Journal Reading

TOXICOLOGY PRACTICAL SESSION ASSIGNMENT

DEVINA-SYARIF-ZAIN-LOVIRA-SANI-AMELIA

Kepanitraan Klinik Ilmu Kedokteran Forensik

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 Intro

▰ Modafinil is a stimulant with a wakefulness promoting property used for

treatment of diseases associated with extreme sleepiness (e.g., narcolepsy)

▰ Modafinil is often misused as a so called "cognitive enhancer" to increase

alertness and to improve mental skills

▰ Adverse effects mainly are tachycardia, insomnia, agitation, dizziness,

increased anxiety, and nausea

▰ To our knowledge, there is no case of lethal outcome after modafinil

monointoxication

▰ The method presented for the detection of modafinil and its two metabolites
in plasma/serum and urine are basic solid phase extraction (SPE) and a
fast high performance liquid chromatography coupled with a photo diode
array detector (HPLC-DAD)

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Case 1

▰ In the first case, witnesses reported a car which accelerated,

suddenly stopped and then crossed over driving into the
oncoming traffic.

▰ The driver turned the car back into the correct lane without
taking note of others thereby nearly hitting one

▰ He drove on a swerving manner and then ignored a red traffic

light. The car was stopped by the alarmed police

▰ A blood sample was collected ~1.5 hrs later and there was no
information regarding modafinil intake according to the police

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 Case 2

▰The police followed a car. The driver drove the vehicle into the left turn lane
without signaling. The policemen observed that he had not fastened his seat
belt. The driver then completed the turn, thereby grazing the curb.

▰The police stopped the car and a blood sample was taken 1.5 h after that.

▰As in the previous case, there was no information for a modafinil intake
according to the police protocol

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 Case 3

▰The case started with a spontaneous traffic control by the police at a petrol station. The
driver exhibited various signs of drug influence. He explained that he takes modafinil
(“400-600 mg”) and an antidepressant the nature of which was initially not further
specified. A blood sample was taken 2 h after the police’s arrival
▰This sample was initially analyzed in a restricted analysis, because in Germany, DUID
can be judged as an administrative offence only when the most important illegal
substances (e.g., cannabis, cocaine)
▰In this case, modafinil and the unknown antidepressant were not initially detected,
because the case was an administrative offense where analysis does not cover these
substances.
▰In the hearing at the court, the accused reported he must take modafinil because he
was diagnosed with narcolepsy & cataplexy. He claimed that he had successfully
proved his driving ability in a sleep laboratory. Furthermore, he stated he had to take
imipramine.
▰However, he expressed doubts that the blood sample which was analyzed was really
his. To settle this counter-claim, a DNA test as well as an extended toxicological
analysis including modafinil and imipramine was ordered by the judge

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Experimental

▰Chemical and reagents

▻Modafinil
▻Alkaline buffer (saturated dipotassium phosphate solution
+ deionized water)
▻Buffer for mobile phase (dipotassium phosphate, ortho-
phosporic acid, a solution of 2,5M NaOH+water)
▻Blank serum

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Experimental

▰Analytical procedure
▻Sample preparation (solid-phase extraction using Bond
Elut C18 columns; papaverine was used as internal standard)
▻Apparatus and chromatographic conditions
(chromatographic separation using Polaris C18-A column in
isocratic run; wavelengths for UV detection 220 nm for
modafinil and 239 nm for internal standard)
▻Quantification of modafinil (a six point-calibration from 0,5
– 5,0 mg/L covering therapeutic range of 0,9 – 3,3 mg/L)
▻Statistics
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Result

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Result

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Result

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 Discussion

▰The therapeutic range of modafinil within blood plasma

concentrations: from 0.9 to 3.3 mg/L
▰The elimination half-life : 7–13 h
▰Blood sample evaluation after 2X100 mg tab Modafinil
consumption in interval up to 72 h post dose :
young males (ages 22–37) : max concentration 4.21 (±0.44)
mg/L after 2.0 (±1.0) h,
young females (ages 19–40) : max concentration 5.20 (±0.83)
mg/L after 1.7 (±0.9) h
elderly males (ages 53–72) : max concentration 4.81
(±0.89)mg/L 1.7 (±0.7) h

