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Effects in Man of the Anticholinesterase Compound Sarin (Isopropyl Methyl Phosphonofluoridate)

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Effects in Man of the Anticholinesterase Compound Sarin (Isopropyl Methyl Phosphonofluoridate) EFFECTS IN MAN OF THE ANTICHOLINESTERASE COMPOUND SARIN (ISOPROPYL METHYL PHOSPHONOFLUORIDATE) David Grob, John C. Harvey J Clin Invest. 1958;37(3):350-368. https://doi.org/10.1172/JCI103615. Research Article Find the latest version: https://jci.me/103615/pdf EFFECTS IN MAN OF THE ANTICHOLINESTERASE COMPOUND SARIN (ISOPROPYL METHYL PHOSPHONOFLUORIDATE)l By DAVID GROB AND JOHN C. HARVEY (From the Departmnent of Aledicine, The Johns Hopkins University and Hospital, Baltimore, Md.) (Submitted for publication August 6, 1957; accepted October 31, 1957) A number of organic esters of phosphoric acid In the present stud) the effect of sarin on hu- derivatives have been synthesized which have man ChE enzymes in vitro was compared with pharmacologic effects attributable to the inhibition that of tabun, TEPP, DFP, neostigmine and of cholinesterase (ChE) enzymes. The effects parathion. Sarin was administered orally to 10 resemble those produced by physostigmine and normal volunteer subjects and observations were neostigmine (Prostigming) but are more intense made of signs and symptoms and of changes in and prolonged. Di-isopropyl fluorophosphate plasma and red blood cell cholinesterase activity, (DFP) has been studied in detail (1-4) and has electrical activity of the brain, movement of air been employed as a therapeutic agent in the man- into and out of the lungs, and response to atropine. agement of abdominal distention (2), urinary re- The effects of the intra-arterial injection and con- tention, and glaucoma (5). Tetraethyl pyrophos- junctival instillation of sarin were also investi- phate (TEPP) (6) and octamethyl pyrophos- gated. phoramide (OMPA) (7) proved to be of some value in the management of myasthenia gravis, METHODS but have been replaced by less potent anticholines- The liquid sarin employed was 90 per cent pure by terase compounds. Parathion, bis- (monoiso- chemical analysis (17), but since the compounds which propylamino)-fluorophosphine oxide (Mipafox®), constitute the remaining 10 per cent may have anti- hexaethyl cholinesterase activity, the material was regarded as tetraphosphate (HETP), and TEPP 100 per cent sarin in all calculations. Solutions of sarin have been widely used as agricultural insecticides, in water and in propylene glycol were administered daily and their indiscriminate dispersal has resulted in over periods of one to four days. The concentration of a number of instances of poisoning, some of them these solutions (4 X 10' to 2.5 X 10' M) was confirmed fatal (8-10). The nerve gases are related com- by colorimetric estimation, and by determination of in- because of their and hibition of plasma and red blood cell cholinesterase in pounds which, high toxicity vitro and of toxicity to rats. Solutions were adjusted physical properties, are among the most potent to a pH of 5 to 6, at which hydrolysis is slowest, and chemical warfare agents (11-14). One of the stored at 50 C. for up to three days. At the end of this most important of these is sarin (isopropyl methyl time there was less than five per cent decrease in the phosphonofluoridate) (15), which has also been active concentration of sarin in aqueous solution, and no and has the structural formula: change in propylene glycol solution. designated GB, The cholinesterase activity of plasma (heparinized) CH3 CH3 and red blood cells was determined in duplicate or tripli- cate by electrometric determination of change in hydrogen H-C{)-P==O ion concentration (18) before and after the adminis- tration of sarin. The standard deviation of parallel repli- CH3 F cate determinations was four per cent for plasma cholines- terase and three per cent for the red blood cell enzyme, Another is tabun (dimethylamido-ethoxyphos- and five per cent for replicate determinations on sepa- phoryl cyanide) (16), which has been designated rate days following storage of frozen plasma or hemo- GA. lyzed red blood cells. For the studies of anticholinesterase activity of sarin 1 This work was supported by a contract between the and tabun carried out in vitro, plasma (heparinized) and Johns Hopkins University and the U. S. Army Chemical red blood cells were obtained from normal subjects, and Corps, and was originally reported in Medical Division skeletal muscle and brain were obtained immediately (Chemical Corps) Research Report Numbers 17 and 18, post mortem from patients who had died of diseases that August, 1950. did not directly involve these tissues. Cholinesterase 350 EFFECTS OF SARIN IN MAN 351 20- 10- 8- _. X - 4- * %.. 