D. M. Green

The central and peripheral activities of anti-acetylcholine drugs. Some concepts of practical relevance.

Five procedures have been used to compare the pharmacological effects and time‐activity profiles of anti‐acetylcholine drugs in the central and peripheral nervous system (ens, pns). In particular, the potencies of optically pure enantiomers of anti‐acetylcholine drugs which contain an asymmetric centre have been determined. The following four observations are made which are of relevance to all studies of anti‐acetylcholine drugs. (1) Times to onset of activity of anti‐acetylcholine drugs in three in vivo tests and the duration of action in one in vivo test are shown to increase as affinity constants, determined in vitro, increase. (2) Below a dose of ca 0.03 μmol kg−1no anti‐acetylcholine drug produces maximum mydriatic effects and all anti‐acetylcholine drugs which have log affinity constant values >9.49 produce maximal effects at approximately this dose. (3) The receptor with which anti‐acetylcholine drugs interact is essentially the same in the eye, salivary gland and ens of the mouse, the guinea‐pig ileum, and in the cat ens. (4) For any anti‐acetylcholine drug the time to onset of effects in the ens is similar to the time of onset of effects in the pns and appears to depend on the affinity constant rather than on the partition properties of the drug. The practical and theoretical significance of these and other observations are discussed.

On the dopamine-like action of apomorphine.

phase, however, to a less extent, as do exogenously administered PGE, and PGE, (1-50 ng/ml). (ii) The ganglionic relay in the peripheral part of the hypogastric nerve was extremely sensitive to the inhibitory substance (cf. Fig. 2) , and the same was found for exogeneous PG (0.1-0.4 ngiml). (iii) Incubation of the vas deferens with an inhibitor of PG synthesis (5,8,11,14-eicosatetraynoic acid, ETA, 1-20 pg/ml) (Downing, Ahern & Bachta, 1970)l led to a partial or total abolishment of the endogeneous inhibition. (iv) Release of prostaglandin-like material, mainly resembling PGE,, from the vas deferens on nerve stimulation, was established by silicic acid thin-layer chromatography (Green & Samuelsson, 1964). It can be concluded from the present results that the mechanical response of the isolated vas deferens to nerve stimulation is under a dual influence from excitatory and inhibitory agents. Several experimental data support the hypothesis that the endogenous inhibition could be due to release of prostaglandins that are acting by restricting the amount of noradrenaline liberated from adrenergic nerves by stimulation (cf. Hedqvist, 1970; Wennmalm, 1971). With regard to the effectiveness of the autoinhibition described even at very low frequencies of stimulation (2-5 Hz), it is tempting to suggest that this process might play a modulating role in the nerve-induced mechanical activity of this organ in in vivo conditions, as recently suggested by Wennmalm (1971) for the rabbit heart. Furthermore, the results provide the first indications of an inhibitory action of PG on ganglionic neuro-transmission.

Dual mechanism of the antidotal action of atropine‐like drugs in poisoning by organophosphorus anticholinesterases

ABSTRACT Although more potent anti-acetylcholine drugs than atropine have been described, attempts to find atropine-like drugs that are significantly superior to atropine for the treatment of poisoning by anticholinesterases have been unsuccessful. Possible reasons for this have been investigated by comparing enantiomeric pairs of atropine-like drugs in a variety of tests for anti-acetylcholine activity (e.g. affinity constants on ileum, mydriasis, blockade of oxotremorine-induced tremors and salivation) and for their anticholinesterase antidotal properties. Large and consistent anti-acetylcholine enantiomeric potency ratios were observed, thereby providing an indication of a similar receptor structure in the PNS, CNS and in different species. However, the enantiomers of any compound studied showed equal antidotal properties. The conclusion reached was that atropine-like drugs have anti-convulsant as well as anti-acetylcholine properties.

Effectiveness of pyridostigmine in reversing neuromuscular blockade produced by soman

The effects of pyridostigmine pretreatment on the neuromuscular blockade produced by soman in anaesthetized, atropinized animals have been studied on the soleus and anterior tibialis muscle (rhesus monkeys, cats and rabbits) and the gastrocnemius muscle (guinea‐pigs and rats). Pyridostigmine pretreatment produced a complete recovery of neuromuscular function following blockade by soman; the rate of recovery was similar in all the species, suggesting a common mechanism of action. In the absence of pyridostigmine or if pyridostigmine was delayed until after blockade by soman, there was no recovery of neuromuscular function. Detailed studies in the guinea‐pig showed that the recovery of neuromuscular function was related to the dose of soman and to the degree of carbamoylation of blood cholinesterase at the time of nerve agent challenge, i.e. to the dose of pyridostigmine and the time interval between the administration of pyridostigmine and soman. It is suggested that the effectiveness of pyridostigmine pretreatment is due to the carbamoylation of a portion of the tissue acetylcholinesterase, which protects it against irreversible inhibition by soman: after poisoning spontaneous decarbamoylation produces sufficient free acetylcholinesterase to restore normal function.

