Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytoprotection utilising amifostine (Ethyol, WR-2721) is an evolving strategy to protect normal cells from the toxicity of chemotherapy. The dosing and administration guidelines are reviewed. The recommended dose of amifostine is 910 mg/m2 as a 15-min infusion prior to chemotherapy. Toxicity of this agent is moderate with hypotension and nausea/vomiting being observed in variable numbers of patients. Administration of amifostine with chemotherapy is simple and is associated with acceptable toxicity.
 ...
PMID:Amifostine (Ethyol): dosing, administration and patient management guidelines. 897 23

The mechanism of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of amifostine are reviewed. Amifostine is a prodrug converted by alkaline phosphatase to the active sulfhydryl compound WR-1065. WR-1065 protects normal cells by scavenging free radicals, donating hydrogen ions to free radicals, depleting oxygen, and binding to active derivatives of antineoplastic agents. The immediate conversion of amifostine to WR-1065, its small volume of distribution, and the limited amount of drug and metabolite recovered in the urine suggest that amifostine is rapidly dephosphorylated and enters cells as its active metabolite. The selectivity of amifostine for normal tissue is hypothesized to be a results of the decreased vascularity of tumors, decreased activity of alkaline phosphatase in tumor cells, and pH dependence of WR-1065 uptake. In clinical studies, amifostine decreased the frequency of cisplatin-induced nephrotoxicity, ototoxicity, neurotoxicity, and myelosuppression. Amifostine has demonstrated an ability to decrease the hematologic toxicity of cyclophosphamide, carboplatin, mitomycin, and antineoplastic drug combinations. Amifostine has FDA-approved labeling for use in reducing cumulative renal toxicity in patients receiving repeat doses of cisplatin for advanced ovarian cancer and non-small-cell lung cancer. The recommended dose in adults is 910 mg/m2 administered as a 15-minute infusion 30 minutes before the start of chemotherapy. The major adverse effects of amifostine include hypotension and emesis. The benefits of amifostine must be weighted against its potential adverse effects, and the drug's impact on the efficacy of antineoplastics should be further investigated. Amifostine has shown promise in protecting non-malignant cells from the toxic effects of antineoplastics, apparently without compromising toxicity against cancer cells.
 ...
PMID:Amifostine for protection from antineoplastic drug toxicity. 977 47

Mitomycin C (MMC)-vinblastine (VBL) is a regimen that has commonly been used as salvage therapy for advanced breast cancer for many years. The hematologic toxicity of this combination is one aspect that limits its usefulness. Amifostine, an organic thiophosphate, has been developed as a selective chemoprotective agent. In this pilot study, we tested the feasibility of MMC/VBL administration in combination with amifostine and we monitored the hematologic toxicity closely. Patients having failed one or two chemotherapy regimens for advanced breast cancer, with a good performance status scored at 2 or better and measurable or evaluable lesion(s), were eligible. They were treated according to the following schedule: mitomycin C 10 mg/m2 i.v. day 1, vinblastine 5 mg/m2 i.v. day 1 and 15, amifostine 910 mg/m2 in short i.v. infusion prior to MMC. Premedication consisted of dexamethasone 3 x 20 mg, haloperidol 2 x 0.5 mg p.o., hydration with 11 of normal saline, metoclopramide 1.5 mg/kg in short infusion and procyclide HCl 10 mg i.v. Cycles were repeated every 4 weeks. In all, 14 cycles were administrated to six heavily pretreated patients. Following the first cycle, five of the six patients experienced grade 3 or 4 neutropenia on day 15, and consequently did not receive the second vinblastine administration as planned. Three out of four patients receiving two or more cycles had moderate thrombocytopenia. There were no patients with neutropenic fever or major bleeding problems. The MMC/VBL+amifostine regimen was well tolerated regarding other toxicities. Neither amifostine-related acute vomiting nor any significant decrease in blood pressure was observed. Administration of amifostine in combination with MMC/VBL was feasible but in this group of heavily pretreated patients there were no hints of a protective effect of amifostine on the hematologic toxicity profile of this chemotherapy regimen.
 ...
PMID:Mitomycin C and vinblastine in combination with amifostine in metastatic breast cancer. A feasibility study of the EORTC--Investigational Drug Branch for Breast Cancer (IDBBC). 932 55

