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MJFMCT - Volume 27 - Issue 2 - Pages 43-56
MJFMCT - Volume 27 - Issue 2 - Pages 43-56
2019 43
ABSTRACT
The market of illicit erection/potency enhancers has grown significantly in the
KEYWORDS last decade. Some of those products lack any data about active ingredients, have
Illicit erection enhancers,
Anthraquinone,
dosage mislabeling or claim to contain only natural substances. The aim of this
Counterfeit sildenafil, study is to elucidate the various contents and concentration of sildenafil in a cheap
Hepatotoxicity, illicit erection enhancer tablets available in local markets and to evaluate its
Sildenafil citrate. potential toxic effects on the liver. An illicit oral preparation (tablet form), sold in
local market as an erection enhancer and claim to contain 130 mg of sildenafil
citrate/ tablet, was analyzed by Gas Chromatography-Mass Spectrometry (GC-
MS). The same preparation was dissolved in distilled water and administered per
oral route in two doses (8.13 mg/Kg/ day and 50 mg/kg/day) for 8 weeks to male
mice to investigate its effects on hepatic tissue. A control group was given distilled
water only. Analysis of the tablets demonstrated several ingredients including the
potential hepatotoxic 1-Bromo-2,4-dimethoxyanthrquinone, and N-
Trichloroacetyl-tryptamine with no traces for sildenafil citrate. The study showed
that the preparation caused dose dependent histopathologic changes in liver of
mice. These changes included lobular inflammation, kupffer cell hyperplasia,
nuclear alterations (nuclear vesiculation, anisonucleosis, binucleation), hydropic
degeneration and large areas of necrosis. Vascular congestion and fibrosis were
also observed. The study has confirmed the phenomenon of counterfeit
preparation for treatment of erectile dysfunction as the investigated product has
been shown to lack active sildenafil despite being marketed as a sildenafil product.
In addition, the study has pointed out the potential hepatotoxicity of
anthraquinone derivatives.
approximately 2.5 million of legal sildenafil capillary column (Agilent DB-5ms), Mass
users (Jackson et al., 2010). Quadrupole Spectrometry detector Model
5975B was used. Measuring peak areas was
In the United Kingdom, analysis of
performed by using a computer data system
2,383 seized samples of counterfeit sildenafil
(MSD Chem Station E.0201.1177).
revealed that only 10% contained the same
concentrations of active sildenafil that were Oven Program: 40 °C for 2 min then 10
advertised on the drug packaging (Stecher et °C/min to 150 °C for 3 min
al., 2010). then 10 °C/min to 220 °C for 6
min then 15 °C/min to 280 °C
Illicit and counterfeit sildenafil from
for 15 min.
various countries were reported to contain
different adulterants as amphetamine, caffeine, Run time: 48 min and 2 min (Post Run) 260
paracetamol, metronidazole, quinine, °C.
clomiphene, chloramphenicol, gamma- Flow Program: 0.5 mL/min for 10.9 min then
aminobutyric acid, and yohimbine. The 1 mL/min per min to 1 mL/min
presence of unknown ingredients and for 30 min.
impurities may lead to serious adverse effects
and drug-drug interactions. Beside variation of The same preparation was administered
dose and mislabeling may lead to unintentional via oral route to male mice for 8 weeks. Thirty
toxicity due to overdose (Jackson et al., 2010). male adult mice weighing 20 - 30 grams were
Furthermore, patients with contraindications to maintained under optimal laboratory
the use of sildenafil can consume products conditions. Feed and water were provided for
claiming to contain only natural substances ad- libitum consumption. All groups were
(Eysenbach, 1999). exposed to the main two stages of the
experiment period as follows; the first 2 weeks
The aim of this study is to elucidate the were the pre-treatment period for
various contents and concentration of acclimatization, followed by 8 weeks of per
sildenafil in a cheap illicit erection enhancer oral administration. The animals were divided
preparation available in local markets and to into 3 groups (each group containing 10 mice).
evaluate its potential toxic effects on the liver.
The first group: used as the control; 10
mice received nothing except distilled
Material and Methods water.
