Download POISONING BY METHYL-PARAFYNOL (DORMISON) Methyl

POISONING BY METHYL-PARAFYNOL (DORMISON)
FATAL SUICIDAL
OVERDOSE OF 3-METHYL-PENTYNE-OL-3, A N E W HYPNOTIC
R E U B E N M. CARES, M . D . , B E R N A R D N E W M A N , C H . E., AND
J O S E P H C. M A U C E R I , M . D .
Office of the Coroner, Suffolk County, Kings Park, New York
Methyl-parafynol (Dormison, Schering Corp., Bloomfield, N. J.) is a nonbarbiturate hypnotic introduced in 1951. In recommended doses of 1 or 2
capsules,8' I0 it is alleged to be rapidly acting, its effect lasting I or 2 hours, and
to be nonhabit forming. It is purported to have negligible side effects and no
known contraindications. The LD50 for rabbits, mice and guinea pigs ranges
from 600 to 900 mg. per Kg. 8
A fatal overdose in an adult woman, probably the first to be recorded, is described in this report. It is of particular interest that the lethal concentration,
on the basis of body weight, was found to be considerably smaller than in experimental animals. In this instance, the ingestion of from 18 to 24 capsules,
representing 90 to 120 mg. per Kg., caused death in from 1 to 3 hours.
R E P O R T OF CASE
History. A white, married woman, 45 .years of age, was last seen alive and well, doing
household chores, about 1 P.M. on April 22, 1952. She was discovered apparently lifeless,
3 hours later, in her bed, and pronounced dead on arrival at the hospital a t 5:05 P . M .
Several years before, she had suffered a nervous breakdown. Since then she had continued
to be depressed and highly emotional, and occasionally had consulted a physician. There
were no other significant features in her past, personal or family history.
An investigation by the Coroner's Office ascertained t h a t the deceased woman was
found lying full}' clothed in her bed on her left side, in a natural posture of sleep. An empty
vial was discovered in the bathroom clothes-hamper. I t was found t h a t a prescription for
24 capsules of Dormison was issued February 8, 1952, and refilled only 3 days prior to the
p a t i e n t ' s death. A detailed search failed to account for the missing Dormison capsules, of
which at least 18 should have remained. The household medications were of the usual type
and appeared to be uninvolved in the death.
Pathologic findings. An autopsy was performed 2 hours after death was pronounced. T h e
deceased was a well developed woman who weighed 110 pounds (50 Kg.) and measured 67
inches (170 cm.). I t was estimated t h a t death had occurred between 2 and 4 P . M . of t h a t
day. There was no rigor mortis, and body warmth was largely retained. T h e torso presented beginning postural congestion of a light bluish red color. T h e upper p a r t of both
thighs, the anterior chest wall and the abdominal wall showed a suffused light pink hue.
T h e pupils were distinctly dilated, equal and regular. T h e nose and mouth passages were
free of fluid, and the mucous membranes showed a normal pink hue.
Internal examination disclosed evidence of normal oxygenation of the tissues, the blood
t h a t oozed from incised tissues appearing red. Only the large veins contained darker venous
Received for publication September 29, 1952.
D r . Cares is Director of Laboratories, Kings P a r k S t a t e Hospital, Kings P a r k , New
York; Mr. Newman is Toxicologist, South Shore Research Laboratories, Islip, New York;
and D r . Mauceri is Coroner of Suffolk County, Kings P a r k , New York.
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AL.
blood. T h e lungs and bronchi were deep-pink to bright red, with early pulmonary edema.
T h e heart was of normal size and shape, with both ventricles somewhat relaxed and moderately distended with dark red fluid blood. T h e stomach contained about 400 ml. of a light
pink and white creamy chyme. A faint odor of a benzene nature was detected. T h e stomach
contents refrigerated overnight showed on t h e following morning a few, small, oily, t r a n s p a r e n t globules floating on the sedimented fluid. They resembled in physical appearance
and odor t h e oily vehicle contained within Dormison capsules. T h e intact gastric mucosa
showed only moderate hyperemia. T h e urinary bladder was pale and contained only 4 ml.
of clear, pale yellow urine having a normal odor. T h e other viscera showed only mild acute
congestion.