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▰A 14 year old girl ingested 20 X 200 tab modafinil and 10 X
10 mg escitalopram:
She was tachycardic, anxious, diaphoretic and complained
of a dry mouth and diarrhea. Modafinil concentration 24 h
after ingestion was 18 mg/L . 33 hours post ingestion:
remained tachycardic and hypervigilant, sleeping only 20
min at a time.
▰A 16-year-old girl was taken to hospital with tachycardic,
headache, “body tingling”, fleeting chest pain, restlessness
and visual hallucinations : A serum sample was taken 18 h
after initial presentation and revealed a modafinil
concentration of 13mg/L. 13
Case 1

▰The modafinil concentration of 2.1 mg/L is within the

therapeutic range.
▰The uninhibited and nervous mood and the incessant :
the activating effects of modafinil.
▰The reddened, glazed eyes : effect of THC, additionally in
a rather low concentration.
▰Sleepiness and the swerving and erratic driving :
combined effect of a decreasing cocaine intoxication with
low concentrations of THC, diazepam and nordazepam.
▰The observed driving mistakes show that modafinil did
not improve the man’s ability to drive or compensate the
effects of the other substances.
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 Case 2

▰The modafinil concentration of 3.8mg/L is slightly above the

therapeutic range (could represent a peak concentration)
▰Being excited, impolite, talkative, uninhibited and having a
varying mood: from modafinil, the co-ingested alcohol and/or
from both.
▰The swaying body motion is probably the result of the alcohol
“co”-intoxication.
▰Only a low concentration of 11-nor-9- carboxy-THC was found
-> influence by cannabis can be excluded.
▰Modafinil does not seem to compensate the negative effects
of the co-ingested alcohol.
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 Case 3

▰The person in case 3 took modafinil for medical reasons

(narcolepsy with cataplexy)
▰Modafinil concentration of 3.6 mg/L is above the therapeutic
range and could be the reason for the man’s nervousness,
restlessness, overconfidence and the trembling body during
the police control
▰Rest of the symptoms more appropriately fit an acute
cannabis intoxication (dry mouth, dilated pupils, disturbances
of balance)
▰Modafinil shows no structural similarities to amphetamines
which would explain a cross-reactivity to the test.
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 Case 4

▰The therapeutic modafinil concentration of 1.3 mg/L was

probably higher during the crimes because the elapsed time
of 4.5 h from the first offence to the blood sampling is quite
long.
▰Aggressiveness towards the police and his victims fit well to
the activating effects of modafinil, as well the symptoms of
exhaustion during doctor’s examination as decreasing effect
of modafinil or the withdrawal symptoms
▰The person in case 4 told the police he was addicted to
modafinil
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 Case 5

▰Very high modafinil concentration of ~34 mg/L but the

mentioned symptoms do not fit the side effects of modafinil.
▰The attending physicians concluded that epileptic seizures
could have possibly occurred due to the intoxication leading
to the loss of consciousness, or the intoxication itself was the
only trigger for the comatose state.
▰Case 5 was determined to be an intoxication with modafinil

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 Limitations

▰Two main metabolites modafinil (sulfone & modafinil acid) were not
analyzed because they both do not contribute to the pharmacologic
effects, thus were not important for the interpretation of the cases.
▰Papaverine was used as internal standard because it is writers’
established routine method. Although the structure is quite different
compared to modafinil, it proved to be well suited for the presented
method; demonstrated by the validation data.
▰Some methods described in the literature use internal standards
which are structurally more closely related to modafinil, i.e., [bis-(4-
fluoro-phenyl)-methylsulfinyl]acetic acid or 3,3-diphenylpropylamine

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 Conclusion

▰There is scant literature on blood concentrations of modafinil in cases

of DUID, suspected misuse and/or intoxications. We have presented five
cases from our routine work with different situations in which a modafinil
ingestion had been proven.

▰ In summary, modafinil is a substance, although rare, has to keep in

mind in forensic and clinical toxicology, but which can be identified and
quantified with simple chromatographic methods. Positive samples
could stem both from misuse of the substance as well as from a
prescribed medication.

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THANKYOU 

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