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Alkaline phosphatase in the developing bursa of Fabricius. A comparative study of the cyclophosphamide- and testosterone-induced immunodeficiencies in the chick embryo.

The ontogeny of alkaline phosphatase in the bursa of Fabricius was studied by histochemical and biochemical methods. According to the quantitative determinations, the activity of alkaline phosphatase increased from the 11th to 17th day of incubation--that is, during the time of the lymphoid follicle formation in the developing bursa. The activity was localized in the mesenchymal tissue surrounding the lymphoid follicles. Testosterone given in ovo prevented the appearance of alkaline phosphatase in the bursal mesenchyme but had no effect on the activity of the embryonic liver. In contrast, in ovo treatment with cyclophosphamide had no effect on the alkaline phosphatase in the bursa. By using transplantation of embryonic bursal stem cells, it was further shown that, in contrast to cyclophosphamide, testosterone destroys the capacity of the bursa to serve as a differentiation site for the B-cell lineage. The results indicate that testosterone affects the stromal cells of the bursa, whereas cyclophosphamide destroys only the lymphoid population undergoing differentiation and leaves the bursal stroma intact.

Alkaline Phosphatase↗

Dexamethasone-cyclophosphamide pulse therapy in pemphigus.

Fifty patients with pemphigus (45 pemphigus vulgaris, 5 pemphigus foliaceus) were treated with dexamethasone-cyclophosphamide pulse therapy. The pulse consisted of 136 mg dexamethasone dissolved in 5% dextrose given in a drip over a period of 1-2 hours on 3 consecutive days. In addition, 500 mg cyclophosphamide was added in the drip on the first day. Such pulses were given at monthly intervals. In between the pulses patients were given 50 mg cyclophosphamide orally each day. The results were encouraging, the chief advantage being freedom from side effects of corticosteroid therapy. The lesions healed in 3-4 days and the patients were able to resume their work within one week. Further scope of such therapy in pemphigus is discussed.

Adolescent↗

Curative effect of dexamethasone-cyclophosphamide pulse therapy for the treatment of pemphigus vulgaris.

In 1982, five patients having pemphigus vulgaris, four men and one woman, ranging in age between 16 and 48 years, were treated with an arbitrary regimen designed by us. The regimen consisted of giving 100 mg dexamethasone in 500 mL of 5% glucose by a slow intravenous infusion on three consecutive days, along with 500 mg cyclophosphamide on one day only. Such dexamethasone-cyclophosphamide pulses (DCP) were meant to be given once a month, but most patients were not regular in this treatment. In between these pulses the patients received only 50 mg cyclophosphamide orally per day. Oral corticosteroids were given only when necessary. After having received a total of 14 to 48 DCPS, further treatment for pemphigus was withdrawn. All the patients are in continuous clinical remission for the last 4 to 9 years and without any treatment for 2 to 7 years. Further studies on more pemphigus patients have yielded similar results suggesting that it may be possible to cure pemphigus.

Administration, Oral↗

The effect of N-acetyl cysteine on cyclophosphamide cystitis.

Further studies on the effect of various compounds of the rat bladder after treatment with cyclophosphamide are reported. The results show that N-acetyl cysteine is a highly effective drug for the prevention of cyclophosphamide cystitis. N-acetyl cysteine does not significantly impair the anti-tumour effect of cyclophosphamide.

Animals↗

Oral cyclophosphamide for the management of hormone-refractory prostate cancer.

Thirty patients with hormone-refractory prostate cancer were treated with cycles of oral cyclophosphamide (100 mg/m2/day for 14 days, with a 14-day gap). Eighteen patients had a significant improvement in symptoms of advanced disease, 6 had objective partial remissions and 13 had stabilisation of disease (criteria of National Prostatic Cancer Project). The median survival from the time of diagnosis was 33.3 months, and from the commencement of cyclophosphamide 12.7 months. The treatment was well tolerated. oral cyclophosphamide is active in the treatment of advanced hormone-refractory prostate cancer and yields symptomatic and objective remissions without undue side effects. This observation requires validation, with further testing of its impact on survival in randomised clinical trials.

Administration, Oral↗

Duodenal mucosa-associated lymphoid tissue lymphoma: treatment with oral cyclophosphamide.

