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In vivo inhibition of blood acetylcholinesterase activity by 9-amino-1, 2, 3, 4-tetrahydroacridine, its 7-methoxy derivative and physostigmine was studied in rats. Changes of enzyme activity in the blood were continually registered using an automatic colorimeter Auto Analyzer system. The dependence of % enzyme inhibition upon time in semilogarithmic transformation was characterized by a two phase curve. The first phase reflected the increase in the concentration of inhibitors in the blood during their resorption; this was followed by a slow second phase of inhibition. The inhibitory effect decreased in the order: physostigmine greater than tacrine greater than 7-methoxytacrine. The relationship between the anticholinesterase and antipsychotomimetic action of the examined substances is discussed.

0-isopropylmethyl phosphonofluoridate and 0-ethyl-S-(2-dimethylaminoethyl) methylphosphonothioate were i.m. administered in doses of 2 x LD50 to female rats and the blood acetylcholinesterase was continuously monitored using the automatic colorimeter Auto Analyzer. This activity rapidly decreased after the injection of the two organophosphates studied. If the blood flow in the leg muscles was stopped by compression and reopened by relaxation at different time intervals, acetylcholinesterase activity was either unaffected (detoxication present) or decreased (detoxication absent). It was observed that phosphonofluoridate was detoxified; on the other hand, phosphonothioate was not detoxified in the rat organism.

Toxicities expressed as LD50 values of 2-dialkylaminoalkyl-(dialkylamid) o-fluorophophates for rats and mice (i. m. administration) were determined. Rats were more sensitive to these compounds than mice: LD50 values varied from 17 to 261 micrograms/kg for rats and from 30.5 to 1222 micrograms/kg for mice, respectively. Different routes of administration in one derivative of this group substituted by methyl groups only were compared. The highest toxicity (lowest LD50 value) in intravenous administration (11 micrograms/kg) and the lowest one in percutaneous (1366 micrograms/kg) were found.

A modification for continual monitoring of the blood acetylcholinesterase activity in the rat on an auto analyzer system was described. With using this technique, inhibition of the enzyme in vitro with O-ethyl-S-(2-dimethylaminoethyl)-methylphosphonothioate was determined. Bimolecular rate constant and I50 values were 1.66-10(6) M-1-min-1 and 1.4-10(-8)M, respectively. Rats treated i.m. with 0.043 mg/kg of this compound showed fast and rapid inhibition of the blood acetylcholinesterase after intoxication. The bimolecular rate constant of inhibition in vivo, calculated analogously as that in vitro was 1.37-10(6) M-1-min-1. On the presumption that both rates of inhibition (in vitro and in vivo) are identical, the concentration of organophosphate producing inhibition effect in vivo was 82% of the dose administered.

The cholinomimemtic substance 7-methoxyacrine was administered to eight patients, incl. 5 patients with tardive dyskinesias after neuroleptic drugs. In all patients an europhorizing effect was recorded, all five patients with tardive dyskinesias improved markedly after a single dose, in one female patient after repeated administration symptoms of tardive dyskinesia were eliminated. The incidence of side effects is minimal. Based on our modest experience we consider 7-methoxyacrine an important extension of therapeutic possibilities, in particular in tardive dyskinesias. The authors plan to test 7-methoxyacrine also in other indications, in particular in Alzheimer's disease and in side-effects caused by psychopharmaceutical preparations.

Toxicities expressed as LD50 values of 2-dialkylaminoalkyl-(dialkylamido)-fluorophosphates for rats and mice (i.m. administration) were determined. Rats were more sensitive to these compounds than mice: LD50 values varied from 17 (rats) to 1222 (mice) micrograms/kg. LD50 values at different routes of administration (i.v., i.m., s.c., p.o. and p.c.) for one derivative of this group, 2-dimethylaminoethyl-(dimethylamido)-fluorophosphate, were determined. Depending on the route of administration, LD50 values varied from 11 (i.v.) to 190 (p.o.) micrograms/kg for rats and from 27.6 (i.v.) to 222 (p.o.) micrograms/kg for mice, respectively. Percutaneous toxicity in rats only (LD50 = 1366 micrograms/kg) was determined.