الفهرس 
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Abstract
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SUMMARY AND CONCLUSION
This research work is concerned with the study of the
toxicological effects of acetaninophen ( a popular nonprescription
analgesic and antipyretic drug), ethanol, caffeine
and the interaction of acetaminophen with ethanol and
caffeine, The experiments were carried out on albino rats.
The toxicity meant to be in: acute, subacute, and short
term chronic toxicity,
The parameters chosen to be studied are:-
1) Behavioral and clinical observations.
2) Postmorte~ picture.
3) The effects on body weight.
4) The bioche~ical changes in SGOT, SGPT, serum alkaline
phosphatase, blood urea, and serum creatinine.
5) Histopathological changes of: liver, kidney, and heart.
(I) ACUTE TOXICITY STUDY:
The study was conducted on 5 groups of normal adult
albino rats of both sexes and body weight range of 120-150
grams, each group comprised 20 ?ats. A group of 20 rats was
used as control, only given the vehicle and kept under the
same environmental and dietary conditions. The first three
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groups received the isolated drugs orally, while the fourth
and fivth groups received acetaminophen in conbination with
ethanol and caffeine respectively, to study the possible
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toxic interaction between acetaminophen and each of them.
The acute toxic dose (LD50 ) of each isolated drug was
given orally, taken from the pertinent literature, as lg/kg
body weight in acetaminophen, 30 g/kg body weight in ethanol
and lg/kg body v1eight in caffeine. For acute toxic interaction,
a dose level which equals half of the r.1edian lethal
dose of both acet&~inophen and the chosen drugs was administred.
The biocher.1ical and histopathological changes were
recorded after 24 hours of administration. The results were
recorded and statistically analysed under the following
headings:
l) Acetaminophen effect:
No behavioral changes could be observed. Congestion of
the internal organs was evident and the liver was grossly
enlarged. Acetaminophen induced a very highly significant
increase (p<0.0005) in serum enzyme activities, blood urea
and sermn creatinine levels in both sexes after 24 hours of
administration. Significant hepatic and renal histopathological
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changes were noticed and correlated well with the biochemical
changes. The heart was not affected. Severe centrilobular
necrosis as well as marked congestion of the central vein
were the most common hepatic lesions, while tubular and
papillary necrosis were .the most common renal lesions. The
hepatotoxicity and nephrotoxicity of acetaminophen have been
attributed to its conver~ion, by a cytochrome P-450 system,
to a rective intermediate which covalently bind to cellular
protein macromolecules to cause cellular death, after suffecient
depletion of intracellular glutathione.
2) Ethanol Effect:
The biochemical analysis showed that ethanol induced
a very highly significant increase (p (0.0005) in SGOT, SGPT
and serum alkaline phosphatase activities as well as blood
urea and serum creatinine levels after 24 hours of administration.
Certain histopathological changes were noticed in
the liver and kidney, which were statistically significant
and confirmed the biochemical changes. It has been reported
that many of the toxic effects of ethanol are seemed to be
a consequence of the biochemical pathway by which it is
degraded, since acetaldehyde is a highly toxic compound.
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3) Caffeine Effect:
All the animals exhibited behavioral excitation, and
most of them developed convulsions and finally died. The
biochemical studies showed that caffeine induced a very
highly significant rise (p(0.0005) in serum aminotransferase
and serum alkaline phosphatase activities, blood
urea and serum creatinine levels after 24 hours of administration.
The hepatic and renal histopathological changes
were statistically significant, while the cardiac lesions
were insignificant.
4) Acetaminophen and Ethanol Toxic Interaction:
Concomitant administration of acute toxic dose of
ethanol with acetaminophen significantly decreased acetami-
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nophen-induced hepatotoxicity and nephrotoxicity, as judged
by decreased serum enzyme activities, and decreased blood
urea and serum creatinine levels as well as decreased incidence
of hepatic centri;obular, renal papillary and tubular
necrosis as compared to those induced by acetaminophen alone.