Small cell mucosa-associated lymphoid tissue (MALT) lymphomas rarely affect the duodenum, and optimal treatment has not been defined. The aim of this case series was to determine the clinical features and outcome of duodenal MALT lymphoma in four patients (three men, one woman; median age 52 yr) treated with cyclophosphamide p.o. Initial manifestations were abdominal pain (n = 4), vomiting (n = 2), and an obstructive syndrome (n = 1). MALT lymphoma was diagnosed on the basis of endoscopic biopsies. It was localized in the duodenum in three cases and involved the entire small bowel in one case. Tumor infiltration was limited to the duodenal wall in one case and was associated with locoregional lymphadenopathy in three cases. The patients were graded EI (n = 1) and EII1 (n = 3), respectively, according to the Ann Arbor classification revised by Musshof. Cyclophosphamide, 100 mg daily, was administered p.o. for 18 months. Gastroscopy with biopsies, radiography of the small intestine and abdominal CT (CT) were performed every 6 months. Complete remission was defined by morphological and histological normalization, and partial remission as morphological normalization only. Follow-up lasted from 9 to 65 months. Three patients were in complete remission at 18 months: two relapsed after 2 yr and one was still in complete remission at 65 months. The patient with 9 months of follow-up was in complete remission at 6 months. The two patients who relapsed did not complain of symptoms, and no morphological abnormalities were seen. Relapse was diagnosed on histological grounds. Cyclophosphamide monotherapy p.o. thus seems well adapted to this slowly progressive disease, but it is unclear whether it should be resumed in the case of histological relapse or only in the case of symptomatic relapse. (Am J Gastroenterol 2000;95:536-539. (O 2000 by Am. Coll. of Gastroenterology)

Administration, Oral↗

Long-lasting effects of cyclophosphamide on lymphocytes in peripheral blood and spinal fluid.

Moderate doses of cyclophosphamide can cause effects on lymphocytes that may last for some time after discontinuation of the treatment. Since cyclophosphamide is also often used at high doses, we studied the short- and long-term effects of such a high dose (8 grams in 20 days) in 50 patients with chronic progressive multiple sclerosis with the use of monoclonal antibodies. The treatment caused a depletion of lymphocytes, especially CD4+ cells resulting in a significant decrease of the CD4/CD8 ratio. These changes can still be found up to 13.5 years after treatment. Although there was some recovery in the first few years after treatment this was only partial. Therefore, some of the effects of high dose cyclophosphamide on cellular immunity may be permanent. These changes should be taken into account when studying immune parameters or considering new treatments in these patients.

Adult↗

Weekly low-dose cyclophosphamide and alternate-day prednisone: an effective low toxicity regimen for advanced myeloma.

10 of 20 patients with advanced myeloma treated with a simple regimen consisting of weekly low-dose cyclophosphamide (C; 150-300 mg/m2; maximum weekly dose = 500 mg) given intravenously or orally, and alternate-day oral prednisone (P; 50-100 mg) responded clinically and with a fall in serum M protein greater than 50% or urine M protein greater than 90%. 3 of these responders were previous primary treatment failures, all having received cyclophosphamide in combination with other drugs given at 3- to 4-wk intervals. 2 patients treated with this regimen as primary therapy also responded. Although the median survival for the 10 responders was reached at 24.5 months, 3 patients remain alive and well 50+ months from the start of CP therapy. An additional 5 patients had disease stabilization or major improvement in bone pain and/or pancytopenia for over 12 months despite failure to meet strict criteria for response. The data suggest that disease control may be achieved by the more frequent scheduling of known active drugs such as cyclophosphamide (although it alone or in combination with other drugs may be ineffective when given at standard 3- to 4-wk intervals) in combination with prednisone or a more continuous basis. This is an effective yet simple therapeutic approach to myeloma with the distinct advantage of less toxicity than the multiple drug regimens in current use. It may have particular applicability to patients who are elderly or debilitated or in patients in whom cytopenia is present initially or develops on standard melphalan/prednisone regimens.

Administration, Oral↗

Pharmacokinetics of cyclophosphamide in renal failure.

The metabolism of cyclophosphamide was determined in five patients with severe renal insufficiency. After the intravenous injection of 14-C-cyclophosphamide the activities due to unchanged cyclophosphamide and metabolites were determined in samples from urine and serum for 2-3 days. Only 22% of the injected radioactivity could be recovered in the urine during the first 3 days as against the normal of some 65% The rate of biotransformation seemed normal and in agreement with these findings a very long term retention of metabolites could be demonstrated. The clinical implications of these results are discussed.

Aged↗

Intravenous dexamethasone-cyclophosphamide pulse therapy in comparison with oral methylprednisolone-azathioprine therapy in patients with pemphigus: results of a multicenter prospectively randomized study.

