-
European Journal of Cancer (Oxford,... Aug 1997The pharmacokinetics of the cytoprotective agent amifostine (EthyolR; WR 2721) and its main metabolites (WR 1065 and the disulphides) were studied in patients... (Clinical Trial)
Clinical Trial
The pharmacokinetics of the cytoprotective agent amifostine (EthyolR; WR 2721) and its main metabolites (WR 1065 and the disulphides) were studied in patients participating in two phase I trials concerning carboplatin or cisplatin in combination with amifostine. Patients were treated with a single dose or three doses of amifostine (740 or 910 mg/m2). The single or first dose was given as a 15 min i.v. infusion just before administration of the chemotherapeutic agent. The additional two infusions were administered 2 and 4 h thereafter. Amifostine was rapidly cleared from the plasma, due to, at least in part, the fast conversion into WR 1065. A biphasic decrease with a final half-life of 0.8 h was observed. The active metabolite WR 1065 was cleared from the plasma with a final half-life of 7.3 +/- 3.6 h. The short initial half-life of WR 1065 can be explained by its fast uptake in tissues and the formation of disulphides. The disulphides were cleared with a final half-life of 8.4-13.4 h and were detectable for at least 24 h after treatment. They may serve as an exchangeable pool of WR 1065. The amifostine peak values at the end of each 15 min infusion did not accumulate in the multiple dosing schedule. For WR 1065 a trend towards an increase in the peak levels was observed [C1,max: 47.5 +/- 11.9 microM, C2,max: 79.0 +/- 13.2 microM, C3,max: 84.8 +/- 15.1 microM, (n = 6)], whereas a trend towards a small decrease was observed for the peak levels of the disulphides [C1,max: 184.2 +/- 12.6 microM, C2,max: 175.0 +/- 23.7 microM, C3,max: 166.0 +/- 17.2 microM, (n = 6)]. This latter finding might suggest a saturation of the disulphide formation or a change in the uptake or elimination of WR 1065, which would result in higher WR 1065 levels in plasma and tissues, after multiple doses of amifostine.
Topics: Adult; Amifostine; Antineoplastic Agents; Carboplatin; Cisplatin; Disulfides; Drug Therapy, Combination; Female; Half-Life; Humans; Male; Mercaptoethylamines; Middle Aged
PubMed: 9337685
DOI: 10.1016/s0959-8049(97)00138-x -
Anticancer Research 1998Amifostine (WR-2721, Ethyol), S-2[3-aminopropylamino]-ethyl-phosphorothioic acid, was selected as a clinically usable radioprotector from more than 4,400 compounds in... (Review)
Review
Amifostine (WR-2721, Ethyol), S-2[3-aminopropylamino]-ethyl-phosphorothioic acid, was selected as a clinically usable radioprotector from more than 4,400 compounds in the 1950s. A considerable amount of preclinical work suggested that amifostine, or its activated thiol WR-1065, protected normal cells effectively against the adverse effects of irradiation and several anticancer drugs without exhibiting tumor protection. In non-randomized and randomized trials in malignant melanoma, colorectal cancer, head and neck cancer, non-small cell lung cancer, and epithelial ovarian carcinoma, amifostine significantly reduced the hematological and non-hematological toxicity of DNA-damaging agents such as alkylators, platinum compounds, or mitomycin C. In more recent studies, the drug also protected patients from side effects produced by taxanes or topoisomerase I inhibitors and is thus likely to allow higher cytostatic doses to be administered. Currently, there is no evidence that amifostine compromises the antineoplastic effect of the drugs studied. Otherwise, W/R-2721 may even improve the therapeutic efficacy of agents like cisplatin, carboplatin, or paclitaxel. Moreover, amifostine appears to produce growth-factor like properties resulting in growth-promoting effects on primitive blood progenitor cells ex vivo. Amifostine offers a rational approach to protect patients against chemotherapy-specific and often dose-limiting effects and is thus likely to improve therapeutic outcome significantly. Future studies should be focused on both new indications like childhood cancer, myelodysplastic syndromes, dose-intensified or high- dose chemotherapy, and multimodality approaches and optimization of amifostine dosage in order to reduce dose-limiting side effects. Then, the drug may play a major role in more specific and individualized oncologic strategies.
