorubicin and cyclophosphamide, none of the serum enzymes was significantly reduced compared to positive control, but non-significant increase in AST and creatine kinase activity was detected (3% and 16.57% respectively). The degree of myocardial damage was significantly higher compared to non-treated group (2.0 and 2.5 at 1.5 and 3 months respectively). Current results show that vitamin E in single oral dose failed to inhibit acute cardiotoxic activity of doxorubicin, but suspended further progression of the heart muscle damage over the time. On the contrary, vitamin E did not attain any cardioprotection against doxorubicin and cyclophosphamide in combination.

Animals↗

PubMed2006

Ginsenoside Rh(2) enhances antitumour activity and decreases genotoxic effect of cyclophosphamide.

Ginsenoside Rh(2), a panaxadiol saponins, possesses various antitumour properties. Cyclophosphamide, an alkylating agent, has been shown to possess various genotoxic and carcinogenic effects, however, it is still used extensively as an antitumour agent and immunosuppressant in the clinic. Previous reports reveal that cyclophosphamide is involved in some secondary neoplasms. In this study, the antitumour activity and genotoxic effect of oral intake of ginsenoside Rh(2) combined with intraperitoneal injection of cyclophosphamide was investigated. Meanwhile, C57BL/6 mice bearing B16 melanoma and Lewis lung carcinoma cells were respectively used to estimate the antitumour activity in vivo. The clastogenic activity in bone marrow polychromatic erythrocytes was assayed by frequency of micronucleus. The DNA damage in peripheral white blood cells was assayed by single cell gel electrophoresis as well. The results indicated that oral administration of Rh(2) (5, 10 and 20 mg/kg body weight) alone has no obvious antitumour activity and genotoxic effect in mice, while Rh(2) synergistically enhanced the antitumour activity of cyclophosphamide (40 mg/kg body weight) in a dose-dependent manner. Rh(2) decreased the micronucleus formation in polychromatic erythrocytes and DNA strand breaks in white blood cells in a dose-dependent way. Our results suggest that ginsenoside Rh(2) is able to enhance the antitumour activity and decrease the genotoxic effect of cyclophosphamide.

Animals↗

PubMed1983

Correlation between in vivo and in vitro studies of modulation of resistance to experimental Candida albicans infection by cyclophosphamide in mice.

Mice receiving a single injection of cyclophosphamide (150 mg/kg) 1 to 6 days before inoculation with viable Candida albicans showed an increased susceptibility to the challenge accompanied by a reduction in peripheral blood polymorphonuclear leukocytes and lymphocytes as well as in spleen cellularity. Several immunological in vitro functions also appeared to be dramatically depressed. Most of these hematological and functional parameters returned to control values by day 9 after cyclophosphamide administration, at a time when resistance to C. albicans infection appeared to be unchanged. However, when exposure to cyclophosphamide occurred 12 to 21 days before inoculation with the live yeast, enhanced resistance was observed with the majority of the animals surviving challenge. To gain some insight into the mechanisms underlying this late increase in resistance to C. albicans infection after cyclophosphamide administration, we analyzed a series of immunological functions, including the in vitro candidacidal activity of polymorphonuclear neutrophils and plastic-adherent and nonadherent spleen cells as well as the activity of natural killer cells and alloreactive T lymphocytes. The results show that a numerical rebound of blood polymorphonuclear neutrophils and the appearance of a highly candidacidal cell population in the spleen may be among the factors underlying the late increase in resistance to C. albicans after administration of cyclophosphamide.

Animals↗

PubMed1972

Respiratory diseases in cyclophosphamide-treated mice. II. Decreased virulence of PR8 influenza virus.

Mice infected intranasally with the PR8 strain of influenza virus were treated with cyclophosphamide, a potent immunologic suppressor. During the first week of infection, mortality in the unmodified influenza infection averaged 65%, whereas in those animals also treated with cyclophosphamide it averaged 22.5%. After the first week, the mortality rate in the infected cyclophosphamide-treated animals rose to that seen during the first week in the animals only infected. This decreased mortality in the first week was found despite the fact that the cyclophosphamide-treated and infected animals had higher virus titers which persisted longer, decreased circulating antibody, and a decreased interferon response. This delayed mortality appeared to be related to the finding of decreased cellular infiltration in the lungs of infected cyclophosphamide-treated animals.

Administration, Intranasal↗

PubMed1990

Eight and 12 week courses of cyclophosphamide in nephrotic syndrome.

Seventy-three children with steroid dependent minimal change nephrotic syndrome were randomly allocated to receive treatment with cyclophosphamide (2 mg/kg/day) for either eight or 12 weeks, in combination with prednisolone. All patients had previously relapsed while the dosage was being reduced or within 14 days of discontinuing prednisolone in the six months before receiving cyclophosphamide treatment (steroid dependent), and had severe steroid toxicity. Thirty two patients were treated with cyclophosphamide for eight weeks, and 41 for 12 weeks. There were no differences between the two groups in age at onset of nephrosis or entry into the study, sex ratio, duration of nephrosis, number of relapses before entry, and follow up period after entry. The relapse free rate of patients treated for eight weeks (25%) was similar to that of those treated for 12 weeks (24%) five years after stopping the treatment, and the mean relapse free interval and the sparing effect of cyclophosphamide (if any) on subsequent treatment with steroids did not differ between the groups. We conclude that cyclophosphamide should be used for no longer than eight weeks at a dose of 2 mg/kg/day in children with steroid dependent minimal change nephrotic syndrome.

Child↗