BACKGROUND: Pemphigus is a potentially life-threatening autoimmune blistering skin disease usually treated with high-dose corticosteroids in combination with immunosuppressive drugs. In a multicenter, prospectively randomized study we compared efficacy and side effects of a dexamethasone-cyclophosphamide (D/C) pulse therapy with a methylprednisolone-azathioprine (M/A) therapy in 22 patients with newly diagnosed pemphigus vulgaris and pemphigus foliaceus. PATIENTS AND METHODS: The 11 patients of the M/A group were treated with daily doses of methylprednisolone (initially 2 mg/kg body weight) and azathioprine (2-2,5 mg/kg body weight) which were subsequently tapered. D/C pulse therapy in 11 patients consisted of intravenous administration of 100 mg dexamethasone/d on 3 consecutive days along with cyclophosphamide (500 mg) on day one. Pulses were initially repeated every 2-4 weeks and then at increasing intervals. In between the pulses, oral cyclophosphamide (50 mg) was given daily for 6 months. RESULTS: Within 24 months after treatment initiation, 5/11 patients of the D/C group had a remission (complete remissions after discontinuation of therapy in 3 patients) and 6/11 patients had a progression. In the M/A group, there were remissions in 9/11 patients (complete remissions after discontinuation of therapy in 3 patients) and progression in 1/11 patients. There were more relapses in M/A therapy after remission than in D/C therapy. Side effects were more common in the M/A group. These differences were not significant (p > 0,05). CONCLUSION: Because of the high number of progressions in patients treated with D/C therapy, we can not confirm the encouraging results of earlier reports about pulse D/C therapy. Nevertheless D/C therapy seemed to be better tolerated and, in case of primary efficacy, was associated with fewer recurrences than M/A therapy.

Administration, Oral↗

Single-drug chemotherapy of canine transmissible venereal tumor with cyclophosphamide, methotrexate, or vincristine.

During a 21-month period, 48 dogs with spontaneous canine transmissible venereal tumor (clinical stage, T1-T3) were presented to the Veterinary Teaching Hospital, Ahmadu Bello University, Zaria, Nigeria, and were divided into one control and four treatment groups to test the efficacy of single-agent chemotherapeutic drugs. The dogs were not randomly assigned to groups because each chemotherapeutic agent was not continuously available during the test period. Group I consisted of four dogs that received oral cyclophosphamide (50 mg/M2 body surface area [BSA]) on the first four days for six weeks. No therapeutic response was noted in any of the four dogs. Group II consisted of ten dogs that received intravenous (IV) cyclophosphamide (50 mg/M2 BSA) for four consecutive days per week for six weeks. Two of the ten had a partial remission. Group III consisted of eight dogs that received oral methotrexate (2.5 mg/M2 BSA) every other day for six weeks. No therapeutic response was noted in any of the eight dogs. Group IV consisted of 20 dogs that were administered IV vincristine sulfate (0.5 mg/M2 BSA) weekly until a response was noted. Complete remission occurred in each of the 20 dogs. One dog had recurrence within 12 months. Group V was the untreated control group, consisting of six dogs among which no spontaneous remission was seen. Instead, tumor progression was noted. Adverse responses to medication, anorexia, vomiting, diarrhea, and weight loss were seen only with dogs treated with cyclophosphamide and methotrexate.

Animals↗

Cyclophosphamide-induced spermatogenic effects detected in the F1 generation by behavioral testing.

Fischer 344 male rats were treated with cyclophosphamide (10 milligrams per kilogram of body weight) for 5 weeks and subsequently mated to females previously treated with saline or cyclophosphamide. The F1 progeny of the cyclophosphamide-treated males exhibited behavior deficits when compared to controls. These data could indicate a chemically induced genetic effect manifested by behavioral alterations.

Animals↗

In vitro microassay for biological activity of cyclophosphamide metabolites.

A rapid tissue culture assay for detecting the activated metabolites of cyclophosphamide in serum is described. Serum obtained shortly after drug administration was added to microtest wells containing a known number of previously planted target cells. The presence and amount of drug was directly correlated with the degree of inhibition of target cell replication. Either transformed or untransformed cells could be used as the target cells. No inhibition of cell growth was observed if cyclophosphamide was added directly to target cells without prior in vivo activation. The appearance and persistence of activated drug in hamster serum was followed by using in vitro microassay. Cyclophosphamide administered intraperitoneally was metabolized to its active form very rapidly, reaching peak activity in 15 min. After 2 h, activity was no longer detectable. Drug given subcutaneously was activated less rapidly and persisted for a longer period of time. The kinetics of drug activation, as determined by tissue culture assay, appeared to be similar to that obtained by chemical assay for other species.

Antineoplastic Agents↗

Effects of cyclophosphamide and ceftriaxone on gastrointestinal colonization of mice by Candida albicans.

Adult male Crl:CD1 (ICR) mice were fed chow containing Candida albicans to induce sustained gastrointestinal colonization by the yeast. Groups of mice were rendered neutropenic with cyclophosphamide and subsequently received ceftriaxone, while other groups received normal saline and served as controls. Stool cultures were obtained immediately before and at the end of treatment. The administration of cyclophosphamide substantially increased the C. albicans counts in the stools of mice. The addition of ceftriaxone to the cyclophosphamide regimen did not significantly increase the level of gastrointestinal colonization by C. albicans. There was no evidence of Candida dissemination to internal organs.

