Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043352 (xerostomia)
 4,250 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amifostine (Ethyol) has been evaluated clinically as a radioprotective agent for the prevention of xerostomia and mucositis for patients receiving radiotherapy (RT). Currently, amifostine is approved for the prevention of xerostomia in head and neck cancer patients receiving RT when administered intravenously (IV) before RT. For the clinician, there would be several advantages to administering the drug subcutaneously and to being able to show its protective effects on mucositis. The authors have developed a rat RT model to examine the protective effects of amifostine after IV and subcutaneous (SC) administration in a mucositis model. Rats (5 per group) were given 200 mg/kg (human dose equivalent of approximately 1,300 mg/m(2)) of amifostine either IV or SC, and their head and neck regions were exposed to 15.3 Gy of gamma radiation 0.5, 2, 4, and 8 hours after amifostine administration. For 10 days after treatment, the oral cavities of the rats were examined for signs of mucositis. Mucosal erythema and mucosal edema were scored according to 0 through 5 and 0 through 2 scales, respectively, with the scores added to indicate overall mucositis. The average mucositis score for the untreated animals was 3.5. Rats were protected from mucositis up to 4 hours when given amifostine either IV or SC. Rats that received amifostine SC, but not IV, were protected from mucositis 8 hours after administration. Preliminary pharmacokinetic data have revealed slightly higher active metabolite (WR-1065) levels in the parotid gland and small intestine in the rats given amifostine SC compared with IV and equivalent levels in the plasma and kidney. The data showed that SC administration of amifostine gave radioprotection comparable to IV administration up to 4 hours before RT and may be more effective than IV administration at longer pretreatment intervals.
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PMID:Preclinical modeling of improved amifostine (Ethyol) use in radiation therapy. 1191 93

Lens epithelium disorganization, glutathione (GSH) depletion, and epithelial cell death have been incriminated in the cytopathogenic mechanisms that lead to cataract formation following UVB and x-ray exposures. The objective of this study was to determine the in vitro capacity of the aminothiol WR-1065, the active metabolite of amifostine, and anetholedithiolethione (ADT or Sulfarlem) to protect bovine lens epithelial cells against x-ray irradiation. WR-1065 and ADT were used at a concentration of 20 microM. A single dose of 10 Gy was delivered at a rate of 2 Gy/min. Fluorimetric assays were then performed using a neutral red probe to evaluate cell viability, a Hoechst 33342 probe (HO) to evaluate nuclear condensation and apoptosis, and a monobromobimane probe to estimate the intracellular GSH pool. Twenty-four hours after x-ray exposure, cells pretreated with WR-1065 showed increased GSH levels, improved cell viability, and decreased HO fluorescence in addition to a lesser proportion of cells with apoptotic nuclear modifications. Between 72 and 120 hr postirradiation, ADT-pretreated cells also showed increased intracellular GSH levels and cell viability and decreased HO fluorescence and apoptotic cell morphology. This in vitro study demonstrates that WR-1065 and ADT protects lens epithelial cells from x-ray injury; thus, ADT and amifostine are appropriate candidates for clinical trials in humans. They are currently used in preventing radiation-induced xerostomia and should be further tested in the prevention of late radiation-induced ocular complications such as sicca syndrome and cataract.
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PMID:Lens epithelial cell protection by aminothiol WR-1065 and anetholedithiolethione from ionizing radiation. 1199 83

The ability to prevent radiotherapy-induced toxicity without affecting antitumor efficacy has the potential to enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects. Among the currently available cytoprotective agents capable of protecting normal tissue against damage caused by either chemo- or radiotherapy, only amifostine has been shown in clinical trials to reduce radiation-induced toxicity. Most notably, it reduces the incidence of xerostomia, which is a clinically significant long-term toxicity arising in patients undergoing irradiation of head and neck cancers. In vitro studies with the active metabolite of amifostine (WR-1065) have shown it to prevent both radiation-induced cell death and radiation-induced mutagenesis. The potential of this agent to prevent secondary tumors, as well as other radiation-induced toxicities is now the focus of ongoing research. Among other novel approaches to radioprotection being explored are methods to increase levels of the antioxidant mitochondrial enzyme manganese superoxide dismutase (MnSOD). In addition, the use of epoetin alfa, alone or in combination with cytoprotectants (e.g., amifostine), to treat radiation-induced anemia is also being investigated. The objective of developing newer cytoprotective therapies is to improve the therapeutic ratio by reducing the acute and chronic toxicities associated with more intensive and more effective anticancer therapies.
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PMID:Radioprotectants: current status and new directions. 1246 39

