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Scientific Reports Aug 2016The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on... (Randomized Controlled Trial)
Randomized Controlled Trial
The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving amifostine. Glucose levels significantly decreased and lactate levels increased in patient venous blood. Although amifostine in vitro did not inhibit the activity of the prolyl-hydroxylase PHD2, experiments with mouse liver showed that on a short timescale WR-1065 induced expression of the Hypoxia Inducible Factor HIF1α, lactate dehydrogenase LDH5, glucose transporter GLUT2, phosphorylated pyruvate dehydrogenase pPDH and PDH-kinase. This effect was confirmed on normal mouse NCTC hepatocytes, but not on hepatoma cells. A sharp reduction of acetyl-CoA and ATP levels in NCTC cells indicated reduced mitochondrial usage of pyruvate. Transient changes of mitochondrial membrane potential and reactive oxygen species ROS production were evident. Amifostine selectively protects NCTC cells against radiation, whilst HepG2 neoplastic cells are sensitized. The radiation protection was correlates with HIF levels. These findings shed new light on the mechanism of amifostine cytoprotection and encourage clinical research with this agent for the treatment of primary and metastatic liver cancer.
Topics: Adenosine Triphosphate; Amifostine; Animals; Basal Metabolism; Blood Glucose; Breast Neoplasms; Female; Glucose Transporter Type 2; Glycolysis; Hepatocytes; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Male; Membrane Potential, Mitochondrial; Mice, Inbred BALB C; Oxygen; Protein Serine-Threonine Kinases; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Radiation-Protective Agents
PubMed: 27507219
DOI: 10.1038/srep30986 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Mar 2023This study aimed to examine whether two different doses of dexamethasone (DXM), which is a corticosteroid, and amifostine (AMI), which reduces cumulative tissue toxicity...
BACKGROUND
This study aimed to examine whether two different doses of dexamethasone (DXM), which is a corticosteroid, and amifostine (AMI), which reduces cumulative tissue toxicity induced by cisplatin in advanced-stage cancer patients, have ameliorative effects on pathologic changes associated with cardiac contusion (CC) induced in rats.
METHODS
Forty-two Wistar albino rats were equally divided into six groups (n=7): C, CC, CC+AMI 400, CC+AMI 200, CC+AMI+DXM, and CC+DXM. Tomography images and electrocardiographic analyzes were performed, mean arterial pressure was measured from the carotid artery, and blood and tissue samples were obtained for histopathological and biochemical analyses after trauma-induced CC.
RESULTS
While the total oxidant status and disulfide parameters in the cardiac tissue and serum were significantly higher (p<0.05), the total antioxidant status, total thiol, and native thiol parameters were significantly lower (p<0.01) in rats with trauma-induced CC. The most frequently observed finding in the electrocardiography analyze was ST elevation.
CONCLUSION
According to evaluation based on histological, biochemical, and electrocardiographic examinations, we believe that only 400 mg/kg dose of AMI or DXM can be effective in the treatment of myocardial contusion in rats. Evaluation based on histological findings.
Topics: Rats; Animals; Rats, Wistar; Thoracic Injuries; Amifostine; Wounds, Nonpenetrating; Heart Injuries; Myocardial Contusions
PubMed: 36880625
DOI: 10.14744/tjtes.2023.84308 -
Oxidative Medicine and Cellular... 2016Cytoprotectant amifostine attenuates radiation-induced oxidative injury by increasing intracellular manganese superoxide dismutase (SOD2) in peripheral tissue. However,...
BACKGROUND
Cytoprotectant amifostine attenuates radiation-induced oxidative injury by increasing intracellular manganese superoxide dismutase (SOD2) in peripheral tissue. However, whether amifostine could protect neuronal cells against oxidative injury has not been reported. The purpose of this study is to explore the protection of amifostine in PC12 cells.
