pralidoxime and Body-Weight

The intranasal route of administration has proven to be an effective method for bypassing the blood brain barrier and avoiding first pass hepatic metabolism when targeting drugs to the brain. Most small molecules gain rapid access to CNS parenchyma when administered intranasally. However, bioavailability is affected by various factors ranging from the molecular weight of the drug to the mode of intranasal delivery.. We examined the effects of animal posture, intranasal application method and animal weight and age on the delivery of radiolabeled pralidoxime (. We found that using upright vs. supine posture did not significantly affect. In view of the emerging interest in the use of intranasal delivery of drugs to combat cognitive decline in old age, we tested effectiveness in very old rats and found the method to be as effective in the older rats.

Topics: Administration, Intranasal; Afferent Pathways; Aging; Animals; Antidotes; Body Weight; Brain; Drug Delivery Systems; Male; Olfactory Bulb; Pralidoxime Compounds; Rats; Rats, Sprague-Dawley; Trigeminal Ganglion; Tritium

The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at α5-, α2-, and α3- but low intrinsic efficacy at α1-containing GABA(A) receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 μg/kg pyridostigmine bromide 30 min prior to 2× LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.

Topics: Acetylcholinesterase; Analysis of Variance; Animals; Atropine; Benzodiazepines; Body Weight; Brain; Chemical Warfare Agents; Cholinesterase Reactivators; Disease Models, Animal; Drug Administration Schedule; Electrocardiography; Electroencephalography; Guinea Pigs; Imidazoles; Lethal Dose 50; Male; Muscarinic Antagonists; Neuroprotective Agents; Neurotoxicity Syndromes; Pralidoxime Compounds; Seizures; Soman; Telemetry; Time Factors

Topics: Acetylcholinesterase; Adipose Tissue; Animals; Arkansas; Body Weight; Cholinesterase Inhibitors; Cholinesterase Reactivators; Cholinesterases; Crops, Agricultural; Environmental Monitoring; Gossypium; Insecticides; Malathion; Organophosphorus Compounds; Organothiophosphorus Compounds; Passeriformes; Phosphoramides; Pralidoxime Compounds

The acute mortality caused by two irreversible inhibitors of cholinesterases [diisopropylfluorophosphate (DFP) and diethoxyphosphorylthiocholine, 217 MI-phospholine iodide] has been investigated on chick embryos at different stages of development. The results demonstrate that the above compounds do not show any acute lethal action when administered before the 9th day of incubation; on the other hand, the administration is regularly followed by death after the 9th day of incubation. The doses are comparable to those causing death in hatched chicks. It has also been observed that no appreciable difference exists in DFP uptake from the yolk before and after the 9th day of incubation and that drug-induced cholinesterase inhibition is of the same order of magnitude at any developmental stage; the compound pyridine-2-aldoxime methanesulfonate (2-PAM) was a good antidote against DFP acute lethality. It seems likely that between the 8th and the 9th day of incubation the target system of organophosphorus inhibitors, that is, the cholinesterase enzymatic system, reaches a new point of maturation.

Topics: Animals; Body Weight; Chick Embryo; Cholinesterase Inhibitors; Cholinesterases; Echothiophate Iodide; Isoflurophate; Lethal Dose 50; Mesylates; Parasympathetic Nervous System; Pralidoxime Compounds; Time Factors