This study compared the therapeutic potential of recombinant, native versus pegylated megakaryocyte growth and development factor (rMGDF PEG-rMGDF, respectively), as well that combined administration PEG-rMGDF r-methionyl human granulocyte colony-stimulating (r-metHuG-CSF) on hematopoietic reconstitution after 700 cGy, 60Co gamma, total body irradiation in nonhuman primates. After irradiation, animals received either rMGDF, r-metHuG-CSF, r-metHuG-CSF or HSA. Cytokines all MGDF protocols were...

Treatment of individuals exposed to potentially lethal doses radiation is paramount concern health professionals and government agencies. We evaluated the efficacy filgrastim increase survival nonhuman primates (NHP) an approximate mid-lethal dose (LD(50/60)) (7.50 Gy) LINAC-derived photon radiation. Prior total-body irradiation (TBI), were randomized either a control (n = 22) or filgrastim-treated 24) cohorts. Filgrastim (10 μg/kg/d) was administered beginning 1 day after TBI continued...

The authors have developed a murine model of the Hematopoietic Syndrome Acute Radiation (H-ARS) for efficacy testing medical countermeasures (MCM) against radiation according to FDA Animal Rule. Ten- 12-wk-old male and female C57BL/6 mice were exposed LD50/30-LD70/30 dose total body irradiation (TBI, (137)Cs, 0.62-0.67 Gy min(-1)) in morning hours when determined be most radiosensitive, they assessed 30-d survival mean time (MST). Antibiotics delivered drinking water on days 4-30 post-TBI at...

The development of medical countermeasures against the hematopoietic subsyndrome acute radiation syndrome requires well characterized and validated animal models. model must define dose- time-dependent relationships for mortality major signs morbidity to include other organ damage that may contribute mortality. Herein, authors these parameters a nonhuman primate exposed total body administered management. A blinded, randomized study (n = 48 rhesus macaques) determined lethal dose-response...

The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of full recovery and damage to system, since all animals succumb subsequent 100% lethal hematopoietic syndrome. A partial-body model with 5% bone marrow sparing was established investigate prolonged effects high-dose radiation on as well concomitant other multi-organ injury including lung. Herein, cellular clinical parameters link delayed coincident sequelae time course...

Leukocyte growth factors (LGF), such as filgrastim, pegfilgrastim and sargramostim, have been used to mitigate the hematologic symptoms of acute radiation syndrome (ARS) after accidents. Although these pharmaceuticals are currently approved for treatment chemotherapy-induced myelosuppression, approval has not granted myelosuppression resulting from exposure. Regulatory drugs treat radiological or nuclear exposure injuries requires their development testing in accordance with Animal Efficacy...

The development of medical countermeasures against the acute gastrointestinal subsyndrome radiation syndrome in humans requires well characterized and validated animal models. These models must adhere to criteria U.S. Food Drug Administration's Animal Rule consider natural history clinical context human response treatment nuclear terrorist scenario. define dose- time-dependent relationships for mortality major signs morbidity, including concurrent damage other organs, such as bone marrow,...

Several radiation dose- and time-dependent tissue sequelae develop following acute high-dose exposure. One of the recognized delayed effects such exposures is lung injury, characterized by respiratory failure as a result pneumonitis that may subsequently into fibrosis. Since this pulmonary subsyndrome be associated with high morbidity mortality, comprehensive treatment irradiation will ideally include treatments mitigate both hematologic gastrointestinal subsyndromes well syndrome....

Radiation accidents are uncontrolled and ill-defined, the exposure is nonuniform may be partial body, forecasting a variable dose distribution sparing of hematopoietic stem cells. We propose that "best" treatment protocol available now for severely irradiated personnel with acute syndrome combination supportive care administration recombinant cytokines as soon possible after irradiation. Herein, we demonstrate significant effect G-CSF on lethally canines. administered early continuously...

