Oral Administration Of Cyclophosphamide Research Articles

Risk of Relapse of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in a Randomized Controlled Trial of Plasma Exchange and Glucocorticoids.

Relapses of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are important events that can cause organ dysfunction and reduce quality of life. Understanding the effects of the initial treatments for ANCA-associated vasculitis on the subsequent risk of relapse may help guide monitoring and treatment. We performed a post hoc analysis of participants with severe ANCA-associated vasculitis enrolled in an international two-by-two factorial randomized controlled trial comparing the effects of plasma exchange (PLEX) to no PLEX and a regimen of reduced glucocorticoid exposure to a standard regimen. We estimated the effects of treatments on relapses of any severity using three competing risk time-to-event models adjusted for patient and disease characteristics and other treatments. Each model was adjusted for disease manifestations in different ways. Of 704 participants, 649 (92.2%) achieved remission and 147 (22.7%) experienced 204 relapses. The relapse rate was 10.3 (95% confidence interval [CI] 8.4-12.1) relapses per 100 patient-years. Neither the use of PLEX (subhazard ratio 0.91-0.94; 95% CIs range from 0.66 to 1.31) nor a glucocorticoid regimen (subhazard ratio 0.93-0.94; 95% CIs range from 0.67 to 1.35) appreciably changed the risk of relapse. Proteinase 3-ANCA and the presence of nonhemorrhagic respiratory manifestations of the disease at trial entry were associated with increased risks of relapse. Receiving dialysis at baseline and administration of oral cyclophosphamide as induction therapy were associated with lower risks of relapse. In patients with severe ANCA-associated vasculitis, relapses remain common; neither the use of PLEX nor an initial glucocorticoid tapering regimen impacted relapse risk.

Successful pregnancy in patient with Wegener’s granulomatosis

The prognosis of Wegener’s granulomatosis (WG), if untreated, is poor in most cases. Fatal outcome occurs due to pulmonary and heart failure, circulatory disorders, uremia and extreme exhaustion. The prognosis for such patients was significantly improved with the initiation of cyclophosphamide and glucocorticoid. Objective — clinical evaluation of Wegener's granulomatosis.Materials and methods. Clinical, laboratory, instrumental methods of research; analysis of available sources of literatureResults and discussion. As for treatment, the standard WG drug therapy is currently based on the oral administration of cyclophosphamide (2—3 mg/kg/day) in combination with glucocorticosteroids (GCS) in a dose equivalent to prednisone (1 mg/kg/day). GCS monotherapy somewhat improves the patient's state but has little effect on the prognosis. The effect of pregnancy on WG is unpredictable. The onset or exacerbation of the disease can occur at any time during pregnancy, but the trimester in which it occurs affects the treatment result and outcome. In this work, we present one of our own long-term follow-ups of a patient with WG who had two pregnancies and childbirth: the first in 2006 and the second in 2015 in the seventh year of the disease.Conclusions. Successful pregnancies and childbirth during the relapse of Wegener's granulomatosis are very rare, therefore young women should be strongly advised to plan a pregnancy during the remission period.The management of Wegener's granulomatosis during pregnancy should be strictly individual under the supervision of a multidisciplinary team of doctors. The choice of drugs, their doses and route of administration depend on the trimester of pregnancy and the severity of the disease.

Immunostimulatory Effect of Zanthoxylum schinifolium-Based Complex Oil Prepared by Supercritical Fluid Extraction in Splenocytes and Cyclophosphamide-Induced Immunosuppressed Rats.

Complex oil of Zanthoxylum schinifolium and Perilla frutescens seed (ZPCO) is used as a traditional medicine due to its pharmacological activities. The aim of this study was to investigate the immunostimulatory effect of ZPCO in isolated splenocytes as well as in an immunosuppressed rat model, which was generated via oral administration of cyclophosphamide. Notably, our results showed that ZPCO exerted an immunity-enhancing effect both in vitro and in vivo. Specifically, ZPCO treatment enhanced the viability and inflammatory cytokine production of splenocytes and NK cell activity in vitro. Moreover, this product improved host defense under immunosuppressive conditions by increasing the number of immune cells and promoting the expression of cytokines involved in immune responses. Our results suggest that complex oil including Z. schinifolium should be explored as a novel immunostimulatory agent that could potentially be used for therapeutic purposes or as an ingredient in functional foods.