Microscopic sections of the thoracic and abdominal organs, stained with hematoxylin
and eosin, presented a uniform picture of moderate acute congestion.
The cause of death was cardiac arrest following coma, due to acute poisoning by ingestion of an agent to be determined. The death was established as having occurred from 1 to
3 hours after ingestion of the agent.
Comment on "pathologic findings. T h e relative state of good oxygenation and moderate
congestion resembled findings encountered in acute deaths from some inhalation anesthetics, such as chloroform. T h e absence of pronounced cyanosis, as well as relaxation of t h e
ventricles, indicated primary cardiac involvement rather than depression of the respiratory center. D e a t h occurred from 1 to 3 hours after the patient had last been seen at 1 P . M .
t h a t day. An odor of the gastric contents, suggestive of benzene, strengthened the suspicion
of acute poisoning.
TOXICOLOGY
Materials. The stomach, stomach contents, liver and blood from the right side
of the heart were subjected to toxicologic analysis. Recovery of residual Dormison from the stomach contents was invalidated through an initial oversight.
The stomach contents had been subjected to acid steam distillation, which destroyed the unstable, unsaturated, aliphatic compound of methyl-parafynol
(see below).
General exclusion procedures. The tissues were subjected to specific analytic
procedures, utilizing methods selected from standard texts on toxicology.1' 6i 12
Spectroscopic examination of the blood disclosed absorption bands of normal
oxyhemoglobin. No evidence was found of common toxic compounds that could
cause death in a few hours by coma and cardiac arrest. The acid steam distillate
of stomach contents and tissues was subjected to the group reaction procedure
of Merley and Bueding9 for common steam-volatile poisons. All tests were negative for chloral hydrate, chloroform, cyanide, aldehydes and alcohols.
Pharmacology and toxicology of Dormison. Dormison belongs to the unsaturated aliphatic carbinols. Chemically, it is 3-methyl-pentyne-ol-3 (methyl-parafynol, Schering).
CH 3
I
HC=C—CH,—CH3
I
OH
3-methyl-pentyne-ol-3
In chemical structure it is related to the saturated tertiary carbinols, the most
important one being amylene hydrate. 6,13 The latter drug, intermediate in hypnotic action between chloral hydrate and paraldehyde, was first proposed in 1887
POISONING BY DORMISON
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by Von Mering as a hypnotic. Amylene hydrate is too hazardous as a hypnotic
or anesthetic. It has limited use as a solvent for tribromoethanol in Avertin
anesthesia.4
Chevalley and associates,3 in a clinical trial of 3-methyl-pentyne-ol-3 (Dormison, brand of methyl parafynol) on 134 patients, found 200 to 300 mg. of the
drug to be the effective dose in most patients. They noted that those patients
who had pain or mental agitation slept for 2 hours after administration of the
drug, and then awakened requiring a second dose. The drug, in recovery experiments on tissue by Perlman and Johnson,10 was found largely metabolized in
the first few hours after ingestion by experimental animals. In mice, rats and
dogs, sustained daily dosages of 200-300 mg. per Kg. (approximately 70 times
the recommended human dosage) caused no pathologic changes.8 •
The presence of the triple bond, as in acetylene derivatives, in the structural
formula between carbons 1 and 2, affords a method of estimation of the drug in
biologic material. Heating or steam distillation is to be avoided with this unstable, unsaturated, aliphatic compound. However, such triple-bonded compounds readily form metallic acetylides, notably silver acetylide, which are
insoluble in aqueous solutions. After precipitation with an ammoniacal silver
solution, the silver acetylide is subsequently dissolved with nitric acid. The
resulting solution reacts with p-dimethylaminorhodanine to produce a colored
compound. This is compared with standard known solutions in a photoelectric
colorimeter.
Recovery of methyl parafynol. Using the analytic procedure of Perlman and
Johnson,10 a drug concentration was obtained of 49 mg. per 100 Gm. of fresh
liver tissue. The patient's liver weighed 1260 grams, giving a total of 617 mg".
of drug in this organ. If we assume that all 24 drug capsules of 250 mg. each had
been ingested, i.e., 6 grams, the amount calculated in the liver represents about
10 per cent of the amount ingested. If 18 capsules had been ingested, the amount
represents 14 per cent. Perlman and Johnson had found that approximately 6
per cent of the fatal amount administered was recovered from the liver of" rats.
