Page 178 - 2014 Printable Abstract Book
P. 178
delayed until there was a biologically-significant increase in radiation-induced azotemia (as blood urea
nitrogen, BUN). Animals were female WAG/RijCMCR rats aged 7-8 weeks at the time of irradiation.
Radiation doses ranges from 8 to 12.5 Gy, and treatment started at time ranging from 44 days after 12 Gy
2
to 245 days after 8 Gy. Captopril (ACEI) was given at 105 mg/m /day (human doses range from 12 to 250
2
2
mg/m /day), and losartan (ARB) was given at 70 mg/m /day (human doses range from 30 to 70
2
mg/m /day). The primary endpoint was the development of end-stage renal disease (defined at BUN>120
mg/dl with hypertension and proteinuria); the secondary endpoint was BUN at intervals after the start of
treatment. The DMFs for both captopril and losartan were 1.1±0.05, and the combination of the two
agents did not increase the DMF. A preliminary analysis suggests that the effect may not be truly dose-
modifying, as the delay in morbidity seems to be greater for the higher doses of TBI. More detailed analysis
is under way. This work was supported in part by NCI grant CA024652 and NIAID contract AI067734.
(PS2-73) Lethality protection in mice exposed to total body irradiation by a clinical formulation of
pasireotide. Wenze Wang; Qiang Fu; Sarita Garg; and Martin Hauer-Jensen, Division of Radiation Health,
UAMS, Little Rock, AR
Background: The second generation somatostatin analog pasireotide (SOM230) is a potent
radiation protector and mitigator after total-body irradiation (TBI). Previously, the radiomitigating
properties were studied by using a formulation made specifically for preclinical investigations, i.e., an
acetate salt of pasireotide. The FDA, for studies conducted under the animal rule, requires that the same
formulation that will be sought approval for also be used for preclinical studies. This study, therefore,
tested the radiomitigating efficacy of a clinical formulation of pasireotide, a diaspartate salt that has
recently been approved for use in Cushing’s disease. Methods: Pasireotide (0.5 to 2 mg/kg) of the
preclinical formulation and 0.05 to 1 mg/kg of the clinical formulation was given to CD2F1 mice starting
24 h after exposure to TBI. Pasireotide was administered as twice-daily subcutaneous injections for 7 to
14 consecutive days. The animals were monitored for survival for 30 days. Results: The preclinical
formulation of pasireotide at doses from 0.5 to 2 mg/kg dose-dependently improved survival when
administration started 24 h after TBI. The optimal dose was found to be 2 mg/kg. In contrast, the clinical
formulation at doses from 0.05 to 0.5 mg/kg dose-dependently improved survival, with the optimal dose
being ≤ 0.25 mg/kg. Administration of pasireotide for 10 days conferred a significant survival benefit and
seemed to be superior to 14 days administration. Conclusions: Compared with the preclinical formulation
of pasireotide, the clinical formulation of pasireotide appears to be approximately 8-fold more potent as
a radiation mitigator when administered 24 h after TBI. Further dose-finding and dose-optimization
studies are needed to confirm these data and to investigate the underlying mechanisms of the difference.
(PS2-74) Filgrastim as a radiation countermeasure: changing paradigm. Merriline M. Satyamitra, PhD
and Venkataraman Srinivasan, PhD, Armed Forces Radiobiology Research Institute, Bethesda, MD
Filgrastim (Neupogen, humanized granulocyte colony stimulating factor) is the preeminent
cytokine for the treatment of Acute Radiation Syndrome (ARS). Filgastim is well-characterized in both
rodents and higher mammals (dogs and primates) leading to some concepts that have become absolutes
(ABS1-ABS4), such as: ABS1. Filgrastim should be initiated within 24 h after irradiation and continued till
neutrophil levels are restored (1-16 d in rodents or 1-21 d in primates). ABS2. Filgrastim should never be
176 | P a g e
nitrogen, BUN). Animals were female WAG/RijCMCR rats aged 7-8 weeks at the time of irradiation.
Radiation doses ranges from 8 to 12.5 Gy, and treatment started at time ranging from 44 days after 12 Gy
2
to 245 days after 8 Gy. Captopril (ACEI) was given at 105 mg/m /day (human doses range from 12 to 250
2
2
mg/m /day), and losartan (ARB) was given at 70 mg/m /day (human doses range from 30 to 70
2
mg/m /day). The primary endpoint was the development of end-stage renal disease (defined at BUN>120
mg/dl with hypertension and proteinuria); the secondary endpoint was BUN at intervals after the start of
treatment. The DMFs for both captopril and losartan were 1.1±0.05, and the combination of the two
agents did not increase the DMF. A preliminary analysis suggests that the effect may not be truly dose-
modifying, as the delay in morbidity seems to be greater for the higher doses of TBI. More detailed analysis
is under way. This work was supported in part by NCI grant CA024652 and NIAID contract AI067734.
(PS2-73) Lethality protection in mice exposed to total body irradiation by a clinical formulation of
pasireotide. Wenze Wang; Qiang Fu; Sarita Garg; and Martin Hauer-Jensen, Division of Radiation Health,
UAMS, Little Rock, AR
Background: The second generation somatostatin analog pasireotide (SOM230) is a potent
radiation protector and mitigator after total-body irradiation (TBI). Previously, the radiomitigating
properties were studied by using a formulation made specifically for preclinical investigations, i.e., an
acetate salt of pasireotide. The FDA, for studies conducted under the animal rule, requires that the same
formulation that will be sought approval for also be used for preclinical studies. This study, therefore,
tested the radiomitigating efficacy of a clinical formulation of pasireotide, a diaspartate salt that has
recently been approved for use in Cushing’s disease. Methods: Pasireotide (0.5 to 2 mg/kg) of the
preclinical formulation and 0.05 to 1 mg/kg of the clinical formulation was given to CD2F1 mice starting
24 h after exposure to TBI. Pasireotide was administered as twice-daily subcutaneous injections for 7 to
14 consecutive days. The animals were monitored for survival for 30 days. Results: The preclinical
formulation of pasireotide at doses from 0.5 to 2 mg/kg dose-dependently improved survival when
administration started 24 h after TBI. The optimal dose was found to be 2 mg/kg. In contrast, the clinical
formulation at doses from 0.05 to 0.5 mg/kg dose-dependently improved survival, with the optimal dose
being ≤ 0.25 mg/kg. Administration of pasireotide for 10 days conferred a significant survival benefit and
seemed to be superior to 14 days administration. Conclusions: Compared with the preclinical formulation
of pasireotide, the clinical formulation of pasireotide appears to be approximately 8-fold more potent as
a radiation mitigator when administered 24 h after TBI. Further dose-finding and dose-optimization
studies are needed to confirm these data and to investigate the underlying mechanisms of the difference.
(PS2-74) Filgrastim as a radiation countermeasure: changing paradigm. Merriline M. Satyamitra, PhD
and Venkataraman Srinivasan, PhD, Armed Forces Radiobiology Research Institute, Bethesda, MD
Filgrastim (Neupogen, humanized granulocyte colony stimulating factor) is the preeminent
cytokine for the treatment of Acute Radiation Syndrome (ARS). Filgastim is well-characterized in both
rodents and higher mammals (dogs and primates) leading to some concepts that have become absolutes
(ABS1-ABS4), such as: ABS1. Filgrastim should be initiated within 24 h after irradiation and continued till
neutrophil levels are restored (1-16 d in rodents or 1-21 d in primates). ABS2. Filgrastim should never be
176 | P a g e
