الفهرس 
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Abstract
For decades, acetaminophen was considered exceptionally harmless and useful. However, during the last few years it was exposed to vehement criticism because physicians and patients have shown that this drug has potential dangers. This research work was concerned with estimating the toxicity of acetaminophen, aspirin, phenobarbital, and the interaction of acetaimnophen with aspirin and phenobarbital.
Experimental procedures employed in this study had been classified into two main categories, acute toxicity studies and chronic toxicity studies. And in both categories a normal adult albino rats of both sexes have been used as an experimental animals. The following parameters have been chossen to be studied :
1)Postmortem picture.
2)the biochemical changes in SCOT, SGPT serum ALK. ph. blood Urea, and serum Creatinine.
3)Histopathological changes in the liver, kidney, stomach, and the heart.
(I) ACUTE TOXICITY STUDIES :
Six groups of normal adult albino rats of both sexes with a body weight range of 120 - 150 grains, each group was consisted of 20 rats. A group of 20 rats was used as a control group, only given distilled water and kept under the same evironmental and dietary conditions.
The first three groups received the isolated drug only orally, the fourth and fifth groups received acetaminophen in combination with aspirin and phenobarbital respectively and group number six received an combination of three drugs. In case of the first three groups each drug was administered orally in a dose equal to the acute toxic dose (LD50), which were taken from a pertinent literature, as 1 gm / kg
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for acetaminophen, 1.2 gm / kg for aspirin, and 150 mg / kg phenobarbital. In combination groups, the dose administered was equal to half of the median lethal dose of each drug.
The biochemical and histopathological changes were observed and recorded after 24 hours from the oral administration as well as statistical analysis of the obtained results for each group.
1)Acetaminophen (ACT) group :
Two of six animals were died after 24 hours with dark congested internal organs especially liver, kidney and the heart. Acetaminophen induced a very highly significant (P < 0.0005) increase in hepatic enzymes (SCOT, SGPT, and serum alkaline phosphatase) and renal biochemical tests (Blood Urea and serum Creatinine) after 24 hours from oral administration. Histopathological findings in the liver and the kidney were significant and confirming the elevated biochemical values. Severe centrilobular necrosis, sinusoidal dilatation and central vein congestion were the characteristic hepatic lesions. Tubular necrosis was the characteristic renal lesion, both hepatic and renal affection were attributed to the formation of reactive intermediate of acetaminophen by the cytochrome P - 450, which covalently bind to cellular protein macromolecules causing cellular death. No significant lesions were observed neither in the heart nor in the stomach.
2)Aspirin (ASA) group :
No mortalities were observed after 24 hours from oral administration. Aspirin was found to induce a very highly significant (P < 0.0005) increase of hepatic and renal biochemical values (SCOT, SGPT, ALK. ph. Blood Urea, and serum Creatinine). Focal hepatic necrosis and lymphocytic infiltration are the most common hepatic lesions, which is thought to be due to intrinsic hepatocellular damage induced by aspirin. Renal tubular necrosis and cloudy swelling were the
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characteristic pathological lesions in the kidney, the inhibition of renal prostaglandin by aspirin leading to fluid retention and diminished sodium excretin was stated to be the main cause of renal damage and even renal failure in extreme cases.
Gastric wall examination after 24 hours revealed that aspirin induced a severe congestion in the gastric mucosa, focal areas of ulceration and necrosis as well as haemorrhage. Meanwhile, examination of the heart showed no significant pathological findings.
3)Phenobarbital (PB) group :
After 24 hours from oral administration of phenobarbital acute toxic dose, three rats were died with generalized congestion of the internal organs. PB - induced a very highly significant (P < 0.0005) increase of SGOT, SON’, Alkaline phosphatase, Blood Urea, and serum Creatinine indicating marked hepato - renal affection, which was confirmed histopathologically by hepatic focal necrosis, hydropic degeneration, and congestion of the central vein as well as renal necrosis, cloudy swelling, and lymphocytic infiltration.
Regarding gastric and cardiac examination there were no significant histopathological lesions .
4)Acetaminophen and Aspirin (ACT +ASA) group :
Simultaneous administration of acetaminophen and aspirin induced a very highly significant (P < 0.0005) decrease of ACT - induced hepatotoxicity as judged by decreased serum enzyme activities as well as decreased incidence of hepatic centrilobular necrosis when compared to those induced by acetaminophen alone. This protective effect of aspirin was thought to be due to ASA prevention of a process subsequent to metabolic activation of ACT, On the other hand, elevated renal biochemical tests (blood urea and serum creatinine) and histopathological
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changes in the kidney showed a non - significant difference from those induced by acetaminophen alone.