The second group (therapeutic dose):
received the preparation dissolved in
An illicit erection/potency enhancer distilled water at a dose equivalent to
tablets carrying the name of “hard on” alleging human therapeutic dose (8.13 mg/Kg/
to contain 130 mg of sildenafil/tablet was day) calculated according to Paget and
analyzed. Analysis was conducted by Gas Barnes (1964).
Chromatography-Mass Spectrometric (GC-MS
7890A-5975B) at Analytical Chemistry Unit, The third group (toxic dose): received
Faculty of Science, Assiut University, Egypt. the preparation dissolved in distilled
Chromatographic separation was conducted by water at a dose of 50 mg/animal/day
Agilent Technologies Gas Chromatograph (1/10th the minimal lethal dose)
(Model 7890A) equipped with temperature (Badwan et al., 2001).
programming capability, split less injector,
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Ahemed et al. 45
At the end of the experiment, liver The study was conducted after ethical
tissues were excised from the sacrificed approval (number 17300302) according to the
animals. Representative sections from the liver Guidelines of the National Institute of Health
tissues were fixed in 10% buffered formalin for Animal Care followed within the Faculty
and then processed for embedding in paraffin of Medicine, Assiut University, according to
wax by routine protocols. After that, 5-mm- referenced authority (ILAR, 2011).
thick sections were cut and were stained with
hematoxylin & eosin stain, periodic acid-
Schiff (PAS) (to assess the glycogen content Results
of the hepatocytes) and Masson's Trichrome
stain (to assess the extent of fibrosis)
(Sajjarattul et al., 2016). Haematoxylin and Analysis of the tablets by GC-MS
Eosin (H&E) stained liver sections were demonstrated the following ingredients: 1-
evaluated for liver injuries including hydropic Bromo-2,4-dimethoxyanthrquinone, N-(4-
degeneration, nuclear alterations, vascular hydroxyphenyl)-acetamide, N-Trichloroacetyl-
congestion, inflammation, necrosis, and tryptamine, 26-Nor-5-cholesten-3,beta,ol-25-
fibrosis. The lesions were scored as: 0=normal, one, Bis(2-ethylhexyl) phthalate, Dibutyl
1= mild (1% to 30%), 2= moderate (31% Phthalate, Hexadecanoic acid,
to70%) and 3=severe (>70%), according to the Hexatriacontane, Isobutyl Phthalate,
percentages of tissues affected. Octadecanoic acid, Octadecanoic acid ethyl
ester, Phytane, Squalane and Sucrose
Statistical analysis: Data was analyzed octaacetate. Retention time and peak area for
using SPSS software version 22. Data was each compound are demonstrated in table (1).
expressed as mean ± Standard deviation (SD), The chromatogram is shown in figure (1).
p value < 0.05 was considered significant.
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Fig. (2): Photomicrographs of representative liver sections from the normal control group.
Hematoxylin and Eosin stained sections showing preserved liver architecture without
any pathological changes (A; x100 & B; x400). Masson’s Trichrome stain showing no
collagen deposition (C; x400). PAS-stain showing normal glycogen content of the
hepatocytes (D; x400).
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Fig. (3): Photomicrographs of representative liver sections from the therapeutic dose group. Hematoxylin
and Eosin stained sections show: lobular inflammation (thick arrow) and binucleation (thin
arrow) (A; x400). Mild hydropic degeneration (thick arrow), mild vascular congestion (star) and
kupffer cell hyperplasia (thin arrow) (B; x400). Nuclear vesiculation, anisonucleosis (arrow) and
necrosis (star) (C; x400). Perivenular and perisinusoidal fibrosis (arrow) (D; x400). Masson’s
Trichrome stain showing perivenular and perisinusoidal fibrosis (arrow) (E; x400). PAS-stain
showing partial depletion of the glycogen within the hepatocytes (arrow) (F; x400).
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Table (2): Mean score of liver injuries of the study groups (30 mice).