The hepatic centrilobular and renal papillary necrosis induced
by acetaminophen alone were totally prevented when the
acute single dose of ethanol was given simultaneously with
acetaminophen. It has been thought that the acute toxic dose of
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ethanol protects against aceta~inophen toxicity by inhibiting
cytochrome P-450 system, thus reducung the rate at which
acetaminophen is converted to its reactive intermediate.
5) Acetaninophen and Caffeine Toxic Interaction:
The biochemical and histopathological changes
observed in the rmimals receiving acetaminophen and caffeine
simultaneously and those in the corresponding acetaminophentreated
rats were not significantly different from each
other. Th• biochemical studies showed that the rise in
SGOT, SGPT,and serum alkaline phosphatase activities as
well as the rise in blood urea and serum creatinine levels
were insignificant (p) 0.05) as compared to those in the
corresponding acetaminophen-treated rats which were very
highly significant as compared to control group. Low incidence
of hepatic centrilobular necrosis was seen when caffeine was
given concomitantely with acetaminophen. Also, acetaminophen
reduced the incidence of seizures produced by caffeine.
(II) SUB!,CUTE /JJD SHORT TERJ;I CHRONIC TOXICITY STUDY:
The subacute and short term chronic toxicity were studied
in 220 adult albino rats of both sexes and body weight
range of 120-150 grams. Each group comprised 40 rats, while
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the remainder 20 rats used ns control and only given the
vehicle. The drugs were given orally at a dose of 1/10 of
the LD
50
daily for 30 days. The results were recorded after
15 days c1s subacute toxicity, then after 30 days as short
term chronic toxicity. The animals of the test and control
groups were weight separately before commencing the experimentation,
then recorded every 10 days. A general behavioral
exa.”lination was cnrried out daily to detect any change.
Blood was drovm fro::1 the retro-orbi tal plexus of veins
before stnrting the experimentation and after 15 days from
half of the rats, rmd ”.nother sanple was drown after 30
days from the remaining aninals in each group. At the end
of 15 and 30 days, the e.nimals were sacrificed and the
parenchymatous organs (liver, kidney, heart) were submi:lited
to histopa.tholor;ical exarnination.
The results were recorded and statistically analysed
under the following headings:
1) Acetaninoohen Effect:
The animals were found to behave and gain weight as
those of the control group. Acetaminophen induced a very
highly sit;nificant increase (p (0.0005) in hepatic enzymes
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activities e.s well llS blood urea and serum creatinine levels
throughout_ the period of subacute and short term chronic
toxicity study. Significant histopathological changes in
the liver and kidney were observed after 15 days. These
lesions increased in their incidence with the chronicity.
The lesions were characterized by the presence of hepatic
centrilobular necrosis, congestion of the central vein, as
well as renal papillary and tubular necrosis which affects
proximr..l nore than distal convoluted tubules. Regarding
heart alterations, no significant histopathological changes
were observed.
2) Ethanol Effect:
The rats were first Rctive, but latter became inactive,
overcrowded and calr.1; their weight was nearly the sane as
that of the corresponding control-non treated rats.
The biocheoical anr;,.lysis revealed that ethanol induced
a very highly signific,,_nt increo.se ( p ( o. 0005) in hepn.tic
enzymes activities throughout the whole period of the study.
The hepatic histopathological changes were significant. the
predor.1inc.nt lesions were the degenere.tive changes, in the
forn of hydropic der:;eneration, fatty change and necrosis, as
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well as conc;estion of the central vein. The incidence P..nd
severity of these lesions were more in shDrt tern chronic
than in subacute toxicity. Also the rise in blood urea and
serun creatinine levels were very highly sienificant after
15 and 30 days. The histopathological studies of the kidney
revealed a high percentage of congestion and cloudy swelling,
the latter decreP.sed with the chronicity. The histopathological
changes in the heart, in both periods of ex:perinentation,
were insignificant and only congestion and degeneration
of sor.1e of cardiac :mscle fibers were observed.