METHODS
PC12 cells exposed to glutamate were used to mimic neuronal oxidative injury. SOD assay kit was taken to evaluate intracellular Cu/Zn SOD (SOD1) and SOD2 activities; western blot analysis and immunofluorescence staining were performed to investigate SOD2 protein expression; MTT, lactate dehydrogenase (LDH), release and cell morphology were used to evaluate cell injury degree, and apoptotic rate and cleaved caspase-3 expression were taken to assess apoptosis; mitochondrial superoxide production, intracellular reactive oxygen species (ROS), and glutathione (GSH) and catalase (CAT) levels were evaluated by reagent kits.
RESULTS
Amifostine increased SOD2 activity and expression, decreased cell injury and apoptosis, reduced mitochondrial superoxide production and intracellular ROS generation, and restored intracellular GSH and CAT levels in PC12 cells exposed to glutamate. SOD2-siRNA, however, significantly reversed the amifostine-induced cytoprotective and antioxidative actions.
CONCLUSION
SOD2 mediates amifostine-induced protection in PC12 cells exposed to glutamate.
Topics: Amifostine; Animals; Apoptosis; Catalase; Glutamic Acid; Glutathione; Intracellular Space; Mitochondria; Models, Biological; Neuroprotection; PC12 Cells; RNA, Small Interfering; Rats; Reactive Oxygen Species; Superoxide Dismutase; Superoxides; Up-Regulation
PubMed: 26770652
DOI: 10.1155/2016/4202437 -
Virulence Jan 2020MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It...
BACKGROUND
MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem.
OBJECTIVE
Idarubicin was profiled to assess its antimicrobial effects and , and the underlying mechanisms.
METHODS
We investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects were studied by transmission electron microscopy, all-atom molecular dynamic simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. Further, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection .
RESULTS
Idarubicin kills MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects.
CONCLUSIONS
Idarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.
Topics: Animals; Anti-Bacterial Agents; Biofilms; Drug Repositioning; Drug Synergism; Female; Fosfomycin; Idarubicin; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Dynamics Simulation; Specific Pathogen-Free Organisms; Staphylococcal Skin Infections
PubMed: 32423280
DOI: 10.1080/21505594.2020.1770493 -
PloS One 2019Chemotherapy often causes side effects that include disturbances in taste functions. Cyclophosphamide (CYP) is a chemotherapy drug that, after a single dose, elevates...
Chemotherapy often causes side effects that include disturbances in taste functions. Cyclophosphamide (CYP) is a chemotherapy drug that, after a single dose, elevates murine taste thresholds at times related to drug-induced losses of taste sensory cells and disruptions of proliferating cells that renew taste sensory cells. Pretreatment with amifostine can protect the taste system from many of these effects. This study compared the effects of a single dose (75 mg/kg) of CYP with effects generated by fractionated dosing of CYP (5 doses of 15 mg/kg), a dosing approach often used during chemotherapy, on the taste system of mice using immunohistochemistry. Dose fractionation prolonged the suppressive effects of CYP on cell proliferation responsible for renewal of taste sensory cells. Fractionation also reduced the total number of cells and the proportion of Type II cells within taste buds. The post-injection time of these losses coincided with the life span of Type I and II taste cells combined with lack of replacement cells. Fractionated dosing also decreased Type III cells more than a single dose, but loss of these cells may be due to factors related to the general health and/or cell renewal of taste buds rather than the life span of Type III cells. In general, pretreatment with amifostine appeared to protect taste cell renewal and the population of cells within taste buds from the cytotoxic effects of CYP with few observable adverse effects due to repeated administration. These findings may have important implications for patients undergoing chemotherapy.
Topics: Amifostine; Animals; Antineoplastic Agents; Cell Count; Cell Proliferation; Cyclophosphamide; Dose-Response Relationship, Drug; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Phospholipase C beta; Protective Agents; Synaptosomal-Associated Protein 25; Taste; Taste Buds
PubMed: 30947285
DOI: 10.1371/journal.pone.0214890 -
World Journal of Gastroenterology Sep 2014To investigate whether amifostine contributes to the antioxidant and cytoprotective effects of histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW)...
AIM
To investigate whether amifostine contributes to the antioxidant and cytoprotective effects of histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions.
