Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic effect of most immunosuppressive agents is unspecific and therefore often limited by an increased risk of infection by viral, bacterial or fungal organisms as well as by an increased incidence of malignant neoplasms. This short review includes the most commonly used immunosuppressants such as corticosteroids, azathioprine, methotrexate, cyclophosphamide and cyclosporine. The most common risks of long-term corticosteroid treatment are Cushing-like changes, decreased glucose tolerance and the usually benign steroid diabetes. Also clinically important is osteoporosis, since it can be prevented by physical training, calcium supplementation and treatment with vitamin D if necessary. Although there is still no proof of a significantly increased risk of peptic ulcer during steroid therapy, patients may develop gastrointestinal hemorrhage and even perforation without producing pain while being treated with corticosteroids. Mineralocorticoid effects, such as salt and water retention, are seen only with hydrocortisone and prednisone, whereas with synthetic steroids such as dexamethasone, sodium retention is absent despite their strong antiphlogistic activity. The most important side effect of the cytotoxic agents azathioprine, methotrexate and cyclophosphamide is marrow suppression. Due to the high turnover of neutrophils, patients most frequently suffer neutropenia rather than thrombocytopenia or anemia. Neutropenia, as well as impaired humoral and cellular immune mechanisms, are responsible for increased susceptibility to bacterial, viral or parasitic diseases during immunosuppressive therapy. Hepatotoxicity has been reported among patients receiving azathioprine (cholestatic hepatitis) and methotrexate (elevated AST levels and, rarely, liver fibrosis or cirrhosis). Cyclophosphamide causes hemorrhagic cystitis in a substantial proportion of patients, as well as an increased incidence of urothelial neoplasms. Both these side effects may be prevented by Mesna. The most important side effects of cyclosporine are acute and chronic nephrotoxicity usually associated with significantly elevated plasma levels of the drug. It must be borne in mind that severe nephrotoxicity may occur in patients receiving cyclosporine and ketoconazole together, since the latter may inappropriately increase the plasma cyclosporine level.
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PMID:[Immunosuppression--a tightrope walk between iatrogenic harm and therapy]. 892 65

High-dose ifosfamide (HD-IFX) has shown significant antitumor activity in advanced sarcoma and breast carcinoma. The use of uroprotective agents and the availability of ambulatory continuous-infusion pumps has allowed dose escalation in the administration of ifosfamide (IFX) on an outpatient schedule. We report the results of a phase II trial of IFX given at high doses to heavily pretreated patients. IFX was infused at 2 g/m2 per day for a total of 7 days through a central venous access, with cycles being repeated every 21 days. Mesna was given concomitantly at equimolar doses. No hematopoietic support was used. A total of 27 heavily pretreated patients whose disease had progressed during conventional-dose chemotherapy were included (14 sarcomas, 10 breast carcinomas, and 3 bladder carcinomas). Reversible neutropenia and gastrointestinal toxicity were the most frequently encountered toxicities. Only two patients developed transient renal failure, and two others developed central nervous system toxicity. No treatment-related death was observed. Of 22 patients who were evaluable for response, 6 (27%) showed an objective response (OR), all ORs being partial responses (PRs) with a median duration of 6 months, and 12 patients had stable disease (SD; 55%) with a median duration of 3.5 months. The median overall survival (OS) was 6 months. Three patients underwent high-dose chemotherapy after showing a response to our IFX schedule. We conclude that continuous-infusion IFX given in an outpatient setting is a feasible and active regimen that produces, a manageable toxicity profile in heavily pretreated breast cancer and sarcoma patients. Early institution of this schedule in less advanced stages could improve the results obtained.
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PMID:Feasibility trial of high-dose 7-day continuous-infusion ifosfamide given on an outpatient basis. 921 13

