Frederick J. Di Carlo
and Linda CUIP Holmes College of St. Elizabeth Convent Station, N e w Jersey 07961
Homicide and Nitroglycerin: A Case of Drug Interaction?
In 1901, a convicted abortionist and a chemist inadvertantly produced early information on the metabolism of nitroglycerin in man. A single subject was involved; she was described contradictorily as 19 years of age in her obituary notice (1) and as 22 years old in the Journal of" the American Chemical Society (2). However, there was no doubt that she was, as a local newspaper puritanically described her (S), "in a delicate condition." (Queen Victoria was alive a t the time.) Mention of pregnancy, incidentally was omitted from the euphemistic obituary which stated that "Miss McW. retired in her usual health on Wednesday, but could not be aroused" (1). In actuality, the trial revealed that Miss McW. was seen in a convulsive state by her parents, her boyfriend, and three physicians (3, 4). She died without regaining consciousness. Nine weeks later, the country prosecutor yielded to the public pressure created by rumors that the girl did not die of natural causes. He ordered that the body be disinterred. An autopsy failed to reveal the cause of death. In an effortto detect poison, the stomach, liver, kidneys, and spleen were submitted for assay to Dr. G. G. Pond at Pennsylvania State College. Dr. Pond assayed not only the organs, but the embalming fluid which served as a "blank"! Following the Dragendorff procedure (5), he submitted a section of the stomach to steam distillation, extracted the distillate with ether, and evaporated the solvent. The residue was an oil which was identified as nitroglycerin because it gave a nitrate test and exploded violently when struck on an anvil (2)! Dr. Pond demonstrated a few explosions in court, but the role of the drug in the death of Miss McW. was never established. Mr. I., a local storeowner and the "accepted suitor" (3) of Miss McW., was indicted for abortion on eight different counts. He was found guilty on only one charge, namely, "an attempt to commit an abortion by the use of unknown instruments, death of the woman ensuing." In retrospect, it seems very doubtful that he was truly guilty on this count. Nothing in the newspapers indicated that the use of the instruments caused the girl's death. The evidence was clear on this issue. Dr. M. L. Houser testified that close examination a t autopsy disclosed no evidence that an abortion had been attempted (3, 4). Dr. G. H. Woods corroborated this testimony and Dr. G. F. Harris added that the convulsions were not caused by any criminal operation (4). It seems that Miss McW. drank a solution of nitroglycerin, presumably furnished by Mr. I. as an abortifacient agent or, as the prosecuting attorneys surmised, as a heart stimulant. The drug has neither of these properties. Although nitroglycerin is absorbed rapidly 726
/ Journal of Chemical Education
when taken sublingually, its absorption is relatively slow when swallowed (6). Indeed, a study performed with a related organic nitrate shoved poor absorption from the stomach (7). Nitroglycerin is susceptible to acid hydrolysis, but more than stomach acidity is required for extensive de-esterification (8). The drug could not have been administered to Miss McW. after 11 pnr because three physicians were in attendance from that time until 7 A U and they could not administer any drug orally because her jaw was locked shut. This period and the ten-hour balance of the victim's life allowed a considerable amount of time for drug absorption. In view of this time clement, it is very probable that the dose of nitroglycerin ingested by Miss NcW. was massive. Dr. Pond estimated the quantity of nitroglycerin in the stomach of the exhumed girl to be 46 mg (2). Did this represent the remnant of a toxic dose? The toxicity of nitroglycerin is \veil-known for a variety of animals, but data on the human tolerance of this compound is scanty. However, accident situations, suicides and attempted suicides with nitroglycerin have yielded some information. The most recent compilation of data on the acute toxicity of nitroglycerin was made in 1965 (9). Unfortunatcly, most