A Case Report of Fatal

Desmethyl Carbodenafil
Toxicity
Oleh: Rahel Imelda Panggabean
190131143
 Abstract
We present the case report of a 34-year-old Hispanic male who was found unresponsive
in the carport of his residence. Surveillance video footage from a security camera showed
that he collapsed as he was walking to his vehicle. The decedent had no medical history
and no history of illicit drug use. Initial toxicology testing revealed no alcohol or illicit drugs.
Autopsy findings indicated a need for additional toxicological analysis due to a lack of
trauma and the paucity of pathophysiologically significant natural disease. Liquid
chromatography time-of-flight mass spectrometry of postmortem blood revealed the
presence of two large peaks corresponding to desmethyl carbodenafil, an unapproved
sildenafil analogue and its hydroxy metabolite. Species that are probable desmethyl and
hydroxydesmethyl metabolites of desmethyl carbodenafil were also found. The mass and
retention time of the parent compound in the decedent’s sample were matched to those of
a commercial standard. Based on this preliminary match, a method was developed and
validated to quantify desmethyl carbodenafil in human blood. This is the first known case
of fatal intoxication by desmethyl carbodenafil, a phosphodiesterase-5 inhibitor that is not
approved for use in the United States. Over the past several years, retailers have issued
voluntary recalls for dietary supplements marketed as sexual performance enhancers on
the basis that these supplements may contain undeclared desmethyl carbodenafil.
Introduction
• Phosphodiesterase-5 (PDE-5) inhibitors have been widely used
for the treatment of erectile dysfunction. PDE-5 is an enzyme
responsible for the breakdown of cyclic GMP (cGMP). Buildup of
cGMP enhances the vasodilatory effect of nitric oxide, leading to
penile erection. The first PDE-5 inhibitor to be commercialized
was sildenafil (Viagra®), which has enjoyed widespread
popularity since its introduction in 1998. Two more drugs,
vardenafil hydrochloride (Levitra®) and tadalafil (Cialis®) were
approved for the treatment of erectile dysfunction in 2003.
• Negative side effects of PDE-5 inhibitors have been reported,
including headaches, flushing, nasal congestion, dyspepsia,
andsmall decreases in systolic and diastolic blood pressure.
This decrease in blood pressure has been observed in both
healthy men and men with a history of cardiovascular disease .
However, PDE-5 inhibitors are contraindicated in patients with a
history of cardiovascular disease or those currently taking
nitrates, as drug interactions can produce a precipitous drop in
blood pressure.
Case Report
A 34-year-old Hispanic male was found unresponsive beneath a
covered carport at his residence. Video footage from a neighbor’s
security surveillance camera showed that the decedent staggered
and collapsed as he was walking from his residence to his vehicle.
He attempted to get up twice but was unable to stand. No other
individuals were observed in the video, and foul play was not
suspected. The decedent had no known medical history and was
reportedly taking no prescription or over-the-counter medications.
He smoked and used alcohol socially but had no history of illicit
drug use. No drugs or paraphernalia were found at the scene.
Autopsy findings were unremarkable with no signs of trauma.
Toxicology testing revealed no alcohol or illicit drugs.
• The decedent was 142 lbs. (64.4 kg) and 70 inches in length. There was
no evidence of decomposition. The only injury was an abrasion of the left
knee, likely sustained during his collapse. The autopsy findings were
notable for pulmonary edema (combined lungs weight: 1,050 g) and
cerebral edema (brain weight: 1,350 g). The heart had a minimally dilated
right ventricle (heart: 325 g); the left adrenal gland had an incidental
ganglioneuroma and the kidneys exhibited arterionephrosclerosis
(combined kidneys weight: 375 g). Histological sections of the heart, lungs,
liver, kidneys, spleen, pancreas, left adrenal gland and brain revealed no
other pathophysiologically significant findings. Given that the natural
disease was not sufficient enough to cause death, toxicological analysis
was indicated. Standard basic and acidic drug screens did not detect
desmethyl carbodenafil. This drug was only detected by LC-TOF-MS,
which highlights the utility of this technique relative to traditional GC–MS
screening techniques. The quantitative method was successfully validated
for each parameter described above. The limit of detection was calculated
as three times the average response of a negative sample.
