Browsing by Author "Medhora, Meetha"

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    Combined hydration and antibiotics with lisinopril to mitigate acute and delayed high-dose radiation injuries to multiple organs
    (Lippincott, Williams & Wilkins, 2016-11) Fish, Brian L.; Gao, Feng; Narayanan, Jayashree; Bergom, Carmen; Jacobs, Elizabeth R.; Cohen, Eric P.; Moulder, John E.; Orschell, Christie M.; Medhora, Meetha; Medicine, School of Medicine
    The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study we have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ∼24 mg m-2 day-1 started orally in the drinking water at 7 days after irradiation and continued to ≥150 days) mitigated late effects in the lungs and kidneys after 12.5 Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 days after 13 Gy leg-out PBI. Furthermore lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg-1 day-1 from days 1-14) which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, we mitigated acute and delayed radiation injuries in multiple organs.
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    Corrigendum: Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes
    (Frontiers Media, 2021-08-25) Gasperetti, Tracy; Miller, Tessa; Gao, Feng; Narayanan, Jayashree; Jacobs, Elizabeth R.; Szabo, Aniko; Cox, George N.; Orschell, Christie M.; Fish, Brian L.; Medhora, Meetha; Medicine, School of Medicine
    [This corrects the article DOI: 10.3389/fphar.2021.634477.].
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    Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes
    (Frontiers Media, 2021-05-17) Gasperetti, Tracy; Miller, Tessa; Gao, Feng; Narayanan, Jayashree; Jacobs, Elizabeth R.; Szabo, Aniko; Cox, George N.; Orschell, Christie M.; Fish, Brian L.; Medhora, Meetha; Medicine, School of Medicine
    There is a need for countermeasures to mitigate lethal acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). In WAG/RijCmcr rats, ARS occurs by 30-days following total body irradiation (TBI), and manifests as potentially lethal gastrointestinal (GI) and hematopoietic (H-ARS) toxicities after >12.5 and >7 Gy, respectively. DEARE, which includes potentially lethal lung and kidney injuries, is observed after partial body irradiation >12.5 Gy, with one hind limb shielded (leg-out PBI). The goal of this study is to enhance survival from ARS and DEARE by polypharmacy, since no monotherapy has demonstrated efficacy to mitigate both sets of injuries. For mitigation of ARS following 7.5 Gy TBI, a combination of three hematopoietic growth factors (polyethylene glycol (PEG) human granulocyte colony-stimulating factor (hG-CSF), PEG murine granulocyte-macrophage-CSF (mGM-CSF), and PEG human Interleukin (hIL)-11), which have shown survival efficacy in murine models of H-ARS were tested. This triple combination (TC) enhanced survival by 30-days from ∼25% to >60%. The TC was then combined with proven medical countermeasures for GI-ARS and DEARE, namely enrofloxacin, saline and the angiotensin converting enzyme inhibitor, lisinopril. This combination of ARS and DEARE mitigators improved survival from GI-ARS, H-ARS, and DEARE after 7.5 Gy TBI or 13 Gy PBI. Circulating blood cell recovery as well as lung and kidney function were also improved by TC + lisinopril. Taken together these results demonstrate an efficacious polypharmacy to mitigate radiation-induced ARS and DEARE in rats.