of the values are reported in terms of "drops" and "teaspoonsful" of solutions and defy quantifying. One person died after swalloaing 9.1 g of nitroglycerin which he mistook for oil (10). The usual medicinal dose of this drug is 0.65 mg which may be taken many times during the same day. There are several reports of illness but survival after doses of 300400 mg (9). So, nitroglycerin offers a large margin of safety. Munch and Friedland (9) concluded their survey xith the estimate that "the fatal dose of oral administration would be of the order of 100 to 125 mg/kg." This value agrees with the figure reported in 1870 by Holst (11) and means that a person weighing 110 lb \vould die from a nitroglycerin dose in the range of 5.0-6.25 g. Miss McW.'s stomach contained only 46 mg. Did this represent less than lyo of her dose? Or was her dose smaller, but potentiated in some manner? The Journal of the American Chemical Society report (8) sheds some light oh this point. Dr. Pond wrote: "The woman had been ill for only 24 hr, and during this time nothing had been administered by the attending physicians through the mouth; small doses of morphia had been given hypodermically." This statement introduces the subject known among pharmacologists as drug interaction. Simply stated, drug interaction refers to the fact that a drug may act synergistically with or antagonistically to another drug in the body at the same time (18). A well-known illustration of synergistic drug interaction was the tragic death in
1965 of Dorothy Kilgallen, noted newspaper columnist and television personality. She had taken her usual dose of sleeping pills soon after cocktails. The ethanol blocked the degradation of the barbiturate to its inactive metabolites and she absorbed, in effect, a toxic barbiturate dose (13). Drug interaction is known to addicts. One example is their use of a barbiturate to enhance the effects of heroin (1 4). Nitroglycerin interacts with barbiturates (16) by inhibiting their oxidation to inactive metabolites (16). Additionally, there are two suggestive reports on nitroglycerin. A fatality reported by Rabinowitch in 1944 (9) concerned the death of a worker who took nitroglycerin and alcohol. The second and more closely related fatality was reported in 1959 by Sutherland (9). It dealt with a 65 year old woman who died from only 0.6 mg of nitroglycerin plus unspecified quantities of codeine and morphine. In their survey of the acute toxicity of nitroglycerin, Munch and Fricdland (9) included the following macabre paragraph: "One cheerful aspect of the criminal use of glyceryl trinitrate was suggested by McVey. One of the criminals testifying for the Statc in the Doctor Ailyer poison case indicated that glyceryl trinitrate was the surest and best poison; he mixed it with whiskey and had the victim drink the mixture on a warm day, then set him adrift in a boat in Lake Michigan. When found dead it would be assumed that the individual had died of heat stroke!" We take issue with the expressions "cheerful aspect" and "best poison" in the foregoing quotation, but other considerations are more important. The first is that nitroglycerin has a sweet taste, a characteristic noted in 1847 by Ascanio Sobrero who was the first to synthesize the compound (17). Whether the taste of the dmg would be noticed would depend upon its concentration, the nature of the diiuent and the sensitivity of the subject. Obviously, one person was victimized. The second point is the involvement of drug interaction. Ethanol might have increased the toxicity of nitroglycerin in this murder and perhaps in the accident reported by Rabinowitch (9). This matter merits experimental investigation. As late as 1965, it was thought that the metabolism of nitroglycerin i n vivo proceeded only so far as to yield glyceryl-1,2-dinitrate and glyceryl-1,3-dinitrate (18, 19). Subsequent studies with 14C-labelednitroglycerin showed this view to be in error. Indeed, not only was the drug found to be de-esterified completely to glycerol, but this compound entered metabolic pools for anaholism as well as for catabolism (20-22). Consequently, 14C02was exhaled, and radioactive macromolecules were produced.