Normal Control Therapeutic dose Toxic dose
group group group
(10 mice) (10 mice) (10 mice)
Type of liver injury Mean Mean ± SEM Mean ± SEM
Hydropic degeneration 0 1.4±0.16 2.2±0.24
Nuclear alterations 0 1.6±0.22 1.8±0.24
Necrosis 0 1.4±0.16 2.6±0.16
Inflammation 0 1.3±0.15 1.6±0.16
Vascular congestion 0 1.5±0.22 2.5±0.16
Fibrosis 0 0.8±0.24 1.2±0.24
Mean score of liver injuries 0 1.33±0.11* 1.98±0.22 *, ≠
≠
SEM: Standard error of mean, *p value<0.05 (significant) when compared to the normal control group. p value<0.05
(significant) when compared to the therapeutic dose group.
Significant histopathologic changes were congestion of the central vein (Figure 4E) and
observed in the hepatic tissues from the toxic portal vessels (Figure 4F) were also observed.
dose group. The mean score of liver injuries Portal, perivenular and perisinusoidal fibrosis
in the toxic dose group was significantly were more prominent than that detected in the
higher than that of the normal control group (p toxic dose group (Figure 4 E & F). Masson’s
= 0.002) and therapeutic dose group (p = Trichrome staining showed perisinusoidal and
0.045). These changes include severe lobular perivenular fibrosis (Figure 4G). Compared
inflammation (Figure 4A), kupffer cell with the control liver, marked reduction in
hyperplasia (Figure 4B), nuclear alterations periodic acid Schiff (PAS) reaction was
(nuclear vesiculation, anisonucleosis (Figure observed in many hepatocytes (Figure 4H).
4B), binucleation (Figure 4C), more prominent The score of liver injuries in the toxic dose
hydropic degeneration (Figure 4C) and large group was summarized in table (2).
areas of necrosis (Figure 4D). Severe
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Fig. (4): Photomicrographs of representative liver sections from the toxic dose group.
H& E stained sections show: severe lobular inflammation (A; x400). Kupffer cell
hyperplasia (thin arrow), nuclear vesiculation, anisonucleosis (thick arrow) (B;
x400). Severe hydropic degeneration (thin arrow) and binucleation (thick arrow)
(C; x400). Large area of necrosis (D; x400). Vascular congestion (star) and
perivenular fibrosis (thin arrow) (E; x400). Portal (thin arrow) and perisinusoidal
fibrosis (thick arrow), congestion of the portal vessels (star) (F; x400). Masson’s
Trichrome stain showing perivenular and perisinusoidal fibrosis (arrow) (G;
x400). PAS-stain showing marked depletion of the glycogen within the
hepatocytes (arrow) (H; x400).
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Tryptamine derivatives are psychoactive mean score of liver injuries was significantly
substances with a long history of licit and higher than that of the normal control group.
illicit use (Sanders et al., 2008). Well-known The present study also showed significant
tryptamines, such as LSD and psilocybin are histopathologic changes in the liver of mice that
thoroughly researched (Griffiths et al., 2006). were administered the erection enhancer in
While little literature is available regarding 1/10th the lethal dose and the mean score of liver
the potential toxicity of the new tryptamine injuries was significantly higher than that of the
derivatives (Araújo et al., 2015). Some group administered the therapeutic dose. These
synthetic tryptamine derivatives are reported changes included severe lobular inflammation,
to produce similar effects to those produced kupffer cell hyperplasia, nuclear alterations
by psilocin. Those effects include visual (nuclear vesiculation, anisonucleosis, bi-
hallucinations, euphoria, exaggerated tactile nucleation, more prominent hydropic
sensations, feeling of flushing, and increased degeneration and large areas of necrosis. Severe
libido (Dargan and Wood, 2013). vascular congestion, portal, perivenular and
Anthraquinones are an important class perisinusoidal fibrosis were observed. Those
of naturally occurring biologically active changes could be attributed to the presence of 1-
compounds produced by different plants of Bromo-2,4-dimethoxyanthraquinone in the
various families (Yeap et al., 2015). studied preparation.