0 z 3 0 24 0 I- -. C.) 40 CU) 4c w UI)I- w * PLASMA z o RBC + BRAIN 0 A z x MUSCLE C) .. 11% ... 4 0.146 -., a a a a -o 2 4 6 90 12 14 16 Is CONCENTRATION OF SARIN (M x 109) FIG. 1. EFFECT OF SARIN ON HUMAN PLASMA, RED BLOOD CELL, BRAIN, AND MUSCLE CHOLINESTERASE ACTIVITY IN VITRO The same data are presented in the upper graph on a logarithmic scale, and in the lower graph on a linear scale. The concentrations of the enzyme preparations are recorded in Table I. activity was determined in duplicate or triplicate mano- tivity (Figure 1). Each increment in concentra- metrically (1). The standard deviation of parallel repli- tion inhibited the same fraction of cholinesterase cate determinations was five per cent. and had a diminishing effect on the amount in- hibited. The logarithm of the fraction of RESULTS cholin- esterase that remained active decreased linearly I. Effect of sarin on the cholinesterase activity of with increasing concentration of sarin, or, the human plasma, red blood cells, muscle and brain logarithm of the reciprocal of the fraction that re- in vitro mained active was directly proportional to the con- centration of sarin: A. Inhibition of cholinesterase ChE o Plasma cholinesterase was slightly less sensitive loChElog __ = k S, or, log ChE S ChEoh0 to inhibition by sarin than the cholinesterases pres- ent in red blood cells, muscle and brain, which where ChE0 equals cholinesterase activity just be- were approximately equally sensitive (Figure 1 fore the addition of sarin; ChEl equals cholines- and Table I). Increasing concentrations of sarin terase activity one hour later; and S equals con- resulted in increasing inhibition of enzyme ac- centration of sarin. One hour after the addition 352 DAVID GROB AND JOHN C. HARVEY TABLE I The in vitro sensitivity of human plasma, red blood cell, brain and muscle cholinesterases to inhibition of sarin, tabun, TEPP, DFP, neostigmine and parathion * Plasma ChE RBC ChE Brain ChE Muscle ChE Sarin 4.2 X 10- 3 X 10 3.3 X 10- 3.6 X 10- Tabun 1.3 X 10-8 1.5 X 10-s 1.5 X 10-8 2 X 10-8 TEPP 5 X 10- 3.5 X 10-8 3.2 X 10-8 3.5 X 10-8 DFP 9.5 X 10 4 X 10-7 3 X 10-7 2.5 X 10-7 Neostigmine 4 X 10-8 8 X 10-7 4 X 10-7 3 X 10-7 Parathion 1 X 10-6 1.2 X 10-5 1.3 X 10-6 1.5 X 10-5 * The molar concentration of each anticholinesterase agent is recorded which produced 50 per cent inhibition of the ChE activity of a solution or homogenate which hydrolyzed 4.8 X 10-4 mM acetylcholine bromide per hour in the absence of inhibitor. This rate of hydrolysis was produced by 51 mg. per ml. of plasma, 124 mg. per ml. of brain (cerebral cortex) homogenate, 58 mg. per ml. of muscle (psoas) homogenate, and 34 mg. per ml. of red blood cell contents. The initial concentration of acetylcholine bromide was 0.015 M. ChE and antiChE compounds were mixed 45 minutes before the addition of acetylcholine. of sarin, cholinesterase could not be reactivated ied. Plasma cholinesterase was slightly less sen- by standing, dilution or dialysis against running sitive than the other cholinesterases to inhibition water. by sarin, more sensitive to inhibition by TEPP, DFP, neostigmine and parathion, and as sensitive B. Comparison vith other anticholinesterase com- as the other enzymes to inhibition by tabun. pounds Sarin resembled tabun and DFP in combining The inhibitory activity of sarin against the cho- with cholinesterase almost irreversibly during the com- linesterase enzymes of the red blood cells, muscle first hour of their reaction. In contrast, the and brain was greater than that of the other bination of TEPP or parathion with cholinesterase anticholinesterase compounds, being approximately is slightly reversible (6, 19), while the combina- 5 times that of tabun, 10 times that of TEPP (6), tion of neostigmine with the enzyme is entirely 100 times that of DFP (1), and 4,000 times that reversible (20). of parathion (19) under the conditions of the experiment (Table I). The inhibitory activity of C. Solubility of sarin in an aqueous and lipoid and comparison with the other anti- sarin against plasma cholinesterase was approxi- medium, mately equal to that of TEPP, and was greater cholinesterase compounds than that of the other anticholinesterase com- Aqueous solutions of each anticholinesterase pounds. The cholinesterases of red blood cells, compound (concentrations as in Table I) were muscle and brain were approximately equally sen- homogenized with equal volumes of peanut oil, sitive to inhibition by each of the compounds stud- following which the latter was removed by centri- TABLE II Oral administration of sarin to ten normal subjects Initial dose of % Reduction of ChE* Total amt. of sarin Maximum reduc- sarin after initial dose admn. over 3 days tion of ChE* Subject mg. mg./Kg. Plasma RBC mg. mg./Kg. Plasma RBC 1. W. B. 0.030 0.0005 10 10 0.426 0.007 14 33 2. E. M.
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