A nonhuman primate (NHP) model of acute high-dose, partial-body irradiation with 5% bone marrow (PBI/BM5) sparing was used to assess the effect Neupogen® [granulocyte colony stimulating factor (G-CSF)] mitigate associated myelosuppression when administered at an increasing interval between exposure and initiation treatment. secondary objective on mortality or morbidity hematopoietic (H)- radiation syndrome (ARS) concurrent gastrointestinal (GI-ARS). NHP were exposed 10.0 11.0 Gy 6 MV...

We investigated the effects of recombinant granulocyte colony-stimulating factor (G-CSF) in a canine model septic shock. Awake 2-yr-old beagles were studied before and after intraperitoneal placement an Escherichia coli-infected clot. Nine days until 3 clot placement, animals received daily high-dose (G-CSF (5 microgram/kg body wt; n = 17), low-dose G-CSF (0.1 or control protein micrograms/kg 20). Survival rate was greater (P < 0.04, Wilcoxon test) group (14/17) than (10/17) (12/20) groups....

We compared the early and late pulmonary effects of human recombinant tumor necrosis factor (TNF) interleukin 1 (IL-1) challenges in awake dogs with chronic tracheostomies. Serial blood gas analysis, bronchoalveolar lavage (BAL) cell protein intravascular catheter hemodynamics, radionuclide left ventricular ejection fractions (LVEF) were determined before after infusion TNF (60 micrograms/kg body wt, n = 8), IL-1 (1,000 6), or heat-inactivated (n 6, controls). Controls given had no changes...

Conventional daily administration of filgrastim is effective in reducing the duration severe neutropenia and enhancing survival following lethal radiation, myelosuppressive cytotoxic therapy or myeloablation stem cell transplantation. A sustained-duration form filgrastim, pegfilgrastim has significantly simplified scheduling protocols after chemotherapy-induced to a single injection while maintaining therapeutic effectiveness filgrastim. We examined ability double (weekly) improve neutrophil...

The use of plasma citrulline as a biomarker for acute and prolonged gastrointestinal injury via exposure to total- partial-body irradiation (6 MV LINAC-derived photons; 0.80 Gy min) in nonhuman primate models was investigated. covered injuries spanning lethal, mid-lethal, sub-lethal doses. assessed measurement small intestinal histopathology over the first 15 d following radiation included total-body at 13.0 Gy, 10.5 7.5 11.0 with 5% bone marrow sparing. dosing schemes time points out day 60...

The identification of the optimal administration schedule for an effective medical countermeasure is critical treatment individuals exposed to potentially lethal doses radiation. efficacy filgrastim (Neupogen®), a potential countermeasure, improve survival when initiated at 48 h following total body irradiation in non-human primate model hematopoietic syndrome acute radiation was investigated. Animals were irradiation, antero-posterior exposure, midline tissue dose 7.5 Gy, (target 50/60)...

The objective of this pilot study was to explore whether administration a catalytic antioxidant, AEOL 10150 (C48H56C15MnN12), could reduce radiation-induced lung injury and improve overall survival when administered after 11.5 Gy whole thorax irradiation in non-human primate model. Thirteen animals were irradiated with single exposure Gy, prescribed midplane, delivered 6 MV photons at dose rate 0.8 min. Beginning 24 h post irradiation, the cohort (n = 7) received daily subcutaneous...

Chronic respiratory diseases are among the leading causes of deaths worldwide and major contributors morbidity global disease burden. To appropriately investigate lung disease, airways must be fixed in their physiological orientation should inflated prior to investigations. We present an inflation-fixation method that enables lipidomic investigations whole samples resected biopsy specimens by matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI)....

The use of plasma citrulline as a biomarker for gastrointestinal acute radiation syndrome via exposure to total-body irradiation in murine model was investigated. covered lethal, mid-lethal, and sub-lethal syndrome. Plasma profiles were generated over the first 6 d following 6-15 Gy. In addition, comprehensively evaluated context matching small intestine histopathology. Higher significantly associated with lower doses insult. Furthermore, higher crypt survival. correlation survival more...