Topics: Amifostine; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Humans; Neoplasms; Radiation-Protective Agents; Randomized Controlled Trials as Topic
PubMed: 9703784
DOI: No ID Found -
Seminars in Oncology Oct 1994Amifostine (WR-2721, S-2 [3-aminopropylamino]-ethylphosphorothioic acid; Ethyol, US Bioscience, Inc. West Conshohocken, PA), developed as a radiation protector, has... (Review)
Review
Amifostine (WR-2721, S-2 [3-aminopropylamino]-ethylphosphorothioic acid; Ethyol, US Bioscience, Inc. West Conshohocken, PA), developed as a radiation protector, has exhibited activity as a chemoprotector. The compound requires activation by dephosphorylation to produce the free thiol, WR-1065. This process is catalyzed by capillary alkaline phosphatase that is close to the desired site of protection. Additionally, the neutral pH of normal tissues, compared with the slightly acidic pH of tumors, favors selective activation. The protective mechanism against radiation damage is produced, and is, most probably, different from that of chemotherapy. The most likely mechanism for radioprotection involves free radical scavenging and hydrogen donation to repair damaged DNA. The hydrogen ion donation by the thiol group is required for both chemoprotection and radioprotection. Chemoprotection is presumed to be mediated by inactivation of the charged carbonium ions of activated alkylating agents through a nucleophilic attack, thereby protecting the nucleic acids from alkylation. Amifostine is able to reduce DNA platination when preincubated or coincubated with cisplatin, but this effect is much weaker when given postincubation. Observations show that maximum protection can only be obtained if amifostine is given before the administration of cytotoxic therapy. Amifostine side effects, as seen in mice, are dose dependent. A dose of 200 mg/kg has been found to be relatively nontoxic, although some hypothermia was observed.
Topics: Amifostine; Animals; Antineoplastic Agents; Bone Marrow; Cell Survival; DNA; Kidney; Prodrugs; Radiation Injuries, Experimental
PubMed: 7973774
DOI: No ID Found -
Frontiers of Radiation Therapy and... 2002
Review
Topics: Amifostine; Animals; Clinical Trials as Topic; Head and Neck Neoplasms; Humans; Mouth Mucosa; Radiation-Protective Agents; Xerostomia
PubMed: 11764651
DOI: 10.1159/000061305 -
Seminars in Radiation Oncology Oct 1998Evidence for the use of amifostine (Ethyol, ALZA Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) as a radioprotectant has been gathered in a number... (Review)
Review
Evidence for the use of amifostine (Ethyol, ALZA Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) as a radioprotectant has been gathered in a number of clinical trials conducted over the past decade. This report briefly reviews those trials, as well as highlights results of a recent phase II trial conducted to evaluate the efficacy of daily amifostine administration in reducing the incidence of radiation-induced esophagitis in patients with stage III non-small cell lung cancer. Of 25 patients evaluated, none experienced grade 3 or 4 esophagitis or dyspnea. No patients required discontinuation of therapy due to amifostine-induced hypotension. There was a 60% objective response rate and 1-, 2-, and 3-year survival rates were 55%, 23%, and 23%, respectively. Thus, amifostine administration reduced radiation-induced toxicities without reducing antitumor efficacy.
Topics: Amifostine; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Esophagitis; Esophagus; Humans; Incidence; Lung Neoplasms; Radiation Injuries; Radiation-Protective Agents; Radiotherapy; Remission Induction; Survival Rate
PubMed: 9794996
DOI: No ID Found -
Leukemia Research May 1998
Review
Topics: Amifostine; Cell Differentiation; Clinical Trials as Topic; Cytoprotection; Hematopoiesis; Humans; Myelodysplastic Syndromes; Phenylbutyrates; Prodrugs
PubMed: 9734693
DOI: 10.1016/s0145-2126(98)00034-4 -
Journal of Cancer Research and... 2014
Topics: Amifostine; Creativity; Humans; Hyperthermia, Induced; Medical Oncology; Organizational Innovation; Radiation-Protective Agents
PubMed: 25579510
DOI: 10.4103/0973-1482.148859 -
Indian Journal of Pharmacology 2015Amifostine is a drug which can eliminate free oxygen radicals that appear in the body after radiation or chemotherapeutic agent exposure. It is used to decrease the...
OBJECTIVES
Amifostine is a drug which can eliminate free oxygen radicals that appear in the body after radiation or chemotherapeutic agent exposure. It is used to decrease the renal toxicity of cisplatin. The aim of this study was to determine the role of amifostine in warm ischemia kidney model for prevention of ischemia/reperfusion injury and also to find out the mechanism for prevention from ischemia/reperfusion injury if such an effect does exist.
MATERIALS AND METHODS
Adult female rats (n = 40) that used in our study were divided into three groups. Group 1: Control (n = 8), group 2: Ischemia-control (n = 16), group 3: Amifostine treated (n = 16). The effect of amifostine on ischemia/reperfusion injury investigated in rat kidneys.
