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Evidence-based Complementary and... 2015The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our... (Review)
Review
The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our understanding of the effects of radiation over the past six decades, efforts to identify effective radiation countermeasures for use in case of a radiological/nuclear emergency have been largely unsuccessful. Vitamin E is known to have antioxidant properties capable of scavenging free radicals, which have critical roles in radiation injuries. Tocopherols and tocotrienols, vitamin E analogs together known as tocols, have shown promise as radioprotectors. Although the pivotal mechanisms of action of tocols have long been thought to be their antioxidant properties and free radical scavenging activities, other alternative mechanisms have been proposed to drive their activity as radioprotectors. Here we provide a brief overview of the effects of ionizing radiation, the mechanistic mediators of radiation-induced damage, and the need for radiation countermeasures. We further outline the role for, efficacy of, and mechanisms of action of tocols as radioprotectors, and we compare and contrast their efficacy and mode of action with that of another well-studied chemical radioprotector, amifostine.
PubMed: 26366184
DOI: 10.1155/2015/741301 -
ACS Applied Materials & Interfaces Mar 2023Radiation-induced brain injury (RIBI) is a severe, irreversible, or even life-threatening cerebral complication of radiotherapy in patients with head and neck tumors,...
Radiation-induced brain injury (RIBI) is a severe, irreversible, or even life-threatening cerebral complication of radiotherapy in patients with head and neck tumors, and there is no satisfying prevention and effective treatment available for these patients. Amifostine (AMF) is a well-known free radical scavenger with demonstrated effectiveness in preventing radiation-induced toxicity. However, the limited permeability of AMF across the blood-brain barrier (BBB) when administered intravenously reduces the effectiveness of AMF in preventing RIBI. Herein, we construct a nanoparticle (NP) platform for BBB delivery of AMF. AMF is conjugated with 1,2-dioleoyl--glycero-3-phosphoethanolamine--[poly(ethylene glycol)]-hydroxy succinamide [DSPE-PEG-NHS, PEG M 2000], and the product is DSPE-PEG-AMF. Then, the nanoparticles (DAPP NPs) were formed by self-assembly of poly(lactic--glycolic acid) (PLGA), DSPE-PEG-AMF, and polysorbate 80 (PS 80). PEG shields the nanoparticles from blood clearance by the reticuloendothelial system and lengthens the drug circulation time. PS 80 is used to encapsulate nanoparticles for medication delivery to the brain. The results of our study showed that DAPP NPs were able to effectively penetrate the blood-brain barrier (BBB) in healthy C57BL/6 mice. Furthermore, in a well-established mouse model of X-knife-induced brain injury, treatment with DAPP NPs (corresponding to 250 mg/kg AMF) was found to significantly reduce the volume of brain necrosis compared to mice treated with AMF (250 mg/kg). Importantly, the use of DAPP NPs was also shown to significantly mitigate the effects of radiation-induced neuronal damage and glial activation. This work presents a convenient brain-targeted AMF delivery system to achieve effective radioprotection for the brain, providing a promising strategy with tremendous clinical translation potential.
Topics: Mice; Animals; Blood-Brain Barrier; Amifostine; Mice, Inbred C57BL; Brain; Polyethylene Glycols; Polysorbates; Brain Injuries; Nanoparticles
PubMed: 36917732
DOI: 10.1021/acsami.3c00502 -
Chinese Journal of Cancer Research =... Oct 2014Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However,... (Review)
Review
Radiation is an important modality in cancer treatment, and eighty percent of cancer patients need radiotherapy at some point during their clinical management. However, radiation-induced damage to normal tissues restricts the therapeutic doses of radiation that can be delivered to tumours and thereby limits the effectiveness of the treatment. The use of radioprotectors represents an obvious strategy to obtain better tumour control using a higher dose in radiotherapy. However, most of the synthetic radioprotective compounds studied have shown inadequate clinical efficacy owing to their inherent toxicity and high cost. Hence, the development of radioprotective agents with lower toxicity and an extended window of protection has attracted a great deal of attention, and the identification of alternative agents that are less toxic and highly effective is an absolute necessity. Recent studies have shown that alpha-2-macroglobulin (α2M) possesses radioprotective effects. α2M is a tetrameric, disulfide-rich plasma glycoprotein that functions as a non-selective inhibitor of different types of non-specific proteases and as a carrier of cytokines, growth factors, and hormones. α2M induces protein factors whose interplay underlies radioprotection, which supports the idea that α2M is the central effector of natural radioprotection in the rat. Pretreatment with α2M has also induced a significant reduction of irradiation-induced DNA damage and the complete restoration of liver and body weight. Mihailović et al. concluded that the radioprotection provided by α2M was in part mediated through cytoprotection of new blood cells produced in the bone marrow; these authors also indicated that an important aspect of the radioprotective effect of amifostine was the result of the induction of the endogenous cytoprotective capability of α2M. The radioprotective effects of α2M are possibly due to antioxidant, anti-fibrosis, and anti-inflammatory functions, as well as the maintenance of homeostasis, and enhancement of the DNA repair and cell recovery processes. This review is the first to summarise the observations and elucidate the possible mechanisms responsible for the beneficial effects of α2M. The lacunae in the existing knowledge and directions for future research are also addressed.