Anthraquinones are found in rhubarb, Senna, Exposure of the liver to unusual amounts
Cascara sagrada, buckhorn, and aloe (Chan of toxic metabolites of anthraquinone glycosides
and Lin, 2009). Anthraquinone and its was reported to cause acute hepatic failure in a
derivatives are a group of quinoids that have 52-year-old woman who had consumed,
wide chemical diversity. These derivatives for more than 3 years, a herbal tea containing
recently gained great attention of the dry senna fruits (Vanderperren et al., 2005).
pharmaceuticals industry and other fields as
clothes dyes, and food colorants (Fouillaud et An experimental animal study reported that
al., 2016). anthraquinones might be responsible for the
hepatotoxicity of Polygonum multiflorum plant
Anthraquinones are mainly used as
(Zhang et al., 2018). In rats, Polygonum
laxatives (Anton and Haag-Berrurie, 1980). multiflorum plant caused liver injury in the form
A recent study reported that anthraquinones of cell swelling, ballooning of degenerating
and anthraquinone glycoside could be novel cells, and focal infiltration of inflammatory cells
drugs for treating erectile dysfunction (Khanh (Lin et al., 2017).
et al., 2018).
A two-year study, conducted by National
The current study showed that Toxicology Program (2001) on one of the main
administration of the erection enhancer tablets anthraquinone derivatives of rhubarb,
to male mice (for 8 weeks daily) in a dose demonstrated its hepatotoxic effects on rats and