METHODS
Forty-eight Sprague Dawley male rats were equally divided into six groups: (1) ringer Lactate (RL) group; (2) RL + amifostine (RL + A) group; (3) HTK group; (4) HTK + A group; (5) UW group; and (6) UW + A group. Rats in the RL + A, HTK + A and UW + A groups were administered amifostine intraperitoneally at a dose of 200 mg/kg prior to laparotomy. The RL group was perfused with RL into the portal vein. The RL + A group were perfused with RL into the portal vein after amifostine administration. The HTK group received an HTK perfusion while the HTK + A group received an HTK perfusion after administration of amifostine. The UW group received a perfusion of UW, while the UW + A group received a UW perfusion after amifostine administration. Liver biopsy was performed to investigate histopathological, immunochemical [transferase mediated dUTP nick end labeling (TUNEL), inducible nitric oxide syntetase (iNOS)] and ultrastructural alterations. Biochemical alterations were determined by examining levels of alanine aminotransferase, alkaline phosphatase and nitric oxide in the perfusion fluid.
RESULTS
Pathological sinusoidal dilatation and centrilobular hydropic alteration were significantly lower in the groups that received amifostine prior to preservation solution perfusion. Although the best results were obtained in the UW + A group, we did not observe a statistically significant difference between the UW + A and HTK + A groups. iNOS grades were significantly lower in the amifostine groups 12 h after treatment. When the amifostine groups were compared against each other, the iNOS grades obtained from the UW + A and HTK + A groups were similar while the RL + A group had a much poorer score. TUNEL assays demonstrated a lower apoptosis ratio in the amifostine groups than in the non-amifostine groups 12 h after treatment. No statistically significant difference was observed between the UW + A and HTK + A groups for apoptosis. Cellular ultrastructure was best preserved in the UW + A and HTK + A groups.
CONCLUSION
Here, we show that preoperative administration of a single dose of amifostine is sufficient to minimize the preservation damage in hepatic cells.
Topics: Adenosine; Alanine Transaminase; Alkaline Phosphatase; Allopurinol; Amifostine; Animals; Antioxidants; Apoptosis; Biomarkers; Biopsy; Cold Ischemia; Cytoprotection; Drug Synergism; Glucose; Glutathione; Hepatectomy; In Situ Nick-End Labeling; Insulin; Liver; Male; Mannitol; Microscopy, Electron, Transmission; Models, Animal; Nitric Oxide; Nitric Oxide Synthase Type II; Organ Preservation; Organ Preservation Solutions; Potassium Chloride; Procaine; Raffinose; Rats, Sprague-Dawley; Time Factors
PubMed: 25232264
DOI: 10.3748/wjg.v20.i34.12292 -
Plastic and Reconstructive Surgery Oct 2014Immediate expander-based breast reconstruction after mastectomy is a prevalent option for many women with breast cancer. When coupled with adjuvant radiation therapy,...
BACKGROUND
Immediate expander-based breast reconstruction after mastectomy is a prevalent option for many women with breast cancer. When coupled with adjuvant radiation therapy, however, radiation-induced skin and soft-tissue injury diminish the success of this reconstructive technique. The authors hypothesize that prophylactic administration of the cytoprotectant amifostine will reduce soft-tissue complications from irradiation, aiding expander-based reconstruction.
METHODS
Sprague-Dawley rats were divided into two groups: operative expander placement (expander group) and operative sham (sham group). Expander specimens received a sublatissimus tissue expander with a 15-cc fill volume; shams underwent identical procedures without expanders. Experimental groups were further divided into control specimens receiving no further intervention, radiation therapy-only specimens receiving human-equivalent irradiation, and amifostine plus radiation therapy specimens receiving both amifostine and human-equivalent irradiation. After a 45-day recovery period, animals were evaluated grossly and with ImageJ analysis for skin and soft-tissue complications.