The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken, PA), is a cytoprotective agent that ameliorates the toxicities of anticancer therapy. In vitro, amifostine promotes the formation and survival of primitive hematopoietic progenitors derived from myelodysplastic bone marrow (BM) specimens. To evaluate the hematological effects of amifostine, 18 patients with myelodysplastic syndrome (MDS) and one or more refractory cytopenias received treatment with amifostine in a Phase I/II study. Four cohorts received intravenous treatment with 100, 200, or 400 mg/m2 amifostine three times a week, or 740 mg/m2 weekly for three consecutive weeks followed by 2 weeks observation. Nonresponding patients received a second course of therapy at the next higher dose level depending upon drug tolerance. Bone marrow (BM) progenitor growth was assessed before treatment and after day 21. Diagnoses included refractory anemia (7), refractory anemia with ringed sideroblasts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic responses occurred in 15 patients (83%) treated with the three-times-a-week dose schedule. Fourteen patients had a 50% or greater increase in absolute neutrophil count with amifostine treatment (range, 426 to 11,348/microL). Platelet count increased in 6 (43%) of 14 patients with thrombocytopenia (absolute increase, 16, 000 to 110,000/microL), and 5 of 15 red blood cell transfusion-dependent patients had a 50% of greater reduction in transfusion needs. Assayable hematopoietic progenitors increased in 13 of 15 evaluable patients; including CFU-GEMM (12), BFU-E (8), and CFU-GM (6). Amifostine doses less than or equal to 200 mg/m2 were well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before enrollment experienced an increase in BM blast percentage and two patients had evolution to acute leukemia that persisted after treatment withdrawal. We conclude that amifostine administered at doses </=200 mg/m2 three times a week is well tolerated and has hematologic activity in patients with MDS.
 ...
PMID:Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. 1153 40

This article provides guidelines for the use of amifostine (Ethyol, Alza Pharmaceuticals, Palo Alto, CA, and U.S. Bioscience, Inc., West Conshohocken, PA), a pancytoprotective agent approved for reducing renal toxicity associated with cisplatin administration in patients with advanced ovarian or non-small cell lung cancer. Pretreatment with amifostine reduces the incidence of serious and cumulative chemotherapy-induced toxicities, thus improving quality of life, and allows administration of optimal doses and scheduling of chemotherapy and radiation therapy, translating into improved survival. Practical guidelines for administration of amifostine are provided in an effort to ameliorate emesis, amifostine's principle side effect.
 ...
PMID:Administration of the cytoprotectant amifostine. 1023 50

Recent advances in chemotherapy have focused on the benefit of high dose regimens, increasing the dose intensity of conventional chemotherapy and using intensified chemotherapy with or without autologous bone marrow rescue. Dose intensity usually increases objective response rates of antineoplastic drugs and might, in some circumstances, improves survival. However, unacceptable acute and/or cumulative toxicity often impairs the proper management of patients, leading to dose reduction or treatment delay, thus reducing the efficacy and potentially the quality of life of patients. Therefore, considerable efforts have been made to manage, to prevent, and to delay many acute and cumulative treatment-related toxicities. Amifostine (WR-2721 ) is a multiorgan cytoprotector which has demonstrated cytoprotective effects, in vitro and in vivo, against the most common cytotoxic drug-related toxicities and against radiation-induced adverse effects in healthy tissues. In vitro and in vivo, cytoprotection was observed in several organs including kidney, haematopoietic stem cells, myocardial cells, neural cells, and mucosa, without detectable protection of malignant cells. In addition, in preclinical studies, amifostine appeared to be able to reduce the risk of radiation-induced secondary neoplasms. Phase I studies showed that nausea/vomiting and hypotension are the dose-limiting toxicities of amifostine and these may be controlled by reducing the duration of injection of amifostine. Phase II and randomised studies have confirmed the efficacy of amifostine in protecting against radiotherapy-induced mucositis, cisplatin-induced nephrotoxicity, cyclophosphamide-induced neutropenia and carboplatin-induced thrombocytopenia. Importantly, the cytoprotection of healthy tissues occurred without any significant deleterious effect on response rate, time to progression, and survival of patients receiving amifostine. However, in addition to the potential quality of life benefit, the most important question of whether the use of a cytoprotective agent might translate into the possibility of maintaining the dose intensity of anticancer therapies has still to be answered. The real benefit of amifostine in the overall management of patients with cancer requires additional studies to determine whether this chemoprotective approach can be of benefit to patients by increasing response rate, time to progression, and long term survival in patients receiving the more recent combination therapies involving new drugs such as the taxanes and oxaliplatin.
 ...
PMID:A risk-benefit assessment of amifostine in cytoprotection. 1055 52