The Hoosier Oncology Group conducted a trial evaluating ifosfamide in patients who had recurrent or metastatic squamous cell carcinoma of the head and neck. Patients must have received no prior chemotherapy for metastatic disease. If prior adjuvant chemotherapy was given, the last cycle must have been at least six months from time of recurrence. All patients were required to have a Karnofsky performance status of > or = 50. Twenty-four patients received treatment consisting of ifosfamide, 1.5 g/m2/day for 5 days, with cycles repeated every 3 weeks. Mesna, 300 mg/m2, was administered intravenously 15 minutes before ifosfamide and 4 and 8 hours after ifosfamide on days 1 through 5. Toxicity was predominantly hematologic, with grade 3--4 neutropenia seen in 13 patients resulting in 4 episodes of neutropenic fever. One partial response was seen in 23 evaluable patients for an overall response rate of 4.3% (95% confidence interval, 0, 12.7%). In conclusion, ifosfamide would appear to have limited single-agent activity in squamous cell carcinoma of the head and neck.
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PMID:Ifosfamide in the treatment of advanced or recurrent squamous cell carcinoma of the head and neck: a phase II Hoosier Oncology Group trial. 953 11

To evaluate activity and toxicity of a non platinum-based triplet including Gemcitabine, Ifosfamide and Navelbine (GIN) in advanced NSCLC. Stage IIIB/IV NSCLC patients with WHO PS < 2 and bidimensionally measurable disease entered the study. Gemcitabine 1000 mg/sqm day 1 and 1000-800 mg/sqm day 4, Ifosfamide 3 g/sqm day 1 (with Mesna), Navelbine 25 mg/sqm day 1 and 25-20 mg/sqm day 4 were administered intravenously every 3 weeks. Objective responses (ORs) were evaluated every 2 courses: a maximum of 6 courses were administered in responding patients. According to Simon's optimal two-stage design more than 18 ORs out of 54 patients were required to establish the activity of this regimen. Fifty patients entered the study. Main characteristics of the 48 evaluated patients were: median age 63 years, ECOG performance status 0 = 65%, stage IV disease 79% and non-squamous histology 71%. The total number of courses administered was 200, median per patient 4 (range 1-6). Toxicities were evaluated according to WHO criteria: neutropenia grade 3-4 occurred in 47% of the courses; thrombocytopenia grade 3-4 in 6.6%; anaemia grade 3 in 3.5%. Twelve episodes of febrile neutropenia were reported and three patients required hospital admission. No toxic death was reported. Non-haematological toxicity, including skin rash, alopecia and fatigue, were generally. Twenty-five ORs (1 complete response and 24 partial responses) were obtained for a response rate of 52% (95% CI: 37.4-66.5%). One-year survival was 46.5%. This non-platinum-based outpatient triplet showed promising activity against NSCLC with myelosuppression, in particular neutropenia, being dose-limiting. The GIN regimen may represent a valuable alternative to standard platinum-based doublets and triplets in the treatment of advanced NSCLC and further studies with this platinum-free combination are warranted.
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PMID:Gemcitabine, Ifosfamide and Navelbine (GIN): activity and safety of a non-platinum-based triplet in advanced non-small-cell lung cancer (NSCLC). 1172 Apr 27