3) Caffeine Effect:
In both periods of experimentation, caffeine was found
to retard the rate of normal erowth of the animals. The rats
were active, irritable, aggressive and bitting each other;
muricide behc.viour (Cannibalism) was observed near the end
of the study. These behavioral changes could be attributed
to central nervous system stimulation.
The biochemical analysis revealed that caffeine induced
e. very highly sicnifice.nt increase in SGOT, SGPT and serum
alkaline phosphatase P.cti vi ties as well as blood urea and
serun cree.tinine levels throughout the whole period of the
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study. The hepatic and renal lesions induced by caffeine
were progressively increased on doubling the period of
administration, but were less in severity and incidence
than those induced by acetaminophen or ethanol. Renal tubular
necrosis was observed only after 30 days. Regarding heart
alterations, certain histopathological changes were observed
in both periods of the study, but were insignificant.
4) Acetaminophen and Ethanol Toxic Interaction:
The bioche11ical analysis ahowed that chronic administration
of acetaminophen with ethanol induced a very highly
significant increase (p,( 0.0005) in hepatic enzymes activities
as well as blood urea and serum creatinine levels in
both periods of the study.
The hepatic lesions induced by chronic administration
of ethanol with ncetn.Jninophen were high in incidence and
marked in_severity than those induced by isolated acetaminophen
throughout the whole period of the study. Centrilobular
necrosis, the characteristic acetaminophen-induced
hepatic dsm~ge, was observed in all rats when ethanol was
given concomitantly with acetaminophen after 30 days. This
means that chronic administration of ethanol significantly
increased acetaminophen-induced hepatotoxicity.
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Regarding renal histopathological changes, chronic
administration of ethanol significantly increased the incidence
and the severity of the lesio•s induced by acetaminophen
alone throughout the whole period of the study. After 30
days, certain cardiac histopathological changes were observed
which were found to be statistically significant.
5) Acetaminophen and Caffeine Toxic Interaction:
The behavioral effects and the changes in body
weight induced by caffeine alone were not markedly affected
whe• acetaminophen was given concomitantly with caffeine in
both periods of the study. However, the rats were less active
lees irritable and less aggressive as compared to those receiving
caffeine alone suggesting soae sort of beneficial antagonistic
interaction between acetaminophen and caffeine as
regard caffeine-induced central nervous systea toxicity.
The biochemical and histopathological cha~es revealed
insignificant differences between the rats receivi•g acetaminophen
and caffeine simultaneously and those treated with
acetaminophen alone throughout the whole period of the study.
However, the reduced incidence and severity of the hepatic
centrilobular and the renal papillary necrosis observed in
the rats treated with the two drugs suggested that chronic
caffeine consumption may decrease the toxicity induced by
acetaainophe•.
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Recommendations:
In view of the results o! the present study and the
previous reported findings, few recommendations can be
recorded:
1) Physicians must be aware of the risks to which their
patients are exposed when treated with multiple drugs,
since drug interactions commonly complicate treataent.
2) It is necessary that both physiciaas and the general
puplic should be readily !aailiar with the potentially
toxic and lethal consequence o! acetaainophen overdosage,
as acetaminophen is a popular noa-prescription and coamon
household antipyretic-analgesic which became a popular
mean of attempting suicide.
J) Alcoholics should be cautioned about the use o! acetaminophen
while they persist in heavy consumption of alcohol,
since chronic alcohol consumption increases the toxicity
of acetaainophen.
4) Physicians should be aware o! the ca!!eine intake of
patients, due to the possible contribution o! caffeine to
the presentiag signs and syaptoas, as well as its possible
interaction with many contaaplated therapeutic regimen.Also,
further studies in rats aad in men are needed to resolve the
question of possible interaction between acetaainophen and
caffeiae, since the clinical use o! the twe drugs aay further
increase.