Amifostine is a protective agent of normal tissue from adverse effects of radiochemotherapy. It is the prodrug that is dephosphorylated by alkaline phosphatase on plasma membrane into the active form named WR-1065. More than 90 per cent of the drug is cleared from plasma in 6 minutes and the peak tissue concentration is 10-30 minutes after intravenous administration. Amifostine has the selective property to protect normal tissue but not cancer cells by mainly scavenging free radicals induced by radiation and chemocytotoxic agents. Both preclinical and clinical studies of this drug provide the significant protection of hematopoietic progentitors from a broad range of cytotoxic agents such as cyclophosphamide, cisplatin, vinblastine, carboplatin, mitomycin-C, fotemustine, doxorubicin, daunorubicin and radiation as well. Moreover, this drug can protect other normal organs or tissues including kidney, salivary gland, liver, heart, lung and small intestine. Amifostine is quite safe, the two major side effects are vomiting and hypotension, and the minor effects are flushing, sneezing, dizziness, chills, metallic taste etc. The drug was approved by the FDA of U.S.A. for use as a cytoprotectant in cyclophosphamide and cisplatin treatment for advanced ovarian cancer and non small cell lung cancer.
 ...
PMID:Amifostine and hematologic effects. 1080 97

Amifostine (WR-2721; Ethyol) is a well-known cytoprotector, but a possible role in preventing extrahaematological toxicity after high-dose therapy (HDT) has never been investigated. We compared two historical groups of patients who either received (group A, n = 35) or did not receive (group B, n = 33) amifostine (740 mg/m2) before high-dose (HD) melphalan, followed by autologous infusion of peripheral blood progenitor cells (PBPCs). Amifostine was well tolerated at this dose level. Emesis grade 1-2 was the most important side-effect, but the interruption of infusion was never required. The incidence and median duration of severe mucositis (grade 3-4) was 21% and 0 d (range 0-11 d) in group A and 53% and 7 d (range 0-11 d) in group B. The duration of analgesic therapy was also significantly lower in group A (0 d; range 0-12) than in group B (6 d, range 0-20) (P = 0.0001). Severe diarrhoea (3% vs. 25%; P = 0.01) and emesis (9% vs. 34%; P = 0.01) were also reduced in group A in comparison with group B. No differences were observed between the two groups for haematological recovery. This retrospective study strongly suggests that amifostine can reduce severe mucositis and the use of analgesic drugs in this setting. A randomized study is warranted to confirm these preliminary results.
 ...
PMID:Amifostine can reduce mucosal damage after high-dose melphalan conditioning for peripheral blood progenitor cellautotransplant: a retrospective study. 1097 85