RESULTS
None of the control, radiation therapy-alone, or amifostine plus radiation therapy sham specimens showed skin and soft-tissue complications. For expander animals, significantly fewer amifostine plus radiation therapy specimens [four of 13 (30 percent)] demonstrated skin and soft-tissue complications compared with radiation therapy-alone specimens [nine of 13 (69 percent); p = 0.041]. ImageJ evaluation of expander specimens demonstrated a significant increase in skin and soft-tissue necrosis for radiation therapy-alone specimens (12.94 percent) compared with animals receiving amifostine plus radiation therapy (6.96 percent) (p = 0.019).
CONCLUSIONS
Amifostine pretreatment significantly reduced skin and soft-tissue complications. These findings demonstrate that amifostine prophylaxis provides protection against radiation-induced skin and soft-tissue injury in a murine model of expander-based breast reconstruction.
Topics: Amifostine; Animals; Male; Mammaplasty; Models, Animal; Radiation Injuries; Radiation-Protective Agents; Rats; Rats, Sprague-Dawley; Tissue Expansion
PubMed: 25357049
DOI: 10.1097/PRS.0000000000000543 -
Basic & Clinical Pharmacology &... Jul 2009Our study aimed to find more effective protective agents against mucosa toxicity induced by methotrexate and 5-fluorouracil. We focused on the relationship between oral...
Our study aimed to find more effective protective agents against mucosa toxicity induced by methotrexate and 5-fluorouracil. We focused on the relationship between oral mucositis and keratinocyte injury and examined methotrexate and 5-fluorouracil-induced cytotoxicity in normal human epidermal keratinocyte cell lines. Cell viability and superoxide radical activity were measured based on converting WST-1 (4-[3-(4-indophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzen disulfonate) to a water-soluble formazan dye. DNA synthesis by 5-bromo-2'-deoxyuridine incorporation was measured as an indirect parameter of cell proliferation. Allopurinol and amifostine were used as the radical scavengers. l-glutamine was used as a mucosa-protective agent. A cyclooxygenase inhibitor interrupting the production of hydroxyl radicals in the arachidonic acid cascade was also examined. 5-fluorouracil and methotrexate caused cytotoxicity due to the activation of intracellular superoxide radicals specifically on normal human epidermal keratinocytes. From the electron spin resonance study, it was found that allopurinol was a superoxide radical scavenger, while amifostine was hydroxyl radical scavenger. Allopurinol showed no effect on the cytotoxicity due to 5-fluorouracil and methotrexate. The cell injury induced by methotrexate was restored by amifostine. However, the cell injury induced by 5-fluorouracil was markedly recovered by a selective cyclooxygenase-1 inhibitor compared to amifostine. It was suggested that amifostine and cyclooxygenase-1 inhibitor could be useful protective agents against methotrexate and 5-fluorouracil chemotherapeutic toxicity. Additionally, this in vitro cell injury model using normal human epidermal keratinocytes may be useful for understanding the pathophysiology of oral mucositis induced by chemotherapeutic agents.
Topics: Allopurinol; Amifostine; Antimetabolites, Antineoplastic; Calcium; Cell Line; Cell Proliferation; Cell Survival; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Interactions; Fibroblasts; Fluorouracil; Free Radical Scavengers; Glutamine; Humans; Keratinocytes; Methotrexate; Periodontal Ligament; Protective Agents; Pyrazoles; Reactive Oxygen Species; Stomatitis
PubMed: 19371262
DOI: 10.1111/j.1742-7843.2009.00400.x -
The Cochrane Database of Systematic... Apr 2011Treatment of cancer is increasingly more effective but is associated with short and long term side effects. Oral side effects remain a major source of illness despite... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment of cancer is increasingly more effective but is associated with short and long term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. One of these side effects is oral mucositis (mouth ulcers).
OBJECTIVES
To evaluate the effectiveness of prophylactic agents for oral mucositis in patients with cancer receiving treatment, compared with other potentially active interventions, placebo or no treatment.
SEARCH STRATEGY
Electronic searches of Cochrane Oral Health Group and PaPaS Trials Registers (to 16 February 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE via OVID (1950 to 16 February 2011), EMBASE via OVID (1980 to 16 February 2011), CINAHL via EBSCO (1980 to 16 February 2011), CANCERLIT via PubMed (1950 to 16 February 2011), OpenSIGLE (1980 to 2005) and LILACS via the Virtual Health Library (1980 to 16 February 2011) were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information.
