The Effects of Intracisternal Sarin and Pyridine‐2‐aldoxime Methyl Methanesulphonate in Anaesthetized Dogs

Abstract

Dogs poisoned by the anticholinesterase sarin could be saved by intravenous administration of atropine sulphate together with a suitable oxime. The central effects of intracisternal sarin were respiratory paralysis and vasomotor stimulation. The problem arose as to whether the oxime, being a quaternary nitrogen compound, could enter the brain from the blood, and could have a central action on the paralysed respiration. The methyl methanesulphonate of pyridine-2-aldoxime administered intracisternally, after sarin poisoning by the same route, was ineffective; atropine, given intravenously, was effective. The central and peripheral effects of sarin were thus reversed by the atropine-oxime therapy, the central effects by atropine, the peripheral by the oxime. Dogs given many times the LD50 of the potent anticholinesterase sarin (isopropyl methyl-phosphonofluoridate) can be saved by the intravenous injection of atropine sulphate and the methiodide of pyridine-2-aldoxime. Atropine alone, while re-starting respiration, is incapable of maintaining it (Brown, Kunkel, Somers and Wills, 1957;Wills, Kunkel, Brown and Groblewski, 1957). The oxime alone is ineffective in re-establishing respiration. If the oxime is given 5 min. after the atropine, respiration improves within 0.5 min. which might be compatible with a central effect although quaternary nitrogen compounds penetrate the blood-brain barrier with difficulty (see Koelle and Steiner, 1956).The experiments were undertaken to assess the central effects of sarin and of pyridine-2-aldoxime and the relative importance of central and peripheral paralysis of respiration in poisoning with sarin. METHODSThe sarin was diluted with saline immediately before use and the volume injected was always less than 0.12 ml. Because of its greater solubility and equal efficacy (Davies and Willey, 1958), the methyl methanesulphonate of pyridine 2-aldoxime was used in the present work instead of the methiodide and was administered in aqueous solution containing 100 jug. or 1,000 ,ug./0.1 ml.; both freshly made and *Present address: Chemical Warfare Laboratories, Army Chemical Center, Maryland, U.S.A. older solutions wer used, and were often tested by the copper acetate-benzidine acetate test for the presence of cyanide. The atropine sulphate solution contained 2 mg./ml., and, except as noted, was always given intravenously, 0.5 mg./kg. The dogs were anaesthetized by pentobarbitone sodium given intravenously, enough being administered to abolish the palpebral reflex, thus giving deep surgical anaesthesia. Additional small doses were given as needed. Blood pressure was recorded on a smoked paper by a mercury manometer from a femoral or common carotid artery. The trachea was cannulated. Respirations were recorded by a Marey tambour connected with the tracheal cannula. Artificial respiration (not recorded) was given by a Starling Ideal pump. An external saphenous vein was used for intravenous injections.The dog was placed on its belly and the neck sharply flexed. A midline incision was made wit...

The protective actions of some anticholinergic drugs in sarin poisoning

“…The role of the latter, in reactivating inhibited cholinesterase, seems to be of prime importance in the periphery although statements (Brown, 1960;Hobbiger, 1963) that quatemary aldoximes do not penetrate into the central nervous system may have to be modified in view of more recent findings, for example those of Firemark, Barlow & Roth (1964), who showed that after large doses of labelled N-methylpyridinium-2-aldoxime it is possible to detect small amounts of the compound in the brain.…”

Neurobiology of Acetylcholine

“…This pressor response has been demonstrated with various OPs in humans (Holmes & Gaon, 1956), as well as in experimental animals (GB: Brown, 1960;Longo et al, 1960;DFP: Koppanyi et al, 1947Koppanyi & Karczmar, 1951), and~y various routes of administration including inhalation. Concomitant with the hypertensive response there is usually some bradycardia (Karczmar et al, 1966).…”

“…One mechanism is a peripheral nicotinic pressor action demonstrated in the presence of atropine (Koppanyi et al, 1947(Koppanyi et al, , 1953Koppanyi & Karczmar, 1951). The second mechanism is-an-atropine-sensitive CNS pressor response demonstrated following intracerebroventricular injection of GD or GB (Brezenoff et al, 1984;Brown, 1960).…”

Pharmacological Antagonists of the Anticholinesterase Agents

“…By comparison of the illustrations in two of KoELLE's papers, it seems that P-2-AM is a more potent reactivator in vivo of AChE inhibited by DFP (KoELLE 1957) than is either MINA or DAM (RAJAPURKAR and KoELLE 1958). Although the quaternary oximes reactivate AChE in vivo in ganglia as well as in muscle (KOELLE 1957, RAJAPURKAR andKoELLE 1958) and in blood (HoBBIGER andSADLER 1959, WILLS 1959), they produce no significant reactivation of AChE in brain (HOBBIGER andSADLER 1959, WILLS 1959), nor do they antagonize significantly the toxic effects of anti-ChE agents on brain functions (SAKAI et al 1958, WILLS and BoRISON 1959, BRoWN 1960. This is true especially of the quaternized oximes; DAM in an i.v.…”