PubMed: 25400428
DOI: 10.3978/j.issn.1000-9604.2014.09.04 -
Critical Reviews in Food Science and... Apr 2017Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side-effect resulting from the administration of neurotoxic chemotherapeutic... (Review)
Review
BACKGROUND
Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side-effect resulting from the administration of neurotoxic chemotherapeutic agents. These pharmaco-chemotherapeutics can include taxanes, vinca alkaloids, platinum analogues, and others. Moderate to severe CIPN significantly decreases the quality of life and physical abilities of cancer patients and current pharmacotherapy for CIPN e.g. Amifostine, and antidepressants have had limited efficacy and may themselves induce adverse side-effects.
METHODS
To determine the potential use of herbal medicines as adjuvants in cancer treatments, a critical literature review was conducted by electronic and manual search on nine databases. These include PubMed, the Cochrane Library, Science Direct, Scopus, EMBASE, MEDLINE, Google Scholar, and two Chinese databases CNKI and CINAHL. Thirty-four studies were selected from 5614 studies assessed and comprising animal studies, case reports, retrospective studies, and minimal randomized clinical trials investigating the anti-CIPN effect of herbal medicines as the adjuvant intervention in patients administered chemotherapy. The thirty-four studies were assessed on methodological quality and limitations identified.
RESULTS
Studies were mixed in their recommendations for herbal medicines as an adjuvant treatment for CIPN.
CONCLUSION
Currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN. Given that the number of cancer survivors is increasing, the long-term side effects of cancer treatment, is of major importance.
Topics: Animals; Antineoplastic Agents; Databases, Factual; Disease Models, Animal; Humans; Neoplasms; Peripheral Nervous System Diseases; Plant Preparations; Plants, Medicinal; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 25849070
DOI: 10.1080/10408398.2014.889081 -
Journal of Advanced Nursing Apr 2016The aim of this study was to perform a systematic review of clinical trials covering interventions used as prophylaxis for oral mucositis induced by ambulatory... (Review)
Review
AIM
The aim of this study was to perform a systematic review of clinical trials covering interventions used as prophylaxis for oral mucositis induced by ambulatory antineoplastic chemotherapy.
BACKGROUND
Oral mucositis in patients undergoing chemotherapy is a side effect that can impact the quality of treatment and can interfere with eating and therapeutic adherence.
DESIGN
Quantitative systematic review.
DATA SOURCES
Relevant databases were searched, from January 2002-July 2013, by using the combination of the keywords mucositis, stomatitis, neoplasms, antineoplastic agents, drug therapy, prevention and control and chemotherapy.
REVIEW METHODS
Two researchers independently read the titles and abstracts from every cross-reference. The quality of the included studies was analysed by the Jadad Scale and the Cochrane Collaboration Risk of Bias Tool. Data were extracted from the selected studies with a data collection form developed specifically for this purpose.
RESULTS
Of the 23 controlled clinical trials that were identified in this study, five articles evaluated the use of oral cryotherapy to prevent oral mucositis and three studies analysed the prophylactic use of glutamine. Interventions of protocols for oral care, palifermin, allopurinol and chlorhexidine were evaluated by two articles each. Interventions of zinc sulphate, amifostine, chewing gum, sucralfate, recombination human intestinal trefoil factor, kefir and vitamin E were evaluated by one article each.
CONCLUSION
There is strong evidence that cryotherapy can prevent oral mucositis arising from ambulatory treatment with 5-flurouracil chemotherapy. Other interventions, although showing positive results in preventing oral mucositis, require further study to confirm their conclusions.
Topics: Allopurinol; Ambulatory Care; Anti-Inflammatory Agents; Antineoplastic Agents; Chlorhexidine; Controlled Clinical Trials as Topic; Cryotherapy; Fibroblast Growth Factor 7; Glutamine; Humans; Neoplasms; Oral Hygiene; Stomatitis
PubMed: 26626711
DOI: 10.1111/jan.12867 -
Bone Marrow Transplantation Dec 2014Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose... (Review)
Review
Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose melphalan. Despite 30 years of clinical and pharmacokinetic (PK) experience with high-dose melphalan, and its continuing central role as cytoreductive therapy for large numbers of patients with myeloma, the pharmacodynamics and pharmacogenomics of melphalan are still in their infancy. The addition of protectant agents such as amifostine and palifermin allows dose escalation to 280 mg/m(2), but at these doses it is cardiac, rather than gut, toxicity that is dose-limiting. Although combination with additional alkylating agents is feasible, the additional TRM may not be justified when so many post-consolidation therapies are available for myeloma patients. Current research should optimise the delivery of this single-agent chemotherapy. This includes the use of newer formulations and real-time PKs. These strategies may allow a safe and effective platform for adding synergistic novel therapies and provide a window of lymphodepletion for the addition of immunotherapies.