equivalent to the human therapeutic dose of mice. The laxative herb Cascara sagrada
sildenafil citrate caused histopathological containing anthracene glycosides was also
changes in the liver. Those changes included reported to cause cholestatic hepatitis through an
mild hydropic degeneration, vascular unknown mechanism (Nadir et al., 2000).
congestion, and kupffer cell hyperplasia.
Nuclei showed vesiculation, anisonucleosis,
binucleation. Focal areas of perivenular and
perisinusoidal fibrosis were detected. The
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ﻗﺴﻢ اﻟﺒﺎﺛﻮﻟﻮﺟﯿﺎ ،ﻛﻠﯿﺔ اﻟﻄﺐ ،ﺟﺎﻣﻌﺔ أﺳﯿﻮط
٢
ﻗﺴﻢ اﻟﻄﺐ اﻟﺸﺮﻋﻲ واﻟﺴﻤﻮم اﻹﻛﻠﯿﻨﯿﻜﯿﺔ ،ﻛﻠﯿﺔ اﻟﻄﺐ ،ﺟﺎﻣﻌﺔ اﺳﯿﻮط
ﺗﺰاﯾﺪت اﻟﺘﺠﺎرة ﻏﯿﺮ اﻟﻘﺎﻧﻮﻧﯿ ﺔ ﻟﻸدوﯾ ﺔ اﻟﻤﺰﯾﻔ ﺔ اﻟﺨﺎﺻ ﺔ ﺑﻌ ﻼج ﺿ ﻌﻒ اﻻﻧﺘ ﺼﺎب ﺑ ﺸﻜﻞ ﻣﻠﺤ ﻮظ ﻓ ﻲ اﻟﻌﻘ ﺪ
اﻟﻤﺎﺿﻲ .ﺑﻌﺾ ھﺬه اﻟﻤﻨﺘﺠﺎت ﺗﻔﺘﻘﺮ إﻟﻰ أي ﺑﯿﺎﻧﺎت ﺣﻮل اﻟﻤﻮاد اﻟﻔﻌﺎﻟ ﺔ ﺑﮭ ﺎ ،أو أن ﺑﯿﺎﻧ ﺎت اﻟﺠﺮﻋ ﺔ ﻣ ﻀﻠﻠﺔ وﺗ ﺸﯿﺮ
إﻟﻰ اﺣﺘﻮاﺋﮭﺎ ﻋﻠﻰ ﻣﻮاد ﻃﺒﯿﻌﯿﺔ ﻓﻘﻂ .ﺗﮭﺪف ھﺬه اﻟﺪراﺳﺔ إﻟﻰ ﻣﻌﺮﻓﺔ ﻣﻜﻮﻧﺎت أﻗ ﺮاص أﺣ ﺪ اﻟﻤﻨﺘﺠ ﺎت اﻟﺪواﺋﯿ ﺔ ﻏﯿ ﺮ
اﻟﻤ ﺸﺮوﻋﺔ اﻟﻤﺘ ﻮﻓﺮة ﻓ ﻲ اﻷﺳ ﻮاق اﻟﻤﺤﻠﯿ ﺔ واﻟﺘ ﻲ ﺗﺒ ﺎع ﻟﻌ ﻼج ﺿ ﻌﻒ اﻻﻧﺘ ﺼﺎب .ﻛﻤ ﺎ ﺗﮭ ﺪف اﻟﺪراﺳ ﺔ أﯾ ﻀﺎ إﻟ ﻰ
ﻣﻌﺮﻓ ﺔ ﺗﺮﻛﯿ ﺰ اﻟ ﺴﯿﻠﺪﯾﻨﺎﻓﯿﻞ ﻓ ﻲ ھ ﺬه اﻷﻗ ﺮاص وﺗﻘﯿ ﯿﻢ آﺛﺎرھ ﺎ اﻟ ﺴﺎﻣﺔ اﻟﻤﺤﺘﻤﻠ ﺔ ﻋﻠ ﻰ اﻟﻜﺒ ﺪ ﻓ ﻲ اﻟﻔﺌ ﺮان .ﺗ ﻢ ﺗﺤﻠﯿ ﻞ
اﻟﻤﺴﺘﺤﻀﺮ ﺑﻮاﺳﻄﺔ ﺗﺤﻠﯿﻞ اﻟﻐﺎز اﻟﻜﺮوﻣﺎﺗﻮﺟﺮاﻓﻲ ذو اﻟﻜﺘﻠﺔ اﻟﻄﯿﻔﯿﺔ ) .(GC-MSﻛﻤﺎ ﺗﻢ اﻋﻄﺎء ﻧﻔﺲ اﻟﻤﺴﺘﺤﻀﺮ
ﺑﻌﺪ إذاﺑﺘﮫ ﻓﻲ ﻣﺎء ﻣﻘﻄﺮ ﻋﻦ ﻃﺮﯾﻖ اﻟﻔﻢ ﯾﻮﻣﯿﺎً ﻟﻤﺪة ٨أﺳﺎﺑﯿﻊ ﻟﻠﻔﺌﺮان اﻟﺬﻛﻮر ﻟﻠﺘﺤﻘ ﻖ ﻣ ﻦ آﺛ ﺎره ﻋﻠ ﻰ أﻧ ﺴﺠﺔ اﻟﻜﺒ ﺪ.
ﺷﻤﻠﺖ اﻟﺪراﺳﺔ ٣ﻣﺠﻤﻮﻋﺎت ﺗﺘﻜﻮن ﻛﻞ ﻣﺠﻤﻮﻋﺔ ﻣﻦ ١٠ﻓﺌﺮان وﻗ ﺪ ﺗ ﻢ اﻋﻄ ﺎء ﻣ ﺎء ﻣﻘﻄ ﺮ ﻟﻠﻤﺠﻤﻮﻋ ﺔ اﻟ ﻀﺎﺑﻄﺔ.