Differentiated thyroid cancer can be effectively treated with high-dose 131I and the other head and neck cancer can also be effectively treated with extra-radiotherapy, but these treatments often result in a reduction in salivary gland function, causing xerostomia. Collectively, these effects can lead to severe secondary complications, including difficulty in speaking and swallowing, decreasing appetite even affecting nutrition and sleep. Amifostine, an analog of cysteamine, is a phosphorlyated aminothiol prodrug and its active metabolite, WR-1065 etc, can selectively protect normal tissues from the cytotoxic effects of drugs and/or radiation while preserve antitumor effects. Many studies have demonstrated that amifostine protects normal tissues from both acute and late extra-radiation damage without protecting the tumor. It has been approved by FDA to be used for protecting the salivary gland from xerostomia caused by radiotherapy. It has also show protecting effects on intra-radiotherapy, but there are many problems waiting for study.
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PMID:[Radioprotective effects on head and neck tumors of amifostine--a broad-spectrum cytoprotection]. 1256 84

Amifostine (Ethyol) is a cytoprotective drug approved for the reduction of xerostomia in head and neck cancer when administered to patients receiving postoperative radiation therapy. Although amifostine is approved for intravenous infusion, the off-label subcutaneous route of administration has become more prevalent. Although human patient data indicate higher plasma bioavailability of the active metabolite (WR-1065) following intravenous compared to subcutaneous administration, there are no corresponding data showing human tissue levels of WR-1065 following either route of administration due to the difficulty in obtaining human specimens. In our study we compared plasma and tissue pharmacokinetics of WR-1065 in primates following both routes of administration. Monkeys received amifostine at a dose of 260 mg/m2 either intravenously or subcutaneously. Plasma samples were analyzed for total WR-1065 by reverse-phase high-pressure liquid chromatography (HPLC) and fluorescence detection up to 4 h after amifostine administration. Tissues were analyzed for free WR-1065 by reverse-phase HPLC and electrochemical detection 30 and 60 min after administration. Following intravenous administration, plasma WR-1065 levels peaked rapidly and showed a bi-exponential decline, while following subcutaneous administration WR-1065 levels rose slowly and declined exponentially. The relative plasma bioavailability of WR-1065 given subcutaneously was lower at 30 and 60 min. Interestingly, after 30 min, tissues showed equal or slightly greater concentrations of WR-1065 following subcutaneous administration. Levels following 60 min were comparable following both routes. The plasma bioavailability studies performed in primates confirm human plasma data. Expanding the study to evaluate primate tissue levels of WR-1065 revealed that despite lower plasma bioavailability following subcutaneous administration, tissue levels of the active metabolite were surprisingly greater than or equal to those measured in animals that received the drug intravenously. These studies strengthen the argument for subcutaneous administration of amifostine in radiation oncology.
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PMID:Tissue levels of WR-1065, the active metabolite of amifostine (Ethyol), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys. 1555 77

Radiotherapy for head and neck cancers commonly causes damage to salivary gland tissue, resulting in xerostomia (dry mouth) and numerous adverse medical and quality-of-life issues. Amifostine is the only Food and Drug Administration-approved radioprotective drug used clinically to prevent xerostomia. However, systemic administration of amifostine is limited by severe side effects, including rapid decrease in blood pressure (hypotension), nausea, and a narrow therapeutic window. In this study, we demonstrate that retroductal delivery of amifostine and its active metabolite, WR-1065, to murine submandibular glands prior to a single radiation dose of 15 Gy maintained gland function and significantly increased acinar cell survival. Furthermore, in vivo stimulated saliva secretion was maintained in retrograde-treated groups at levels significantly higher than irradiated-only and systemically treated groups. In contrast to intravenous injections, retroductal delivery of WR-1065 or amifostine significantly attenuated hypotension. We conclude that localized delivery to salivary glands markedly improves radioprotection at the cellular level, as well as mitigates the adverse side effects associated with systemic administration. These results support the further development of a localized delivery system that would be compatible with the fractionated dose regimen used clinically.
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PMID:Localized Delivery of Amifostine Enhances Salivary Gland Radioprotection. 2973 87