RESULTS
At the 7(th) day, blood urea nitrogen level was statistically significantly higher in ischemia-control group than all groups (P = 0.001) and mean serum creatinine levels were found to be the highest in ischemia-control group (P = 0.091). Mean malondialdehyde levels in left kidneys removed on the 7(th) day were not significantly different (P = 0.105) at all three groups. Between ischemia-control group and amifostine group, there was a significant difference in reduced glutathione (GSH) levels (P = 0.001). In amifostine group, grade 4 necrosis was not detected neither on 7(th) day nor day 0.
CONCLUSION
Amifostine could decrease the degree and severity of necrosis after reperfusion. Amifostine could not prevent membrane lipid peroxidation caused by superoxide anion radicals in kidney but they could protect tissues from the harmful effects of ischemia/reperfusion injury by increasing the level of reduced GSH which is a well-known oxygen radical eliminator.
Topics: Amifostine; Animals; Antioxidants; Disease Models, Animal; Female; Glutathione; Kidney; Kidney Function Tests; Lipid Peroxidation; Necrosis; Rats; Reperfusion Injury; Treatment Outcome; Warm Ischemia
PubMed: 25878379
DOI: 10.4103/0253-7613.153427 -
Radiation and Environmental Biophysics May 2022Radiotherapy can be employed as a therapeutic modality alone in the early stages of cancer and is used together with other treatments such as surgery and chemotherapy in...
Radiotherapy can be employed as a therapeutic modality alone in the early stages of cancer and is used together with other treatments such as surgery and chemotherapy in more advanced stages. However, exposure to ionizing radiation in association with radiotherapy affects several organs in the head and neck and can give rise to early and late side effects. Exposure to ionizing radiation used in radiotherapy is known to cause cell damage by leading to oxygen stress through the production of free oxygen radicals (such as superoxide radicals, hydroxyl radical, hydrogen peroxide, and singlet oxygen), depending on the total radiation dosage, the fractionation rate, radiosensitivity, and linear energy transfer. The purpose of the present study was to determine the potential protective role of a powerful and highly selective α2-adrenoreceptor agonist with a broad pharmacological spectrum against salivary gland damage induced by ionizing radiation exposure. Forty Sprague-Dawley rats were divided into five groups-control, ionizing radiation, ionizing radiation + dexmedetomidine (100 µg/kg), ionizing radiation + dexmedetomidine (200 µg/kg), and ionizing radiation + amifostine (200 mg/kg). Following exposure to ionizing radiation, we observed necrosis, fibrosis, and vascular congestions in parotid gland epithelial cells. We also observed increases in malondialdehyde (MDA) and cleaved Caspase-3 levels and a decrease in glutathione (GSH). In groups receiving dexmedetomidine, we observed necrotic epithelial cells, fibrosis and vascular congestion in parotid gland tissue, a decrease in MDA levels, and an increase in GSH. Dexmedetomidine may be a promising antioxidant agent for the prevention of oxidative damage following radiation exposure.
Topics: Amifostine; Animals; Dexmedetomidine; Fibrosis; Glutathione; Oxidative Stress; Parotid Gland; Rats; Rats, Sprague-Dawley; X-Rays
PubMed: 35147734
DOI: 10.1007/s00411-022-00964-8 -
Environmental Toxicology Apr 2010Amifostine is the most effective radioprotector known and the only one accepted for clinical use in cancer radiotherapy. In this work, the antigenotoxic effect of...
Amifostine is the most effective radioprotector known and the only one accepted for clinical use in cancer radiotherapy. In this work, the antigenotoxic effect of amifostine against gamma-rays was studied in Escherichia coli cells deficient in DNA damage repair activities. Assays of irradiated cells treated with amifostine showed that the drug reduced the genotoxicity induced by radiation in E. coli wild-type genotypes and in uvr, recF, recB, recB-recC-recF mutant strains, but not in recN defective cells. Thus, the mechanism of DNA protection by amifostine against gamma-radiation-induced genotoxicity appears to involve participation of the RecN protein that facilitates repair of DNA double-strand breaks. The results are discussed in relation to amifostine's chemopreventive potential.
Topics: Amifostine; Bacterial Proteins; DNA Damage; DNA Repair; DNA Restriction Enzymes; Escherichia coli; Escherichia coli Proteins; Gamma Rays; Radiation-Protective Agents
PubMed: 19399845
DOI: 10.1002/tox.20483