This pilot study evaluates the degree of side effects during high-dose chemotherapy (HD-VIC) plus autologous bone marrow transplant (HDCT) and its possible prevention by the cytoprotective thiol-derivate amifostine. Additionally, the in-patient medical costs of both treatment arms were compared. 40 patients with solid tumours were randomized to receive HD-VIC chemotherapy with or without amifostine (910 mg/m(2)at day 1-3) given as a short infusion prior to carboplatin and ifosfamide. Patients were stratified according to pretreatment. HDCT consisted of an 18 h infusion of carboplatin (500 mg/m(2/)d over 18 h), ifosfamide (4 g/m(2)/d over 4 h) and etoposide (500 mg/m(2)/d) all given for 3 consecutive days. All patients received prophylactic application of G-CSF (5 microg kg(-1)subcutaneously) to ameliorate neutropenia after treatment. Patients were monitored for nephrotoxicity, gastrointestinal side effects, haematopoietic recovery, as well as frequency of fever and infections. The median fall of the glomerular filtration rate (GFR) was 10% from baseline in the amifostine group (105 to 95 ml min(-1)) and 37% in the control patient group (107 to 67 ml min(-1)) (P< 0.01). Amifostine-treated patients revealed a less pronounced increase in albumin and low molecular weight protein urinary excretion. Stomatitis grade III/IV occurred in 25% without versus 0% of patients with amifostine (P = 0.01). Acute nausea/vomiting was frequently observed immediately during or after the application of amifostine despite intensive antiemetic prophylaxis consisting of 5-HT3-receptor antagonists/dexamethasone/trifluorpromazine. However, delayed emesis occurred more often in the control patients. Engraftment of neutrophil (> 500 microl(-1))and thrombocytes (> 25 000 microl(-1))were observed at days 9 versus 10 and 10 versus 12, respectively, both slightly in favour of the amifostine arm. In addition, a lower number of days with fever and a shortened duration of hospital stay were observed in the amifostine arm. The reduction of acute toxicity observed in the amifostine arm resulted in 30% savings in costs for supportive care (Euro 4396 versus Euro 3153 per patient). Taking into account the drug costs of amifostine, calculation of in-patient treatment costs from the start of chemotherapy to discharge revealed additional costs of Euro 540 per patient in the amifostine arm. This randomized pilot study indicates that both organ and haematotoxicity of HD-VIC chemotherapy can be ameliorated by the use of amifostine. Additionally, a nearly complete preservation of GFR was observed in amifostine-treated patients which may be advantageous if repetitive cycles of HDCT are planned. Larger randomized trials evaluating amifostine cytoprotection during high-dose chemotherapy are warranted.
 ...
PMID:A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplantation. 1116 94

Intrinsic radioresistance, tumor hypoxia and ability of cancer cells to undergo rapid repopulation during radiotherapy are associated with failure of radiotherapy. Tumors with low alpha/beta-ratio values or hypoxic tumors unable to undergo re-oxygenation, are unlikely to be eradicated with standard radiotherapy. Although the therapeutic efficacy of accelerated regimens based on low-dose per fraction may be high since they minimize the adverse role of rapid tumor repopulation, the cellular compartment with low alpha/beta-ratio values (i.e. hypoxic cells) remains a limiting factor. Accelerated hypofractionation, which may be more effective in such tumors, cannot be safely applied unless normal tissues are protected. In the present study we assessed the feasibility of hypofractionated and accelerated radiotherapy supported by cytoprotection (HypoARC) with high dose daily amifostine. Fifteen breast cancer patients with locally advanced disease entered radiation-dose escalation protocoL Twelve consecutive fractions of 3.5-4Gy (5 fractions/week) were given to the breast/chest wall, supraclavicular and axillary area, within 17 days. A high dose of amifostine, at 1,000 mg flat dose, was given 20 minutes before each radiotherapy fraction. Amifostine administration was well- tolerated with minor side-effects (vomiting in 6 out of 15 and hypotention in 2 out of 15 patients). Radiation induced acute skin toxicity was negligible (grade 3 in 1 out of 15 patients). Ten out of 15 patients survived more than 12 months and 7 out of 15 more than 18 months following HypoARC. None of these patients showed any signs of late sequellae, such as lung and myoskeletal fibrosis, or brachial plexopathy. Complete and partial responses were obtained in 11 out of 15 (73%) and in 4 out of 15 (27%) patients, respectively. High dose daily amifostine during hypofractionated radiotherapy is feasible. HypoARC regimen is well-tolerated, effective and has minimal acute and late toxicity to normal breast, chest and axillary tissues.
 ...
PMID:High dose daily amifostine and hypofractionated intensively accelerated radiotherapy for locally advanced breast cancer. A phase I/II study and report on early and late sequellae. 1171 96


1 2 3 Next >>