واﻟﻤﺴﺘﺤﻀﺮ اﻟﻤﺬاب ﻓﻲ اﻟﻤﺎء اﻟﻤﻘﻄ ﺮ ﺗ ﻢ اﻋﻄ ﺎءه ﻟﻤﺠﻤ ﻮﻋﺘﯿﻦ ﻣ ﻦ اﻟﻔﺌ ﺮان ﻓ ﻲ ﺟ ﺮﻋﺘﯿﻦ ) ٨٫١٣ﻣ ﺞ /ﻛ ﺞ/اﻟﯿ ﻮم
و ٥٠ﻣﺠ ﻢ/ﻛﺠ ﻢ/اﻟﯿ ﻮم( .أﻇﮭ ﺮ ﺗﺤﻠﯿ ﻞ اﻷﻗ ﺮاص اﻟﻌﺪﯾ ﺪ ﻣ ﻦ اﻟﻤﻜﻮﻧ ﺎت ﺑﻤ ﺎ ﻓ ﻲ ذﻟ ﻚ -١ﺑﺮوﻣ ﻮ -٢،٤-
دﯾﻤﯿﺜﻮﻛ ﺴﯿﺎﻧﺜﺮﻛﻮﯾﻨﻮن ،و ﺗ ﺮاي ﻛﻠ ﻮرو اﺳ ﯿﺘﺎﯾﻞ ﺗﺮﯾﺒﺘ ﺎﻣﯿﻦ ﻣ ﻊ ﻋ ﺪم وﺟ ﻮد اﻟ ﺴﯿﻠﺪﯾﻨﺎﻓﯿﻞ .أوﺿ ﺤﺖ اﻟﺪراﺳ ﺔ أن
اﻟﻤﺴﺘﺤﻀﺮ ﺗﺴﺒﺐ ﻓﻲ ﺗﻐﯿﺮات ﻧﺴﯿﺠﯿﺔ ﻓﻲ ﻛﺒﺪ اﻟﻔﺌﺮان ﻣﻘﺎرﻧﺔ ﺑﺎﻟﻤﺠﻤﻮﻋﺔ اﻟﻀﺎﺑﻄﺔ .ﺗﻨﺎﺳﺒﺖ ﺗﻠ ﻚ اﻟﺘﻐﯿ ﺮات ﻃﺮدﯾ ﺎ
ﻣ ﻊ اﻟﺠﺮﻋ ﺔ .ﺷ ﻤﻠﺖ اﻟﺘﻐﯿ ﺮات إﻟﺘﮭ ﺎب ﻓﺼﯿ ﺼﻲ وﻓ ﺮط ﺗﻨ ﺴﺞ ﻟﺨﻼﯾ ﺎ ﻛ ﻮﺑﻔﺮ وﺗﻐﯿ ﺮات ﺑﺄﻧﻮﯾ ﺔ اﻟﺨﻼﯾ ﺎ )اﻟﻨ ﻮاة
اﻟﺤﻮﯾﺼﻠﯿﺔ ،ﻇﮭﻮر ﺧﻼﯾﺎ ﺛﻨﺎﺋﯿﺔ اﻟﻨﻮاة وﺧﻼﯾﺎ ﺑ ﺪون ﻧ ﻮاة( ،واﻟﺘ ﻨﻜﺲ اﻟﻤ ﺎﺋﻲ وﻣ ﺴﺎﺣﺎت ﻛﺒﯿ ﺮة ﻣ ﻦ اﻟﻨﺨ ﺮ .وﻟ ﻮﺣﻆ
أﯾﻀﺎ اﺣﺘﻘﺎن اﻷوﻋﯿﺔ اﻟﺪﻣﻮﯾﺔ واﻟﺘﻠﯿﻒ .اﻟﺨﻼﺻﺔ :ﺗﺆﻛﺪ اﻟﺪراﺳﺔ ﻋﻠﻰ ﻇﺎھﺮة ﺗﺠﺎرة اﻟﻤﺴﺘﺤ ﻀﺮات اﻟﻤﺰﯾﻔ ﺔ ﻟﻌ ﻼج
ﺿﻌﻒ اﻻﻧﺘﺼﺎب ﺣﯿﺚ أن ﺗﺤﻠﯿﻞ أﻗﺮاص أﺣﺪ اﻟﻤﻨﺘﺠﺎت أوﺿﺢ ﻋ ﺪم وﺟ ﻮد ﺳ ﯿﻠﺪﯾﻨﺎﻓﯿﻞ ﺑ ﺎﻟﺮﻏﻢ ﻣ ﻦ ادﻋ ﺎء اﺣﺘ ﻮاء
اﻟﻤﻨ ﺘﺞ ﻋﻠ ﻰ ١٣٠ﻣﺠ ﻢ ﻣ ﻦ اﻟ ﺴﻠﯿﺪﯾﻨﺎﻓﯿﻞ ﺑﻜ ﻞ ﻗ ﺮص .ﻛﻤ ﺎ ﺗ ﺸﯿﺮ إﻟ ﻰ اﻟ ﺴﻤﯿﺔ اﻟﻜﺒﺪﯾ ﺔ اﻟﻤﺤﺘﻤﻠ ﺔ ﻟﻤ ﺸﺘﻘﺎت
اﻷﻧﺜﺮﻛﻮﯾﻨﻮن.
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