Obviously, a great number of intermediates were involved in these biosyntheses, and many more compounds were formed by the turnover of the tissue components. In a sense, then, nitroglycerin can be metabolized completely. Taken in very large doses, however, some of the compound may he expected to be excreted intact in the urine and, as Dr. Pond demonstrated, to remain in the stomach. The unfortunate demise of Miss McW. and the recent studies of nitroglycerin metabolism suggest areas for study. Most interesting and having clinical relevance would be the development of information on the interaction of nitroglycerin with a wide variety of drugs. Our literature survey has turned up little besides the synergistic effect of nitroglycerin upon barbiturates in animals (15, 16). A brief letter to the editor of the New Angland Journal of Medicine stated that, ' I . . . nitroglycerin can result in cardiovascular collapse when taken in conjunction with alcohol" (23). The opposite effect,that is, reduced nitroglycerin activity, was noted when this drug was administered to a person who had taken phenobarbital rcpcatedly (24). During the preparation of this manuscript, we discussed our findingswith several physicians. Considcration was given to the possibilities that Miss McW. died from the ingestion of some unknown compound or from a cerebral aneurism. However, no supporting evidence was found; the autopsy report is no longer on record in the prothonotary office in Bellefonte. Our hypothesis that death might have resulted from the combined action of morphine and a massive dose of nitroglycerin has, at least, the merit of being consistcnt with the facts. What happened to Mr. I.? After being declared responsible for the death of Miss AilcW., he filed an appeal for a new trial. On June 17, 1901, his motion was denied and he was sentenced to serve a prison term of three years and four months (25). Literature Cited (1) (2) (31 (4) .. (5) (6)
Thc Centre Democrat, Bellefonte, Pa.. Jan. 17. 1901, D. 4 . POND, G. G., J . A m w . Chem. Soc., 24, 18 (1902). The Centre Democrat, Bellefonte, Pa.. May 2, 1901, pp. 1. 2 Kevslone Garetle. Hellefonte. Pa.. Mav 3 . 1901. on. 1. 2. D n A o ~ ~ o o n rG., r . "~rmitt&ng vonCXften" idth ed.), 1895, p. 84. K n m ~ z J. . C., JR. AND CAR%C. J.. "Phsrmaoologiod Principles of Mediosl Praotioe" (5th ed.), Williams and Wilkins, Baltimore 1961, p. 1026. D1 C*RLO. F. J.. C ~ " T , N " ~C,I. B.. *No CREW. M. C.. Arnh. r n t . Phavmocodyn. Ther., 167, 163 (1967). CREW.M. C., A N D Dr CARLO, F. J., J. Chromolog?r.,35,506 (1968). MUNCR,J. C.. A N D FRIEDLAND, B.,Ind.Mad. Sur0..34, 143 (1985) H u ~ ~ & A T. N NH., , Schmidt's Johresber.. 134, 344 (1867). HOLBT. J. c.. J . ~ , C S ~ C I .&:os. u s a 1 1.7 11117") ~ GOTH.A , . "Medical Pharm acology" (2nd ed.). The C. V. Mosby Co.. R. ~ St. Louia. 196dI..,n . R.. New Fork T i m m Nov. 19, 1965, p . 2 9 . Cham. En#.News 8. Nov: 2. 1950, p. 26. W o o s m ~ ,H. A Jn.: AND SUNDERMAN. PI W.. J . P h o r m a d . E S P . The,., 97 , 140 (1949). , DI C A ~ L F. O ,J.. cnau. M. C.. A N 6 Yourq.J. E.. B*chsm. Phormoool.. 66, 1147 (1967). S o a n ~ n oA.. , Comp. Rand.. 25,247 (1847). NEEDLEMAN, P., A N D KRANTZ,J. C., JA.,Biochem. Phormncol., 14, 1225 (1965). NEEDLEMAN, P.. A N D HVNTBR,P. E., JR., Mol. Phormoeol.. 1, 77 i (19651. DICARLO,F. J.. HIYNDS, L. J.. MBLOAR. M. D . , A N D CREW.M. C.. Biochcm. Biophys. Rcs. Commun., 31,738 (1968). Dr C*nr.o, F. J . , C m w , M. C.. H * r ~ e s .L. J.. M e b o * ~ ,M. D., A N D GALA,R. L., Biorhsm. Phnrmoeol., 17,2179 (1968). Dr C A ~ L O F.. J.. V r ~ uJ.-P., . AND M n b o ~ nM. . D.. Biochcm. Phormocol.. 18, 965 (1969). SHAFER, M., New Eng. J. Msd., 273, 1169 (1965). H O ~ A E R TM. . G.. ROBBEEL, M.-T. nNn BmP*m% I?. hl.. Arch. I n f . Pharmoeodyn. Ther., 191, 198 (1971). Keystone Gordle, Bellefonte, Pa.. June 21, 1901.
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Volume
49, Number 1 I, November 1972 / 727