SELECTION CRITERIA
Randomised controlled trials of interventions to prevent oral mucositis in patients receiving treatment for cancer.
DATA COLLECTION AND ANALYSIS
Information regarding methods, participants, interventions, outcome measures, results and risk of bias were independently extracted, in duplicate, by two review authors. Authors were contacted for further details where these were unclear. The Cochrane Collaboration statistical guidelines were followed and risk ratios calculated using random-effects models.
MAIN RESULTS
A total of 131 studies with 10,514 randomised participants are now included. Overall only 8% of these studies were assessed as being at low risk of bias. Ten interventions, where there was more than one trial in the meta-analysis, showed some statistically significant evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis, compared to either a placebo or no treatment. These ten interventions were: aloe vera, amifostine, cryotherapy, granulocyte-colony stimulating factor (G-CSF), intravenous glutamine, honey, keratinocyte growth factor, laser, polymixin/tobramycin/amphotericin (PTA) antibiotic pastille/paste and sucralfate.
AUTHORS' CONCLUSIONS
Ten interventions were found to have some benefit with regard to preventing or reducing the severity of mucositis associated with cancer treatment. The strength of the evidence was variable and implications for practice include consideration that benefits may be specific for certain cancer types and treatment. There is a need for further well designed, and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.
Topics: Antineoplastic Agents; Candidiasis, Oral; Humans; Neoplasms; Oral Ulcer; Randomized Controlled Trials as Topic; Stomatitis
PubMed: 21491378
DOI: 10.1002/14651858.CD000978.pub5 -
Journal of Radiation Research Jan 2015This review gives a comparative evaluation of the radioprotective properties and the therapeutic index (TI) of radioprotectors from various pharmacological group in... (Comparative Study)
Comparative Study Review
This review gives a comparative evaluation of the radioprotective properties and the therapeutic index (TI) of radioprotectors from various pharmacological group in experiments on both small and large animals. It presents a hypothesis explaining the decrease in the TI of cystamine and 5-methoxytryptamine (mexamine), and the retention of that of α1-adrenomimetic indralin, and also compares the effects on large and small animals. The considerable differences in the therapeutic indices of catecholamines, serotonin and cystamine are a consequence of specific features of their mechanisms of radioprotective action. Radioprotectors acting via receptor mediation tend to provide a more expanded window of protection. The reduction in the TI of cystamine in larger animals, such as dogs, may be caused by the greater increase in toxicity of aminothiols in relation to the decrease in their optimal doses for radioprotective effect in going from mice to dogs, which is a consequence of the slower metabolic processes in larger animals. The somatogenic phase of intoxication by cystamine is significantly longer than the duration of its radioprotective effect, and increases with irradiation. The decrease in the radioprotective effect and the TI of mexamine in experiments with dogs may be caused by their lower sensitivity to the acute hypoxia induced by the mexamine. This is because of lower gradient in oxygen tension between tissue cells and blood capillaries under acute hypoxia that is determined by lower initial oxygen consumption in a large animal as compared with a small animal. Indralin likely provides optimal radioprotective effects and a higher TI for large animals via the increased specificity of its adrenergic effect on tissue respiration, which supports the development of acute hypoxia in the radiosensitive tissues of large animals. The stimulatory effect of indralin on early post-irradiation haematopoietic recovery cannot provide a high level of radioprotective action for large animals, but it may promote recovery.
Topics: 5-Methoxytryptamine; Adrenergic Agents; Amifostine; Animals; Cricetinae; Dogs; Dose-Response Relationship, Drug; Evidence-Based Medicine; Haplorhini; Mice; Radiation Injuries; Radiation Tolerance; Radiation-Protective Agents; Rats; Serotonin Agents; Species Specificity; Treatment Outcome
PubMed: 25312329
DOI: 10.1093/jrr/rru087