Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration

Ranganathan, Kavitha; Simon, Eric S.; Lynn, Jeremy V.; Snider, Alicia; Nelson, Noah S.; Donneys, Alexis; Rodrı́guez, José J.; Buchman, Lauren; Reyna, Dawn; Lipka, Elke; Buchman, Steven R.

doi:10.1007/s11095-018-2386-5

Cited by 10 publications

(7 citation statements)

References 27 publications

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“…Amifostine is a phosphorylated aminothiol prodrug, which is rapidly hydrolysed in vivo by alkaline phosphatase to the active cytoprotective thiol metabolite, WR-1065. This metabolite has a terminal half-life of 90 min ( Ranganathan et al, 2018 ). Intracellularly WR-1065 detoxifies reactive metabolites of chemotherapeutic agents and scavenges free radicals ( Bensadoun et al, 2006 ); it may also accelerate DNA repair and inhibit apoptosis.…”

Section: Possible Treatment Options For Cimmentioning

confidence: 99%

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

et al. 2021

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The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40–100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).

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Section: Possible Treatment Options For Cimmentioning

confidence: 99%

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

et al. 2021

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“…16 Initial studies indicated daily amifostine (200 mg/m 2 intravenous [IV]) reduced xerostomia severity during and after radiotherapy, but the benefits were small and likely not clinically significant. 13 17 18 19 20 21 22 23 A 2017 systematic review examining pharmacologic interventions to prevent xerostomia concluded that there was low-quality evidence that amifostine may reduce the risk of moderate to severe xerostomia. 13 Although amifostine was the first radioprotectant medication approved by the U.S. Food and Drug Administration (FDA), it has never achieved widespread use due to its cost and unfavorable side-effect profile, which includes severe nausea and hypotension, as well as difficulties associated with administration (in IV form, it must be administered within 30 minutes of radiotherapy).…”

Section: Prophylactic Treatments Studied In Head and Neck Cancer Pati...mentioning

confidence: 99%

“…13 Although amifostine was the first radioprotectant medication approved by the U.S. Food and Drug Administration (FDA), it has never achieved widespread use due to its cost and unfavorable side-effect profile, which includes severe nausea and hypotension, as well as difficulties associated with administration (in IV form, it must be administered within 30 minutes of radiotherapy). 16,21,24,25 However, oral formulations of amifostine may have similar efficacy with fewer side effects and may be worth revisiting as a preventative adjunct. 21…”

Section: Amifostinementioning

confidence: 99%

Noninvasive Systemic Modalities for Prevention of Head and Neck Radiation-Associated Soft Tissue Injury: A Narrative Review

Kim

Rubenstein

Chu

et al. 2022

J Reconstr Microsurg

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Background Radiation-associated soft tissue injury is a potentially devastating complication for head and neck cancer patients. The damage can range from minor sequelae such as xerostomia, which requires frequent daily maintenance, to destructive degenerative processes such as osteoradionecrosis, which can contribute to flap failure and delay or reverse oral rehabilitation. Despite the need for effective radioprotectants, the literature remains sparse, primarily focused on interventions beyond the surgeon's control, such as maintenance of good oral hygiene or modulation of radiation dose. Methods This narrative review aggregates and explores noninvasive, systemic treatment modalities for prevention or amelioration of radiation-associated soft tissue injury. Results We highlighted nine modalities with the most clinical potential, which include amifostine, melatonin, palifermin, hyperbaric oxygen therapy, photobiomodulation, pentoxifylline–tocopherol–clodronate, pravastatin, transforming growth factor-β modulators, and deferoxamine, and reviewed the benefits and limitations of each modality. Unfortunately, none of these modalities are supported by strong evidence for prophylaxis against radiation-associated soft tissue injury. Conclusion While we cannot endorse any of these nine modalities for immediate clinical use, they may prove fruitful areas for further investigation.

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“…It is postulated that by decreasing peak drug levels, there may be a possible decrease in the side effect profile. 31 However, further studies are required to investigate the radioprotective effects with this formulation.…”

Section: Pharmaceutical and Cellular-based Therapeuticsmentioning

confidence: 99%

Overcoming Nuclear Winter: The Cutting-edge Science of Bone Healing and Regeneration in Irradiated Fields

Daniel

Luby

Buchman

et al. 2021

Plastic and Reconstructive Surgery - Global Open

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Background: The incidence of cancer worldwide is expected to be more than 22 million annually by 2030. Approximately half of these patients will likely require radiation therapy. Although radiotherapy has been shown to improve disease control and increase survivorship, it also results in damage to adjacent healthy tissues, including the bone, which can lead to devastating skeletal complications, such as nonunion, pathologic fractures, and osteoradionecrosis. Pathologic fractures and osteoradionecrosis are ominous complications that can result in large bone and soft tissue defects requiring complex reconstruction. Current clinical management strategies for these conditions are suboptimal and dubious at best. The gold standard in treatment of severe radiation injury is free tissue transfer; however, this requires a large operation that is limited to select candidates. Methods: With the goal to expand current treatment options and to assuage the devastating sequelae of radiation injury on surrounding normal tissue, our laboratory has performed years of translational studies aimed at remediating bone healing and regeneration in irradiated fields. Three therapeutics (amifostine, deferoxamine, and adipose-derived stem cells) have demonstrated great promise in promoting healing and regeneration of irradiated bone. Results: Amifostine confers prophylactic protection, whereas deferoxamine and adipose-derived stem cells function to remediate postradiation associated injury. Conclusions: These prospective therapeutics exploit a mechanism attributed to increasing angiogenesis and ultimately function to protect or restore cellularity, normal cellular function, osteogenesis, and bone healing to nonirradiated metrics. These discoveries may offer innovative treatment alternatives to free tissue transfer with the added benefit of potentially preventing and treating osteoradionecrosis and pathologic fractures

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Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration

Abstract: Orally administered AMF achieves a similar systemic bioavailability and decreased peak plasma level of WR-1065 compared to intravenously administered AMF, suggesting oral AMF formulations maintain radioprotective efficacy without causing onerous side effects, and are clinically feasible.

Cited by 10 publications

References 27 publications

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

Noninvasive Systemic Modalities for Prevention of Head and Neck Radiation-Associated Soft Tissue Injury: A Narrative Review

Overcoming Nuclear Winter: The Cutting-edge Science of Bone Healing and Regeneration in Irradiated Fields

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