RESUMO
BACKGROUND: CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by L-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous L-cysteine. Further, Institutional Animal Care and Use Committee-approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. METHODS: Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by L-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated. RESULTS: ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; L-cysteine readily antagonized block in monkeys: 5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95. CONCLUSIONS: The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by L-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.
RESUMO
In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation.