Topics: Amifostine; Antineoplastic Agents, Alkylating; Fibroblast Growth Factor 7; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Neoplasms; Obesity; Reproducibility of Results
PubMed: 25133893
DOI: 10.1038/bmt.2014.186 -
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 -
The Oncologist Apr 2015Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment... (Review)
Review
Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.
Topics: Antineoplastic Agents; Humans; Neuroprotective Agents; Neurotoxicity Syndromes; Pharmacogenetics; Platinum Compounds; Polymorphism, Genetic
PubMed: 25765877
DOI: 10.1634/theoncologist.2014-0044 -
Pharmaceutics Jun 2023The conventional dosage form of Ethyol (amifostine), a sterile lyophilized powder, involves reconstituting it with 9.7 mL of sterile 0.9% sodium chloride in accordance...
The conventional dosage form of Ethyol (amifostine), a sterile lyophilized powder, involves reconstituting it with 9.7 mL of sterile 0.9% sodium chloride in accordance with the United States Pharmacopeia specifications for intravenous infusion. The purpose of this study was to develop inhalable microparticles of amifostine (AMF) and compare the physicochemical properties and inhalation efficiency of AMF microparticles prepared by different methods (jet milling and wet ball milling) and different solvents (methanol, ethanol, chloroform, and toluene). Inhalable microparticles of AMF dry powder were prepared using a wet ball-milling process with polar and non-polar solvents to improve their efficacy when delivered through the pulmonary route. The wet ball-milling process was performed as follows: AMF (10 g), zirconia balls (50 g), and solvent (20 mL) were mixed and placed in a cylindrical stainless-steel jar. Wet ball milling was performed at 400 rpm for 15 min. The physicochemical properties and aerodynamic characteristics of the prepared samples were evaluated. The physicochemical properties of wet-ball-milled microparticles (WBM-M and WBM-E) using polar solvents were confirmed. Aerodynamic characterization was not used to measure the % fine particle fraction (% FPF) value in the raw AMF. The % FPF value of JM was 26.9 ± 5.8%. The % FPF values of the wet-ball-milled microparticles WBM-M and WBM-E prepared using polar solvents were 34.5 ± 0.2% and 27.9 ± 0.7%, respectively; while the % FPF values of the wet-ball-milled microparticles WBM-C and WBM-T prepared using non-polar solvents were 45.5 ± 0.6% and 44.7 ± 0.3%, respectively. Using a non-polar solvent in the wet ball-milling process resulted in a more homogeneous and stable crystal form of the fine AMF powder than using a polar solvent.
PubMed: 37376145
DOI: 10.3390/pharmaceutics15061696 -
European Journal of Medical Research Jan 2024Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy.
OBJECTIVE
We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis.
METHODS
C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-β1), followed by amifostine (WR-1065, 1-4 µg/mL) treatment. The effects of TGF-β1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine monophosphate activated kinase (AMPK).
RESULTS
Three doses of amifostine significantly attenuated lung inflammation and pulmonary fibrosis. Pretreatment and post-treatment of human fibroblast cells with amifostine blocked TGF-β1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-β1 shifted energy metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) and towards glycolysis, as observed by an altered metabolite profile including a decreased ratio of NAD + /NADH and increased lactate concentration. Treatment with amifostine significantly restored energy metabolism and activated SIRT1, which in turn activated AMPK. The activation of AMPK was required to mediate the effects of amifostine on mitochondrial homeostasis and pulmonary fibrosis. This study provides evidence that repurposing of the clinically used drug amifostine may have therapeutic applications for IPF treatment.
CONCLUSION
Amifostine inhibits bleomycin-induced pulmonary fibrosis by restoring mitochondrial function and cellular metabolism.
Topics: Humans; Animals; Mice; Bleomycin; Transforming Growth Factor beta1; Amifostine; Sirtuin 1; AMP-Activated Protein Kinases; NAD; Reactive Oxygen Species; Lung; Idiopathic Pulmonary Fibrosis; Fibroblasts; Mitochondria; Pneumonia; Mice, Inbred C57BL
PubMed: 38245795
DOI: 10.1186/s40001-023-01623-4