Applications cholinesterase inhibitors

DeFrank 11 (1991) Organophosphorus cholinesterase inhibitors detoxification by microbial enzymes. In Applications of Enzyme Biotechnology (Ed IW Kelly and TO Baldwin), pp. 165-180. Plenum Press, New York. 

Many pesticides are neurotoxicants poisoning the nervous system. A number of pesticides are acetyl cholinesterase inhibitors (Serat and Mengle 1973). Generally, pesticides determination has been performed by GC since the 1960 s (Morrison and Durham 1971 Fournier et al. 1978). There are no reference materials for pesticides in urine or serum, although as with PAHs there are a number biological matrices certified for the content of various pesticides available for environmental food and agriculture analysis and which may have some application in clinical chemistry. 

Oxime carbamates are generally applied either directly to the tilled soil or sprayed on crops. One of the advantages of oxime carbamates is their short persistence on plants. They are readily degraded into their metabolites shortly after application. However, some of these metabolites have insecticidal properties even more potent than those of the parent compound. For example, the oxidative product of aldicarb is aldicarb sulfoxide, which is observed to be 10-20 times more active as a cholinesterase inhibitor than aldicarb. Other oxime carbamates (e.g., methomyl) have degradates which show no insecticidal activity, have low to negligible ecotoxicity and mammalian toxicity relative to the parent, and are normally nondetectable in crops. Therefore, the residue definition may include the parent oxime carbamate (e.g., methomyl) or parent and metabolites (e.g., aldicarb and its sulfoxide and sulfone metabolites). The tolerance or maximum residue limit (MRL) of pesticides on any food commodity is based on the highest residue concentration detected on mature crops at harvest or the LOQ of the method submitted for enforcement purposes if no detectable residues are found. For example, the tolerances of methomyl in US food commodities range from 0.1 to 6 mg kg for food items and up to 40 mg kg for feed items. ... 

Giacobini, E. (1998) Invited review cholinesterase inhibitors for Alzheimer s disease therapy from tacrine to future applications. Neuro chemistry International 32,413-419. 

The courts, however, are not bound by the decision of the Patent Office to issue the patent. In considering whether the application had utility, the Federal Circuit approvingly quoted the district court s determination that the application "did not provide analysis or insight connecting the [summaries of the six references]. .. to galantamine s potential to treat Alzheimer s disease [4]." In conjunction with this analysis, witness testimony given at trial was also considered. For example, the sole inventor testified that "when I submitted this patent, I certainly wasn t sure, and a lot of other people weren t sure, that cholinesterase inhibitors [such as galantamine] would ever work [to treat Alzheimer s disease] [5]." (Emphasis added). 

These systems have been used in many bioanalytical applications. A Prospekt system coupled with MS quantitated eserine N-oxide, a cholinesterase inhibitor, in human plasma for low level (4.5 mg) oral administration pharmacokinetic studies (Pruvost et al. 2000). After conditioning of the SPE cartridge (PLRP-S, Spark) with methanol (5 mL/min, 0.5 min) and water (5 mL/min, 0.5 min), a volume of 250 jj.L plasma plus internal standard was injected and washed (water, 1 mL/min, 3 min). The analytes were flushed out with 80 20 ammonium acetate (20 mM, pH 3.5 adjusted with formic acid) and acetonitrile (0.3 mL/min) and separated on a Zobax SB-CN column (150 x 2.1 mm inner diameter, 5 jim). A calibration range of 25 pg/mL to 12.5 ng/mL was achieved with a run time of 10.5 min. 

The short-acting cholinesterase inhibitor edrophonium was used to treat supraventricular tachyarrhythmias, particularly paroxysmal supraventricular tachycardia. In this application, edrophonium has been replaced by newer drugs (adenosine and the calcium channel blockers verapamil and diltiazem). 

Organophosphate and carbamate cholinesterase inhibitors (see Chapter 7) are widely used to kill insects and other pests. Most cases of serious organophosphate or carbamate poisoning result from intentional ingestion by a suicidal person, but poisoning has also occurred at work (pesticide application or packaging) or, rarely, as a result of food contamination or terrorist attack (eg, release of the chemical warfare nerve agent sarin in the Tokyo subway system in 1995). 

By utilizing rats, to which were administered different doses of cholinesterase inhibitors by dermal application, Knaak and co-workers established the relative potency of these insecticides for dermal exposure. This rat potency was then related to human safe levels by using proportional equations so that the dermal cholinesterase inhibiting potency of a reference compound could be adjusted to reflect the dermal potency of a compound whose safe level was being determined. 

The cholinesterase inhibitors have multiple practical applications - from medicine to warfare. Physostigmine was actually the first practically used cholinesterase antagonist. To describe its initial use as medical , however, would mean a bit of a stretch - instead, the seed containing it was used to extort confessions from persons accused of crimes or witchcraft in Guinea. This seed used to be called the ordeal bean by the local people. 

Once touted as the medication of choice to treat lethal tricyclic antidepressant overdoses, physostigmine (antilirium ) has very limited uses today in overdose management. Physostigmine is a cholinesterase inhibitor and finds its primary application in the treatment of severe anticholinergic poisoning. When indicated, physostigmine is administered preferably in small incremental doses of 2 mg mixed in 10 cc of saline by slow intravenous infusion over 10 min. 

A novel series of tacrine-selegiline hybrids for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B) have also been synthesized [181]. 

Lotions and mists for the control and rcpellency of ear mites of dogs/puppies. cals/kittens, and rabbits are frequently formulated with PBO. A typical formulation will contain 0.15% pyrethrins synergized at a I 10 ratio with PBO-Since synergized pyrethrins are not cholinesterase inhibitors, they may be used in conjunction with flea and tick dips, collars and oral medications- Products based on pyreth ram and PBO offer veterinarians safe, effective residual action without (he inclusion of toxic additives and without restrictions on repeat applications or concomitant treatments with other insecticides or anthelmintics (MacDonald and Miller, 1986). 

Irreversible Cholinesterase Inhibitors. These are a large group of organophosphorus compounds, only a few of which have therapeutic applications. They share the following structure ... 

In F. hepatica and schistosomes, the nicotinic agonist carbachol is a more potent agonist of muscle relaxation/inhibition than is ACh (perhaps because of its insensitivity to esterase). Muscarine is ineffective. Application of the muscarinic antagonist atropine stimulates increased muscle tone, contraction and/or motility and reverses the paralysis induced by carbachol and ACh (9-11, 13, 32). The stimulatory effect of atropine and the ability of eserine (a cholinesterase inhibitor) to relax muscle have fed several investigators to suggest that a tonic release of transmitter from cholinergic cells may be... 

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