Physostigmine hemisulfate

Acetylcholinesterase inhibition and locomotor function after motor-sensory cortex impact injury.[Pubmed:21787180]

J Neurotrauma. 2011 Sep;28(9):1909-19.

Traumatic brain injury (TBI) induces transient or persistent dysfunction of gait and balance. Enhancement of cholinergic transmission has been reported to accelerate recovery of cognitive function after TBI, but the effects of this intervention on locomotor activity remain largely unexplored. The hypothesis that enhancement of cholinergic function by inhibition of acetylcholinesterase (AChE) improves locomotion following TBI was tested in Sprague-Dawley male rats after a unilateral controlled cortical impact (CCI) injury of the motor-sensory cortex. Locomotion was tested by time to fall on the constant speed and accelerating Rotarod, placement errors and time to cross while walking through a horizontal ladder, activity monitoring in the home cages, and rearing behavior. Assessments were performed the 1st and 2nd day and the 1st, 2nd, and 3rd week after TBI. The AChE inhibitor Physostigmine hemisulfate (PHY) was administered continuously via osmotic minipumps implanted subcutaneously at the rates of 1.6-12.8 mumol/kg/day. All measures of locomotion were impaired by TBI and recovered to initial levels between 1 and 3 weeks post-TBI, with the exception of the maximum speed achievable on the accelerating Rotarod, as well as rearing in the open field. PHY improved performance in the accelerating Rotarod at 1.6 and 3.2 mumol/kg/day (AChE activity 95 and 78% of control, respectively), however, higher doses induced progressive deterioration. No effect or worsening of outcomes was observed at all PHY doses for home cage activity, rearing, and horizontal ladder walking. Potential benefits of cholinesterase inhibition on locomotor function have to be weighed against the evidence of the narrow range of useful doses.

Micronized emulsion for controlled release of physostigmine after oral administration. Part I. Formulation design.[Pubmed:2765106]

Drug Des Deliv. 1989 Mar;4(2):135-42.

Our aim was to incorporate physostigmine in a fine micronized emulsion delivery system which would prolong drug release following oral administration. Investigation of various types of equipment and experimental conditions led to a fine micronized emulsion of mean droplet size around 1 micron, which was stable at pH 5.5. The effect of physostigmine concentration and salt formation on the interfacial tension and zeta potential of the emulsion was studied. Physostigmine base markedly decreased the interfacial tension as compared to Physostigmine hemisulfate and salicylate. Zeta potential was highest in the case of the salicylate. After storage at 4 37 degrees C for four months, the emulsion did not undergo any significant change.

Anticholinesterases: medical applications of neurochemical principles.[Pubmed:7722478]

J Neurochem. 1995 May;64(5):1909-18.

Cholinesterases form a family of serine esterases that arise in animals from at least two distinct genes. Multiple forms of these enzymes can be precisely localized and regulated by alternative mRNA splicing and by co- or posttranslational modifications. The high catalytic efficiency of the cholinesterases is quelled by certain very selective reversible and irreversible inhibitors. Owing largely to the important role of acetylcholine hydrolysis in neurotransmission, cholinesterase and its inhibitors have been studied extensively in vivo. In parallel, there has emerged an equally impressive enzyme chemistry literature. Cholinesterase inhibitors are used widely as pesticides; in this regard the compounds are beneficial with concomitant health risks. Poisoning by such compounds can result in an acute but usually manageable medical crisis and may damage the CNS and the PNS, as well as cardiac and skeletal muscle tissue. Some inhibitors have been useful for the treatment of glaucoma and myasthenia gravis, and others are in clinical trials as therapy for Alzheimer's dementia. Concurrently, the most potent inhibitors have been developed as highly toxic chemical warfare agents. We review treatments and sequelae of exposure to selected anticholinesterases, especially organophosphorus compounds and carbamates, as they relate to recent progress in enzyme chemistry.