A new perspective in cancer treatment: Low dose metronomic chemotherapy with old known drugs in advanced breast cancer patients—Phase II clinical trial.

e13500 Background: The oral administration of Cyclophosphamide (Cy) and Celecoxib (Cel) encourage the use of low-dose metronomic chemotherapy (MC) to treat heavily pretreated, multidrug resistant, ...

Bone marrow micronucleus frequencies in the rat after oral administration of cyclophosphamide, hexamethylphosphoramide or gemifloxacin for 2 and 28 days

Cyclophosphamide (CPA), hexamethylphosphoramide (HMPA) and gemifloxacin (GF) were administered orally to Han Wistar rats for 2 and 28 days up to their maximum tolerated doses. For CPA, the sensitivity, as measured by the increases at the lowest active dose, was greater after 28 days. However, published data show that blood levels at 28 days are the same as at 2 days. The sensitivity to HMPA was also greater at 28 days but toxicokinetic analysis showed a reduction in blood levels. Although apparently anomalous, this probably reflected increased metabolism of HMPA to its genotoxic metabolite, formaldehyde. In contrast, GF gave a clear increase in micronucleus frequency after 2 doses but not after 28 and the maximum dose tolerated for 28 days gave blood levels 80% greater than the same dose after 2 days. It is apparent that for these three compounds there are differences between responses after dosing for 2 and 28 days that cannot be ascribed simply to differences in blood levels. It is important to note that although the responses were quantitatively different, the two established rodent carcinogens gave positive results at both sampling times. Because rodent oncogenicity data are not available for GF, it is not known whether the positive or negative result in the rat bone marrow micronucleus test is predictive. The purpose of this work was not to support the use of either acute or sub-chronic dosing for the rat micronucleus assay but to point out that sampling times can give both qualitatively and quantitatively different results. Cyclophosphamide (CPA), hexamethylphosphoramide (HMPA) and gemifloxacin (GF) were administered orally to Han Wistar rats for 2 and 28 days up to their maximum tolerated doses.

An all-oral combination of metronomic cyclophosphamide plus capecitabine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: a phase II study

Oral administration of cyclophosphamide (CTX) and capecitabine may have a greater potential for treatment of metastatic breast cancer (MBC) due to anti-angiogenesis resulting from the metronomic dosage and upregulation of thymidine phosphorylase by CTX. The purpose of this phase II study was to evaluate the efficacy and safety profile of an all-oral combination of metronomic CTX plus capecitabine for women with anthracycline- and taxane-pretreated MBC. In this prospective single-center, open-label, phase II trial, patients with measurable disease received oral metronomic CTX 65 mg/m(2) daily on days 1-14 plus capecitabine 1,000 mg/m(2) twice daily on days 1-14. The treatment was repeated every 3 weeks, and continued until disease progression, unacceptable toxicity or withdrawal of informed consent. The primary endpoint of the study was time to progression (TTP). A total of 68 patients were enrolled and received 537 cycles of chemotherapy with a median of 8 cycles (range: 1-30 cycles) per patient. Sixty-six patients were evaluated for efficacy with all patients for toxicity. With a median follow-up time of 26 months, the median time to progression was 5.2 months (95% CI, 4.2-6.2 months), and the median overall survival was 16.9 months. The overall response rate was 30.3% (95% CI, 20-43%). Clinical benefit rate was 53.0% (95% CI, 38-62%). The doublet was well tolerable, with anorexia (7.5%), the only grade 3/4 adverse events occurring in more than 5% of patients. Grade 3 hand-foot syndrome was 4.4%. The all-oral combination of metronomic CTX plus capecitabine is an effective and convenient and well-tolerated regimen for MBC. (ClinicalTrials.gov number, NCT00589901).