Result and Discussion
• The limit of quantitation was administratively set at 100 μg/L. No
interferences were observed from the internal standard, the matrix or other
drugs. the concentration of desmethyl carbodenafil in the decedent’s blood
was found to be 0.92 ± 0.13 mg/L (95% level of confidence). The
chromatogram of the extracted postmortem blood is shown in Figure 3. As
desmethyl carbodenafil is a sildenafil analog, its pharmacokinetics may
bear some resemblance to those of sildenafil. Oral doses of 50 mg
sildenafil (the mid-level commercially manufactured dosage) result in peak
plasma concentrations of approximately 0.15 mg/L, while dosages of 200
mg result in peak plasma concentrations of approximately 1mg/L. It is
noteworthy that sildenafil is not manufactured in a 200mg dose, and the
maximum recommended dose is 100 mg. Vardenafil is active at even lower
plasma concentrations. Thus, the concentration of desmethyl carbodenafil
in portmortem blood is at the higher end of the range reported in the
literature for PDE-5 inhibitors. Upon quantitation of desmethyl carbodenafil
at 0.92 ± 0.13 mg/L, the cause of death was listed as “Acute desmethyl
carbodenafil toxicity” with the manner of death as “accident.”
Result and Discussion
• In cases where PDE-5 inhibitors have been identified in products in the
United States, they were not listed on the label as active ingredients.
Therefore, while it is possible that consumers are aware of the presence of
these drugs in supplements, the labeling and marketing of these
supplements, positioning the products as “natural” or “herbal,” make it
more likely that consumers are unaware of the specific ingredients
contained in the supplement. Thus, this case may be an example of the
mislabeling and potentially fraudulent marketing that so often takes place
with dietary supplements. The U.S. Food and Drug Administration reports
that the practice of adulteration is a “growing trend” among dietary
supplements
Result and Discussion
• Although approved PDE-5 inhibitors are generally well tolerated, negative
side effects have been reported. However, until now, no adverse effects
from desmethyl carbodenafil specifically have been documented in the
literature. This is the first known case of fatality resulting from desmethyl
carbodenafil intoxication. However, given the popularity of these drugs and
the prevalence of adulterated supplements containing PDE-5 inhibitors, it
is possible that unapproved PDE-5 inhibitor fatalities are being
underreported, especially as these compounds were not detected by GC–
MS techniques in our laboratory. LC-TOF-MS analysis should be
considered in cases where PDE-5 inhibitors are suspected but
toxicological findings are otherwise lacking.
Conclusion
Little has been published regarding the safety or toxicological profiles of
desmethyl carbodenafil, a PDE-5 inhibitor that is not approved by the
Food and Drug Administration for use in the United States. We have
described a first case of fatality associated with desmethyl carbodenafil
intoxication in a 34-year-old male, who presented during autopsy with no
signs of trauma and no natural disease significant enough to contribute to
cause of death. An LC-TOF-MS screen revealed the presence of
desmethyl carbodenafil and putative metabolites in the postmortem
blood. A method was subsequently developed and validated, and
desmethyl carbodenafil was quantified in the decedent’s blood as 0.92 ±
0.13 mg/L. The presence of this drug in the decedent’s postmortem blood,
coupled with the video surveillance footage, suggests that the drug may
have induced a severe episode of hypotension from which the decedent
did not recover.
Conclusion
The case was subsequently certified with the cause of death as “Acute
desmethyl carbodenafil toxicity” with a manner of death as “accident.” In
light of other reports of undeclared PDE-5 inhibitors in dietary
supplements, as well as the fact that desmethyl carbodenafil is not
approved for use in the United States, it is likely that the desmethyl
carbodenafil in the decedent’s blood originated from a mislabeled dietary
supplement. In cases where trauma, genetic history or anatomical findings
are lacking, and toxicology results are unremarkable, this case highlights
the need for enhanced screening capabilities that can reveal the presence
of PDE-5 inhibitors as a sole cause of fatal toxicity.
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