Dataset Information

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.

ABSTRACT: Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality.

SUBMITTER: Krishnan JKS

PROVIDER: S-EPMC4808345 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.

Krishnan Jishnu K S JKS Arun Peethambaran P Appu Abhilash P AP Vijayakumar Nivetha N Figueiredo Taíza H TH Braga Maria F M MFM Baskota Sudikshya S Olsen Cara H CH Farkas Natalia N Dagata John J Frey William H WH Moffett John R JR Namboodiri Aryan M A AMA

Neurotoxicology 20160102

Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisonin ...[more]

PMID: 26751814

Similar Datasets

Project description:IntroductionIn this study, we investigated the outcomes for patients with intentional organophosphate poisoning. Previous reports indicate that in contrast to normal heart rate-corrected QT intervals (QTc), QTc prolongation might be indicative of a poor prognosis for patients exposed to organophosphates.MethodsWe analyzed the records of 118 patients who were referred to Chang Gung Memorial Hospital for management of organophosphate poisoning between 2000 and 2011. Patients were grouped according to their initial QTc interval, i.e., normal (<0.44 s) or prolonged (>0.44 s). Demographic, clinical, laboratory, and mortality data were obtained for analysis.ResultsThe incidence of hypotension in patients with prolonged QTc intervals was higher than that in the patients with normal QTc intervals (P = 0.019). By the end of the study, 18 of 118 (15.2%) patients had died, including 3 of 75 (4.0%) patients with normal QTc intervals and 15 of 43 (34.9%) patients with prolonged QTc intervals. Using multivariate-Cox-regression analysis, we found that hypotension (OR = 10.930, 95% CI = 2.961-40.345, P = 0.000), respiratory failure (OR = 4.867, 95% CI = 1.062-22.301, P = 0.042), coma (OR = 3.482, 95% CI = 1.184-10.238, P = 0.023), and QTc prolongation (OR = 7.459, 95% CI = 2.053-27.099, P = 0.002) were significant risk factors for mortality. Furthermore, it was revealed that non-survivors not only had longer QTc interval (503.00±41.56 versus 432.71±51.21 ms, P = 0.002), but also suffered higher incidences of hypotension (83.3 versus 12.0%, P = 0.000), shortness of breath (64 versus 94.4%, P = 0.010), bronchorrhea (55 versus 94.4%, P = 0.002), bronchospasm (50.0 versus 94.4%, P = 0.000), respiratory failure (94.4 versus 43.0%, P = 0.000) and coma (66.7 versus 11.0%, P = 0.000) than survivors. Finally, Kaplan-Meier analysis demonstrated that cumulative mortality was higher among patients with prolonged QTc intervals than among those with normal QTc intervals (Log-rank test, Chi-square test = 20.36, P<0.001).ConclusionsQTc interval helps predict mortality after intentional organophosphate poisoning.

Dataset Information

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.

Publications

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets