PMID- 30217478
OWN - NLM
STAT- MEDLINE
DCOM- 20181226
LR  - 20181226
IS  - 1872-7786 (Electronic)
IS  - 0009-2797 (Linking)
VI  - 296
DP  - 2018 Dec 25
TI  - Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin 
      exposure in guinea pigs.
PG  - 34-42
LID - S0009-2797(18)30794-4 [pii]
LID - 10.1016/j.cbi.2018.09.004 [doi]
AB  - The efficacy and pharmacokinetics of the aqueous co-formulation contents of the 
      Trobigard (atropine sulfate, obidoxime chloride) auto-injector were evaluated in 
      a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses 
      were evaluated in guinea pigs instrumented with brain and heart electrodes for 
      electroencephalogram (EEG) and electrocardiogram (ECG). Sarin challenge doses 
      were chosen to reflect exposure subclasses with sublethal (moderate to severe 
      clinical signs) and lethal consequences. The level of protection of intramuscular 
      human equivalent doses of the co-formulation was defined by (1) the mitigation of 
      signs and symptoms at a sublethal level and (2) the increase of survival time at 
      the supralethal sarin dose levels. Pharmacokinetics of both atropine sulfate and 
      obidoxime were proportional at 1 and 3 human equivalent doses, and only a small 
      increase in heart rate was observed briefly as a side effect. At both sarin 
      challenge doses, 54 mug/kg and 84 mug/kg, the co-formulation treatment was 
      effective against sarin-induced effects. Survival rates were improved at both 
      sarin challenge levels, whereas clinical signs and changes in EEG activity could 
      not in all cases be effectively mitigated, in particular at the supralethal sarin 
      challenge dose level. Reactivation of sarin inhibited cholinesterase was observed 
      in blood, and higher brain cholinesterase activity levels were associated with a 
      better clinical condition of the co-formulation treated animals. Although the 
      results cannot be directly extrapolated to the human situation, pharmacokinetics 
      and the effects over time related to plasma levels of therapeutics in a freely 
      moving guinea pig could aid translational models and possibly improve prediction 
      of efficacy in humans.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Joosen, Marloes J A
AU  - Joosen MJA
AD  - TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, 
      Rijswijk, the Netherlands. Electronic address: Marloes.joosen@tno.nl.
FAU - Klaassen, Steven D
AU  - Klaassen SD
AD  - TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, 
      Rijswijk, the Netherlands.
FAU - Verheij, Elwin
AU  - Verheij E
AD  - TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, 
      Rijswijk, the Netherlands.
FAU - van Groningen, Tomas
AU  - van Groningen T
AD  - TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, 
      Rijswijk, the Netherlands.
FAU - Cornelissen, Alex S
AU  - Cornelissen AS
AD  - TNO Defense, Security and Safety, CBRN Protection, Lange Kleiweg 137, 2288, GJ, 
      Rijswijk, the Netherlands.
FAU - Skiadopoulos, Mario H
AU  - Skiadopoulos MH
AD  - Emergent BioSolutions, Emergent Prod. Dev. Gaithersburg, 300 Professional Drive, 
      Gaithersburg, MD, 20879, USA.
FAU - Cochrane, Laura
AU  - Cochrane L
AD  - Emergent BioSolutions, Emergent Prod. Dev. Gaithersburg, 300 Professional Drive, 
      Gaithersburg, MD, 20879, USA.
FAU - Shearer, Jeff D
AU  - Shearer JD
AD  - Emergent BioSolutions, Emergent Prod. Dev. Gaithersburg, 300 Professional Drive, 
      Gaithersburg, MD, 20879, USA.
LA  - eng
PT  - Journal Article
DEP - 20180912
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
RN  - 0 (Cholinesterase Reactivators)
RN  - 3HXR312Z9M (Obidoxime Chloride)
RN  - 7C0697DR9I (Atropine)
RN  - B4XG72QGFM (Sarin)
RN  - EC 3.1.1.8 (Cholinesterases)
SB  - IM
MH  - Animals
MH  - Atropine/administration & dosage/chemistry/pharmacokinetics/*pharmacology
MH  - Cholinesterase Reactivators/administration & 
      dosage/chemistry/pharmacokinetics/pharmacology
MH  - Cholinesterases/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Compounding
MH  - Electroencephalography
MH  - Guinea Pigs
MH  - Injections, Subcutaneous
MH  - Male
MH  - Obidoxime Chloride/administration & 
      dosage/chemistry/pharmacokinetics/*pharmacology
MH  - Sarin/*antagonists & inhibitors/pharmacology
MH  - Structure-Activity Relationship
MH  - Survival Rate
OTO - NOTNLM
OT  - Atropine sulfate
OT  - Autoinjector
OT  - EEG
OT  - Nerve agent
OT  - Obidoxime
OT  - Sarin
EDAT- 2018/09/16 06:00
MHDA- 2018/12/27 06:00
CRDT- 2018/09/16 06:00
PHST- 2018/06/21 00:00 [received]
PHST- 2018/08/10 00:00 [revised]
PHST- 2018/09/11 00:00 [accepted]
PHST- 2018/09/16 06:00 [pubmed]
PHST- 2018/12/27 06:00 [medline]
PHST- 2018/09/16 06:00 [entrez]
AID - S0009-2797(18)30794-4 [pii]
AID - 10.1016/j.cbi.2018.09.004 [doi]
PST - ppublish
SO  - Chem Biol Interact. 2018 Dec 25;296:34-42. doi: 10.1016/j.cbi.2018.09.004. Epub 
      2018 Sep 12.