In the blood, a recovery of 0.48 mg. per 100 ml. of blood was obtained. The
patient's blood volume was estimated from data given by Cantarow and Trumper,2 of 7.1.9 ml. per Kg. for females. Since the patient weighed 50 Kg., the calculated total blood volume would be 3595 ml. and the total quantity of methylparafynol in the circulating blood would be 17.3 mg.
In control-and-recovery experiments, carried out to check on the efficiency
of the recommended methods employed, 25 mg. of Dormison in its vehicle was
added to 15 Gm. of fresh normal human liver. This gave a working proportion of
drug to tissue of 1:600, a concentration suitable for recovery experiments. Of
the original 25 mg., 17 mg. was recovered. Negative controls similarly run from
the same normal liver and routine blood specimens failed to yield evidence of
any Dormison-like substance.
COMMENT
7
Jenkins and Hartung found that 3-methyl-pentyne-ol-3 had no analgesic
effects on dogs, rats and mice. Margolin and associates8 found a consistent pat-
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tern of consecutive symptoms from therapeutic doses in animals: sedation, loss
of reflexes and finally sleep. They also stated, "in marked contrast to the
barbiturates and other hypnotics, 3-methyl-pentyne-ol-3 did not depress the
respiration." This is in accord with our observation at autopsy of evidence of
good oxygenation of tissues. The immediate cause of death of the patient was
believed to be cardiac arrest. The concentrations that we obtained of methyl
parafynol in the patient's liver were somewhat higher (10 to 14 per cent) than
was present in the livers of poisoned rats (6 per cent of the fatal dose). From
18 to 24 capsules of the prescription for Dormison had been swallowed and
largely absorbed. The fatal dose of 4.5 to 6.0 grams is calculated as ranging from
90 to 120 mg. per Kg. This is equivalent to one-sixth to one-tenth of the acute
oral LD50 for rats, mice and guinea pigs of 600 to 900 mg. per Kg. It may mean
greater toxicity for human beings than has been determined in animals.
Of more serious import is the rapidity of death in a few hours of this patient
from an overdose 9 to 12 times the recommended therapeutic dose of 2 capsules
in a 2-hour period. Considering her history of emotional instability, we may
assume that the overdose was intentional. The conclusions of Chevalley and
associates that methyl parafynol is completely safe even in large overdoses,
may have to be modified. We know of no specific antidotes or contraindications.
Rescue measures are frequently successful in overdoses from common hypnotics
and narcotics that usually produce coma lasting up to 24 hours or more before
death. In this case death ensued within 3 hours after ingestion, and there was no
opportunity for life-saving measures. The simulation of natural sleep in an overdosage would likewise divert attention.
Peterson, Haines and Webster's text11 lists the chief factors modifying the
effect of poisons as: age, idiosyncrasy, tolerance, habituation and the presence
of organic disease. This woman was middle-aged, and was not known to have
shown any idiosyncrasy after consuming the original prescription for 24 capsules
issued 2 months before. She was free of clinical and pathologic evidences of organic disease. The history of a "nervous breakdown" with depression and emotional disturbance is assumed to have motivated the suicidal overdose of the
hypnotic drug, Dormison.
SUMMARY
Fatal poisoning due to suicidal overdose of methyl parafynol (3-methylpentyne-ol-3) is reported in a 45-year-old woman. Death occurred 1 to 3 hours
after ingestion of from 18 to 24 capsules of the drug, Dormison. Postmortem
findings consisted of mild congestion of the viscera and skin, dilatation of the
pupils and cardiac arrest in ventricular diastole.
Chemical analysis revealed a concentration of 49 mg. of methyl parafynol
per 100 Gm. of liver tissue, or 10 to 14 per cent of the estimated dose. In this
patient, the lethal dose is estimated as 90 to 120 mg. per Kg., which is from onesixth to one-tenth the LD50 for common experimental animals.
P O I S O N I N G BY DORMISON
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