Dramatic regression of mesenteric abnormalities demonstrated on angiography following prednisolone and cyclophosphamide combination therapy in a patient with polyarteritis nodosa associated with Sjögren’s syndrome

A 63-year-old woman, who had been followed for Sjögren's syndrome, was admitted due to cryoglobulinemia, leukocytoclastic vasculitis, and mononeuritis multiplexa. In spite of the administration of 60 mg prednisolone, fecal occult blood was strongly positive. The colonoscopy showed multiple colonic ulcers, and a diagnosis of polyarteritis nodosa (PAN) was made because abdominal angiography revealed markedly serpentine and narrowed superior and inferior mesenteric arteries. After steroid pulse therapy and daily oral administration of cyclophosphamide were initiated, her symptoms improved and abdominal angiographic findings were finally normalized. Although there are only three case reports on improvements in abdominal angiographic findings of PAN in the literature, our case and previously reported cases suggest that improvements in angiographic findings may reflect a good prognosis of PAN.

Immunosuppressive Therapy and Clinical Evolution in Forty-nine Patients with Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis

Immunosuppressive therapy and clinical evolution were studied in 49 patients (29 females) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The mean age of patients at presentation was 55 years, and the mean (+/-SD) follow-up was 43 months (+/-33) (range, 3-140). Among the 49 patients, 10 had biopsy-proven Wegener's granulomatosis, 33 microscopic polyangiitis, 2 Churg-Strauss syndrome, and 4 idiopathic crescentic glomerulonephritis. IgG ANCA autoantibodies were detected in all patients. Induction therapy included pulses and oral administration of methylprednisolone (MP) with oral administration of cyclophosphamide (CP) and plasma exchange in patients with alveolar hemorrhage and serum creatinine (SCr) levels >/= 6 mg/dL. CP was converted to azathioprine (AZA) or mycophenolate mofetil (MMF) after 3-6 months of therapy. Low doses of MP with or without AZA or MMF were administered until the end of follow-up. Therapy institution resulted in remission of disease in all patients. The mean SCr levels decreased from 4.9 mg/dL (+/-2.5) at the onset of the disease to 2.8 mg/dL (+/-1.7) (P > 0.0001), and 3.2 mg/dL (+/-2.3) (P > 0.0001) after 3 and 6 months, respectively. At the end of follow-up, 17 (35%) patients progressed to end-stage renal disease after 34 months (+/-29) (range, 3-98), and 30 (61%) patients maintained sufficient renal function. Two patient deaths were attributed to immunosuppression. Patients with high SCr levels at diagnosis and severe interstitial fibrosis found in renal biopsy had poor renal outcome (P > 0.01 and P > 0.02, respectively). Induction therapy with MP and CP seems to be the regimen of choice in patients with ANCA-associated glomerulonephritis. Early diagnosis and therapy institution as well as long-term treatment lead to acceptable renal survival.

Oral Combination of Cyclophosphamide, Uracil plus Tegafur and Estramustine for Hormone-Refractory Prostate Cancer

Objective: To evaluate the clinical usefulness of an oral combination of cyclophosphamide, uracil plus tegafur (UFT) and estramustine in the treatment of patients with hormone-refractory prostate cancer (HRPC). Methods: Twenty-one patients were treated with oral administration of cyclophosphamide (100 mg/day), UFT (400 mg/day) and estramustine phosphate (560 mg/day). The median age of the patients was 70 years. Twelve patients had symptomatic bone metastasis, 6 had asymptomatic bone metastasis, 5 had lymph node metastasis, while 2 had only biochemical progression evaluated by prostate-specific antigen (PSA). Results: Twelve (57%) out of 21 patients showed a PSA decline of 50% or greater. The median response duration was 7 months (range 2–15 months). Among the 20 patients assessable for bone pain, 2 (10%) improved, 12 (60%) remained stable and 6 (30%) progressed. Among the 10 patients assessable for bone metastasis, 1 (10%) improved, 5 (50%) were stable and 4 (40%) progressed on bone scan. Among 3 patients assessable for measurable disease (lymph node metastasis), 2 (67%) showed partial response and 1 (33%) progression. Most toxicities were mild. Conclusions: The combination of cyclophosphamide, UFT and estramustine is an active and well-tolerated regimen for HRPC. To evaluate the survival benefit, further randomized studies are required.

Effect of ascorbic acid supplementation on liver and kidney toxicity in cyclophosphamide-treated female albino rats.

