Superior efficacy of HI-6 dimethanesulfonate over pralidoxime methylsulfate against Russian VX poisoning in cynomolgus monkeys (Macaca fascicularis).

Organophosphorus nerve agents still represent a serious risk to human health. In the French armed forces, the current emergency treatment against OP intoxications is a fully licensed wet-dry dual-chambered autoinjector (Ineurope ®), that contains pralidoxime methylsulfate (2-PAM) to reactivate inhibited acetylcholinesterase (AChE), atropine sulfate (AS) and avizafone chlorhydrate (AVZ). While this treatment is effective against several of the known nerve agents, it shows little efficacy against the Russian VX (VR), one of the most toxic compounds. HI-6 dimethanesulfonate (HI-6 DMS) is an oxime able to reactivate in vitro and in vivo VR-inhibited AChE. To confirm the superiority of HI-6 DMS towards 2-PAM prior to licensing, we compared the two 3-drug-combinations (HI-6 vs 2-PAM, 33 and 18 mg/kg respectively, equimolar doses; AS/AVZ 0.25/0.175 mg/kg respectively) in VR-poisoned cynomolgus macaques, the model required by the French drug regulatory agency. In parallel we performed HI-6 pharmacokinetics analysis using a one compartment model. A better efficacy of the HI-6 DMS combination was clearly observed: up to 5 LD50 of VR (i.m.), a single administration of the HI-6 DMS combination, shortly after the onset of clinical signs, prevented death of the four intoxicated animals. Conversely 2-PAM only prevented death in one out of three subjects exposed to the same amount of VR. As expected with V agents, reinhibition of blood AChE was observed but without any apparent impact on the clinical recovery of the animals. A single administration of the HI-6 DMS combination was still but partially effective at 15 LD50 of VR, allowing a 50% survival rate.

Revisiting Biomarkers of Total-Body and Partial-Body Exposure in a Baboon Model of Irradiation.

In case of a mass casualty radiation event, there is a need to distinguish total-body irradiation (TBI) and partial-body irradiation (PBI) to concentrate overwhelmed medical resources to the individuals that would develop an acute radiation syndrome (ARS) and need hematologic support (i.e., mostly TBI victims). To improve the identification and medical care of TBI versus PBI individuals, reliable biomarkers of exposure could be very useful. To investigate this issue, pairs of baboons (n = 18) were exposed to different situations of TBI and PBI corresponding to an equivalent of either 5 Gy 60Co gamma irradiation (5 Gy TBI; 7.5 Gy left hemibody/2.5 right hemibody TBI; 5.55 Gy 90% PBI; 6.25 Gy 80% PBI; 10 Gy 50% PBI, 15 Gy 30% PBI) or 2.5 Gy (2.5 Gy TBI; 5 Gy 50% PBI). More than fifty parameters were evaluated before and after irradiation at several time points up to 200 days. A partial least square discriminant analysis showed a good distinction of TBI from PBI situations that were equivalent to 5 Gy. Furthermore, all the animals were pooled in two groups, TBI (n = 6) and PBI (n = 12), for comparison using a logistic regression and a non parametric statistical test. Nine plasmatic biochemical markers and most of hematological parameters turned out to discriminate between TBI and PBI animals during the prodromal phase and the manifest illness phase. The most significant biomarkers were aspartate aminotransferase, creatine kinase, lactico dehydrogenase, urea, Flt3-ligand, iron, C-reactive protein, absolute neutrophil count and neutrophil-to-lymphocyte ratio for the early period, and Flt3-ligand, iron, platelet count, hemoglobin, monocyte count, absolute neutrophil count and neutrophil-to-lymphocyte ratio for the ARS phase. These results suggest that heterogeneity could be distinguished within a range of 2.5 to 5 Gy TBI.

Assessment of total- and partial-body irradiation in a baboon model: preliminary results of a kinetic study including clinical, physical, and biological parameters.

This biodosimetry study used irradiated baboons to investigate the efficacy of a kinetic multiparameter (clinical, physical, and biological) approach for discriminating partial-body irradiation (PBI) and total-body irradiation (TBI). Animals were unilaterally (front) exposed to 60Co gamma rays (8 to 32 cGy min) using either TBI or vertical left hemi-body irradiation (HBI), as follows: 2.5 Gy TBI (n = 2), 5 Gy TBI (n = 2), 5 Gy HBI (n = 2), and 10 Gy HBI (n = 2). Midline tissue doses were measured at the anterior iliac crest level with an ionization chamber, and body dosimetry was performed using thermoluminescent dosimeters. Blood samples were collected before exposure and from 1 h until 200 d after irradiation. Clinical status, complete blood cell count, biochemical parameters, and cytogenetic analysis were evaluated. The partial least square discriminant analysis chosen for statistical analysis showed that the four groups of irradiated baboons were clearly separated. However, the dicentric chromosome assay may not distinguish HBI from TBI in confounding situations where equivalent whole-body doses are similar and the time of exposure is sufficient for peripheral blood lymphocyte homogenization. Interestingly, as bone marrow shielding in HBI animals prevented aplasia from happening, hematologic parameters such as the platelet count and Flt-3 ligand level helped to distinguish HBI and TBI. Moreover, the ratio of neutrophil to lymphocyte counts, creatine kinase, and citrulline levels may be discriminating biomarkers of dose or injury. Both early and delayed clinical signs and bioindicators appear to be useful for assessment of heterogeneous irradiation.