Pharmacology of o‐chlorobenzylidene malononitrile (CS)

1 The effects of o‐chlorobenzylidene malononitrile (CS) have been studied on several isolated organs and tissues, anaesthetized animals and cat encéphale isolé preparations. 2 On the isolated guinea‐pig ileum an initial dose of CS produced a small, non‐maintained contraction. Subsequent doses had reduced effects. There was no effect on peristalsis when the substance was given intraluminally. 3 No significant effects of CS were detected on the rat phrenic nerve‐diaphragm preparation, the isolated perfused rabbit heart or on the contractor response of the indirectly stimulated cat tibialis muscle. 4 In the cat encéphale isolé preparation 1 mg/kg (i.v.) produced a brief period of electrocortical alerting but no abnormal activity in the electrocorticogram. Doses in excess of 10 mg/kg produced cortical depression. 5 Intravascular injection into the chloralose anaesthetized cat resulted typically in a pressor response accompanied by a brief period of apnoea. The threshold dose for the pressor response varied with the route of administration, but generally lay between 2·5 and 12·5 μg/kg; the threshold dose for apnoea was slightly higher. Small variations in this pattern of response were seen with different species and other anaesthetics. 6 When administered by stomach tube to chloralose anaesthetized cats, CS produced no measurable effects at doses of up to 100 mg/kg. 7 No changes in blood pressure or respiration were detected in anaesthetized cats given pure CS aerosol for 1 h in concentrations of between 345 mg/m3 and 1·39 g/m3 via a tracheal cannula or through the upper respiratory tract. Pure CS solution given by slow intravenous infusion at a similar dose and over a similar period produced significant effects on blood pressure and respiration. 8 Pyrotechnically generated (grenade) CS produced variable effects when given by inhalation in concentrations of between 460 and 1,040 mg/m3 for 1 hour. Respiratory depression, possibly reflex in nature, regularly occurred when the material was given via the upper respiratory tract, and respiratory stimulation occurred when it was given via a tracheal cannula. 9 Some cats were pre‐exposed to a dose of 500 (mg/min)/m3 on 4 successive days and on the fifth day anaesthetized and exposed to high concentrations of grenade CS. Three out of six cats died during or after this final exposure compared to one out of six among animals not so pre‐exposed. The general pattern of response to the final exposure to CS in the two groups was similar.

A comparison of the stereochemical requirements of cholinergic and anticholinergic drugs

Mescaline had no effect on the metabolism of pentobarbitone in mice. Although it also caused increases in accumulation of pentobarbitone in brain, plasma, liver and kidney, the pentobarbitone sleeping time in animals treated with mescaline was shortened. Furthermore, the barbitone sleeping time was unaffected. If the increase of concentration in the tissues of experimental animals was the result of an increase in binding of pentobarbitone by mescaline, a reduction of the “free” pentobarbitone for exerting hypnotic action could account for the resulting decrease of pentobarbitone sleeping time in mice. This work was partially supported by Grant MH-12959, U. S. Public Health Service.

Central and peripheral actions of anticholinergic drugs when administered with triflupromazine.

Abstract Triflupromazine was found to potentiate the actions of six anticholinergic drugs in producing elevation of EEG arousal thresholds, and dissociation between EEG and behavioural arousal thresholds, in cat encephale isole preparations. The effects of triflupromazine on the anticholinergic activity of the six drugs were studied using as tests antagonism of oxotremorine-induced salivation and tremors and production of mydriasis in mice. It is concluded that the potentiating effect of triflupromazine on the EEG cannot be explained on the basis of an addition of anticholinergic activities and that other, as yet not understood, synergistic mechanisms are involved.

The ganglion blocking activity of diastereoisomeric dimethylaminobornyl acetates and their methiodides

Some diastereoisomeric dimethylaminobornyl acetates and their methiodides have been prepared and tested for ganglion blocking activity. Included in these compounds was an enantiomeric pair and associated quaternary salts. These optical antipodes displayed virtually no difference between their actions at the ganglion. Differences between the activities of the least and most potent diastereoisomers was limited to a factor of about five. Assays were made upon the cat superior cervical ganglion and also the guinea‐pig vas deferens preparation the successful quantitative use of which is described.

Neuromuscular blocking and antimuscarinic activity of a series of bis-atropinium and N-n-alkyl atropinium compounds

Measurements of neuromuscular blocking and antimuscarinic activity have been made in a series of bis‐atropinium (BA) and N‐n‐alkyl atropinium (N‐AA) compounds. That the second atropinium group contributed to the neuromuscular blocking activity of BA compounds was shown by the relative lack of such activity in the N‐AA series of compounds. Peak neuromuscular blocking activity occurred when two atropinium groups were separated by a chain of either 10 or 11 methylene groups. Members of both series of compounds displayed antimuscarinic properties but estimates of activity differed according to whether they were obtained by determination of affinity constants on guinea‐pig isolated ileum or production of mydriasis in mice. From measurements of affinity constant on the guinea‐pig ileum it is concluded that BA compounds interact with only one muscarinic receptor. However, the high activity of the deca‐ and undecamethylene BA compounds in producing mydriasis suggest that these compounds possibly interact with two receptors at once.

Dual Mechanism of the Antidotal Action of Atropine-like Drugs in Poisoning by Organophosphorus Anticholinesterases

Although more potent anti-acetylcholine drugs than atropine have been described, attempts to find atropine-like drugs that are significantly superior to atropine for the treatment of poisoning by anticholinesterases have been unsuccessful. Possible reasons for this have been investigated by comparing enantiomeric pairs of atropine-like drugs in a variety of tests for anti-acetylcholine activity (e.g. affinity constants on ileum, mydriasis, blockade of oxotremorine-induced tremors and salivation) and for their anticholinesterase antidotal properties. Large and consistent anti-acetylcholine enantiomeric potency ratios were observed, thereby providing an indication of a similar receptor structure in the PNS, CNS and in different species. However, the enantiomers of any compound studied showed equal antidotal properties. The conclusion reached was that atropine-like drugs have anti-convulsant as well as anti-acetylcholine properties.