Effects of ascorbic acid supplementation on the activity of acid phosphatase (ACP), alkaline phosphatase (ALP), glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) on liver, kidney and serum in cyclophosphamide-treated female virgin rats were investigated. Oral administration of cyclophosphamide at the dose of 5 mg/kg body weight/day for 12 days resulted in a significant elevation in ACP and ALP activities in liver, kidney and serum. Ascorbic acid supplementation at the dose of 25 mg/kg body weight/day showed a significant protection in the activity of ACP in liver, kidney and serum, but only in ALP activity in kidney. ALP activities in liver and serum were not restored to control level by ascorbic acid supplementation. Activities of GOT and GPT were elevated significantly in liver, kidney and serum after cyclophosphamide treatment, and were protected and restored to control level by ascorbic acid supplementation.

An experimental model of nephritis induced by calf serum injection in mice.

Acute glomerulonephritis characterized by proteinuria, hypoalbuminemia and leukocytosis was induced in mice by repeated intraperitoneal injections of calf serum (1 ml/mouse X 10). In mice treated with calf serum, hypercellularity, karyorrhexis, expansion of the mesangium and hyalinosis in the glomeruli were observed by light microscopy. Furthermore, circulating immune complexes were detected in the serum, and deposits of mouse IgG and C3 on the basement membranes of the glomeruli were demonstrated immunohistochemically. Oral administration of cyclophosphamide or 6-mercaptopurine at a dose of 20 mg/kg/day significantly suppressed the development of this nephritis. Dexamethasone (0.5 mg/kg/day) caused moderate inhibition of the nephritic changes. These results suggest that this experimental model may be useful for evaluation of anti-nephritic drugs.

An Experimental Model of Nephritis Induced by Calf Serum Injection in Mice

Acute glomerulonephritis characterized by proteinuria, hypoalbuminemia and leukocytosis was induced in mice by repeated intraperitoneal injections of calf serum (1 ml/mousex 10). In mice treated with calf serum, hypercellularity, karyor-rhexis, expansion of the mesangium and hyalinosis in the glomeruli were observed by light microscopy. Furthermore, circulating immune complexes were detected in the serum, and deposits of mouse IgG and C3 on the basement membranes of the glomeruli were demonstrated immunohistochemically. Oral administration of cyclophosphamide or 6-mercaptopurine at a dose of 20 mg/kg/day significantly suppressed the development of this nephritis. Dexamethasone (0.5 mg/kg/day) caused moderate inhibition of the nephritic changes. These results suggest that this experimental model may be useful for evaluation of anti-nephritic drugs.

Factor VIII Antibodies in Rheumatoid Arthritis

Three patients with rheumatoid arthritis had bleeding and bruising and were found to have circulating antibodies specifically directed against factor VIII. Review of the literature indicates that this is an unusual but serious complication of rheumatoid arthritis. In two of our three cases, disappearance of the factor VIII antibody coincided with the oral administration of cyclophosphamide; in the third patient, antibody titers declined several weeks after cyclophosphamide therapy was discontinued. Our collected experience involving 11 nonhemophilic patients with factor VIII antibodies indicates that a good response to cyclophosphamide therapy may be expected if the antibody titer is less than 10 Bethesda units at the initiation of treatment. While optimum treatment of these patients is not yet established, we suggest an initial trial of prednisone and, if there is no response, then therapy with cyclophosphamide.

Antitumor activity of improsulfan by the fractionated dose schedule on rat ascites tumors.

The antitumor activity of improsulfan was examined with respect to an increase in the lifespan of rats bearing ascites tumors when a relatively low dose (5 and 20 mg/kg) was given intraperitoneally in two equal fractions and in a single dose. The fractionated dose schedule, even when given in a time interval of over 24 hr, was more effective against tumors sensitive to alkylating agents, Yoshida sarcoma and AH-272. Against other tumors, the fractionated dose schedule was more effective only when given in an interval of within 3 hr or was equally effective at all of the intervals tested as the single dose schedule. The toxicity of improsulfan to normal healthy rats was severer in a single dose than in two equal fractions of the same total dose, 150 mg/kg. Therapeutic synergism was observed against Yoshida sarcoma when intraperitoneal administration of improsulfan and oral administration of cyclophosphamide were made simultaneously. The pharmacokinetic process in tissue concentrations of alkylating agents like that presumed in the fractionated dose schedule of improsulfan may occur by this combination.