Purpose Because we had observed in the synovial sarcoma subgroup of a broad phase III advanced soft tissue sarcoma study a significantly greater objective regression rate from ifosfamide+doxorubicin (88%) than from doxorubicin alone (20%) (P = 0.02), the Eastern Cooperative Oncology Group (ECOG) decided to further assess this two drug combination in a subsequent Phase II study.Patients Between 1994 and 1999, twelve adult patients with advanced synovial sarcomas were enrolled to receive, as their initial chemotherapy, ifosfamide 7.5 gm/m(2) plus doxorubicin 60 mg/m(2), given intravenously over two consecutive days every 3 weeks.Methods Each day for 2 days doxorubicin 30 mg/m(2) was infused over 5 min through a running i.v., followed by ifosfamide 3750 mg/m(2) over 4 h. Continuous i.v. fluid was infused at 300 mL/h for 3 h on day 1, before chemotherapy was begun; then the infusion was continued at 100 mL/h for a total of 3 days. Mesna 750 mg/m(2) was given 15 min before ifosfamide and at 4 and 8 h after ifosfamide on days 1 and 2 of each treatment cycle. Filgrastim (G-CSF) 5 mug/kg was given subcutaneously each day for 14 days beginning on day 3 of each treatment cycle to limit the severity of neutropenia.Results Five of our 12 patients (42%) experienced partial regression of their advanced synovial sarcomas; however, this first stage result was borderline for proceeding to the second planned stage of accrual and our case accrual was quite poor. Thus, the study was closed after stage one accrual. Our patients received a median of four cycles of chemotherapy (range: 1 to 6). All patients experienced at least grade 3 neutropenia (grade 4 in nine of them), and one patient died of treatment-related sepsis following the initial cycle of chemotherapy. Median survival was 11 months.
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PMID:Phase II Study of Ifosfamide+Doxorubicin in Patients With Advanced Synovial Sarcomas (E1793): A Trial of the Eastern Cooperative Oncology Group. 1852 63

Docetaxel, ifosfamide and cisplatin have proven activity in a broad range of solid tumours and interfere with different phases of the cell cycle. We performed a phase I study with the aim to determine the maximum tolerated dose (MTD) of docetaxel, ifosfamide and cisplatin in patients with solid tumours and to define the safety, dose-limiting toxicity (DLT) and the recommended dose and administration schedule of docetaxel, ifosfamide and cisplatin for further phase II testing. Docetaxel was given by 1-h infusion on day 1, followed by ifosfamide 1000 mg/m(2)/day as a continuous infusion for 5 days. Mesna was added at the same doses to the same infusion bag and was continued for 12 h after the end of ifosfamide. Cisplatin was administered as a 24-h infusion concomitantly with ifosfamide, but in separate infusion bags, either on day 5 (schedule A) or on day 1 (schedule B). Escalation steps were planned only for docetaxel (60, 75, 85 mg/m(2)) and cisplatin (50, 75, 100 mg/m(2)). No intrapatient dose escalation was permitted. Prophylactic ciprofloxacin was used after a protocol amendment was implemented. No prophylactic haematopoietic growth factors were used. Cycles of docetaxel, ifosfamide and cisplatin were given at 3-week intervals. Toxicity was scored according to National Cancer Institute Canada-Common Toxicity Criteria 2. The MTD was defined as the dose at which a DLT was observed in fewer than two of six patients during the first treatment cycle. In total, 85 patients received 309 cycles. Only three escalation steps could be explored and DLTs were observed at each dose level. In total, 32 patients and 49 cycles showed DLTs. Febrile neutropenia occurred in 20 patients (24%). Only two DLTs were nonhaematological (one cerebral infarction and one encephalopathy grade 4). Neutropenia grade 4 lasted for greater than 7 days and/or thrombocytopenia grade 4 was dose limiting in 10 patients. Febrile neutropenia occurred in five of 41 patients (12%) who received prophylactic ciprofloxacin and in 15 of 44 patients (34%) who did not. MTD was reached at level 3 (docetaxel, 75 mg/m(2) and cisplatin, 75 mg/m(2)). With a lower dose of docetaxel (60 mg/m(2)) both schedules A and B were feasible, although, overall, schedule A seemed to be better tolerated. On the basis of this phase I study, the recommended docetaxel, ifosfamide and cisplatin regimen is docetaxel (60 mg/m(2)) on day 1, ifosfamide (1000 mg/m(2)/day) on days 1-5 and cisplatin (75 mg/m(2)) given on day 5. It is associated with substantial haematological toxicity, but this is feasible provided prophylactic antibiotics are used.
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PMID:Docetaxel, ifosfamide and cisplatin in solid tumour treatment: a phase I study. 2008 71