Alkylating Agents↗

Immunomodulatory and protective effects of moxifloxacin against Candida albicans-induced bronchopneumonia in mice injected with cyclophosphamide.

In a previous study, moxifloxacin was shown to ameliorate immunosuppression and enhance cytokine production in several tissues, including the lungs of cyclophosphamide-injected mice. We examined here the effects of moxifloxacin on Candida albicans lung infection in cyclophosphamide-injected mice. Mice were injected on day 0 with 250 mg of cyclophosphamide/kg, and on days 1 to 4 they were given moxifloxacin at 22.5 mg/kg/day compared to controls given ceftazidime at 75 mg/kg/day or saline. On day 6, C. albicans (10 7 CFU/mouse) was inoculated intratracheally, and animals were observed for the development of bronchopneumonia, weight loss, mortality, the presence of C. albicans, and lung cytokine production. Histopathology on day 10 postinoculation revealed bronchopneumonia in 50, 67, and 0% of saline-, ceftazidime-, and moxifloxacin-treated mice, respectively (P < 0.05). The mortality rates were 28, 17, and 5%, respectively (P < 0.05), and weight loss occurred at 20, 32, and 0%, respectively (P < 0.05). By day 15, C. albicans was eliminated from all moxifloxacin-treated mice but was still isolated from lung homogenates of 50 to 60% of the saline- and ceftazidime-treated groups. Among the cytokines tested on days 0 to 15, we found an increased production of tumor necrosis factor alpha, KC (functional interleukin-8), and gamma interferon in the lungs of ceftazidime- and saline-treated controls compared to the moxifloxacin pretreatment that abolished their secretion. In conclusion, moxifloxacin protected cyclophosphamide-injected mice from C. albicans-induced lung infection and significantly reduced pneumonia, weight loss, and mortality despite the lack of direct antifungal activity. This is most likely due to an immunomodulating activity conferred by moxifloxacin, as shown in this model and in our previous studies. Its potential protective role should be studied in patients undergoing chemotherapy and immune suppression.

Animals↗

Effect of cyclophosphamide on the response of chickens to a virulent strain of Marek's disease virus.

The effect of cyclophosphamide on the pathogenesis of Marek's disease was examined in a line of chickens which is relatively resistant to Marek's disease. The injection of cyclophosphamide into newly hatched chickens delayed and reduced viremia and also reduced the development of Marek's disease lesions until 2 weeks after exposure to Marek's disease virus. The data indicate that a population of T cells susceptible to infection with virus and possibly viral transformation is affected by cyclophosphamide.

Animals↗

Effect of cyclophosphamide on experimental Nocardia asteroides infection in mice.

It was found that cells of Nocardia asteroides GUH-2 (virulent) were approximately 10 times more virulent than cells of N. asteroides 14759 (intermediate) and greater that 500 times more virulent than N. asteroides 10905 (avirulent) cells when early-stationary-phase cultures suspended in saline were injected intravenously into "normal" mice. There appeared to be a specific organ tropism for each strain. Thus, N. asteroides GUH-2 infected primarily the kidneys, N. asteroides 14759 infected the lungs and heart, and N. asteroides 10905 (in large doses) infected the lungs. Cyclophosphamide treatment of the mice 72 h prior to infection dramatically increased host susceptibility to nocardial infection, especially to N. asteroides 14759. However, cyclophosphamide treatment did not significantly alter the organ specificity for each strain. Cyclophosphamide greatly enhanced the ability of the nocardial strain to grow within its target organ and significantly altered normal host clearance from these organs.

Animals↗

Enhancement of delayed-type hypersensitivity to Trypanosoma cruzi in mice treated with Mycobacterium bovis BCG and cyclophosphamide.

C57BL/10J mice treated with Mycobacterium bovis BCG and cyclophosphamide were immunized with disrupted epimastigotes or with living blood trypomastigotes from Trypanosoma cruzi and assayed for delayed hypersensitivity by footpad testing with epimastigote antigens. Enhanced and lasting reactions were observed in mice pretreated with BCG or cyclophosphamide or both and immunized with epimastigotes. Whereas BCG pretreatment clearly reduced the mortality rates of mice immunized with living blood forms, no enhancement of the delayed hypersensitivity responses was observed in animals treated with BCG or cyclophosphamide or both before infection. The production of high levels of delayed hypersensitivity in the absence of infection and its adoptive transfer with cells could help to evaluate the participation of cell-mediated immunity in the protection against T. cruzi.

Animals↗