Gastric affection was much lower than that induced by aspirin alone as proved by the mild mucosal congestion and the very limited areas of focal ulceration and necrosis, which thought to be due to acetaminophen inhibition of prostaglandin synthesis by aspirin.
5)Acetaminophen and phenobarbital (ACT + PB) group :
Concomitant oral administration of acetaminophen and phenobarbital resulted in a very highly significant increase of the hepatic and renal toxicity as compared to those induced by ACT alone. Which was demonstrated by the marked elevation of the biochemical values (SGOT, AGPT, ALK. ph ., Blood Urea, and serum Creatinine) and marked increase in the severity of the histopathological lesions in the liver (centrilobular necrosis) and kidney (tubular necrosis). This enhancement of ACT - induced hepato - renal toxicity by phenobarbital was stated to be due to induction of cytochrome P - 450 and shifting ACT to the toxic metabolite pathway.
6)Acetaminophen, Aspirin, and Phenobarbital (ACT + ASA + PB) group:
After 24 hours from concomitant administration of the three drughs, a very highly significant (P < 0.0005) decrease of hepatic affection measured by reduced values of SGOT, SGPT, and ALK. ph. as well as lowered incidence of hepatic centrilobular necrosis as compared to those results induced by acetaminophen alone due to the protective effect of aspirin. On the other hand, renal biochemical values and pathological changes showed a non - significant changes from the changes induced by ACT alone.
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Very mild affection of the gastric mucosa was recorded after oral administration of the three drugs combination as compared to the effects induced by aspirin alone.
(H) CHRONIC TOXICITY STUDIES
260 adult normal albino rats of both sexes with an average weight of 120 -150 grams were used for the chronic toxicity studies as each group composed of 20 rats and the remainder 20 rats were used as control group receiving only distilled water. The drugs were administered orally at a dose (LD50) daily for 30 days.
Every 10, 20 and 30 days, blood is withrawn from the back of the eye (retro - blubar plexus of veins) and applied for biochemical examination for estimating the values of SGOT, SGPT, ALK. ph., Blood Urea, and Creatinine. After every 10 days from the oral administration of the drugs, the animals were sacrified and the liver, kidney, heart, and stomach were examined histopathologically.
The results obtained every 10 days were recorded and analyzed statistically for each group.
1) Acetaminophen (ACT) group :
ACT - induced a very highly significant (P < 0.0005) increase of hepatic and renal biochemical values (SGOT, SGPT, ALK. ph., Blood Urea, and Creatinine) throughout the period of the chronic study. Significant histopathological lesions in both liver and kidney were observed after 10 days and became more severe after 20 and 30 days in the form of hepatic centrilobular necrosis, bile duct proliferation, and fatty changes as well as renal tubular necrosis and cast formation. Regarding gastric and cardiac examination, no significant histopathological lesions were observed all over the period of experimentation.
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2)Aspirin (ASA) group :
Oral daily administration of aspirin for 30 days induced a very highly significant (P < 0.0005) increase in hepatic and renal biochemical values (SGOT, SGPT, ALK. ph., Blood Urea, and Serum Creatinine) after 10 days and much increased after 20 and 30 days. Also, the hepatic lesions start to appear after 10 days in the form of hepatic focal necrosis, sinusoidal dilatation and central venous congestion, after 20 and 30 days the same lesions became sever with the appearance of bile duct proliferation and fatty changes. Renal lesions were more severe after 30 days than after 10 and 20 days in the form of tubular necrosis, shrunken glomeruli, and renal congestion. Gastric examination revealed marked mucosal congestion after 10 days, focal ulceration and necrosis together with haemorrhage and shedding of the gastric mucosa after 20 and 30 days.
3)Phenobarbital (PB) group :
After daily oral administration of PB for 30 days, a very highly significant (P < 0.0005) increase of hepatic enzymes and renal function tests, which were ascending in the severity throughout the period of experimentation. Biochemical values were confirmed by the histopathological findings in the liver as centrilobular necrosis, fatty changes, and bile duct proliferation which tend to be more severe by the end of the experiment. The renal lesions were also more severe after 20 and 30 days than after 10 days in the form of tubular necrosis and lymphocytic infiltration.
4)Acetaminophen and Aspirin (ACT + ASA) group :
Oral daily administration of acetaminophen and aspirin induced a very highly significant (P < 0.0005) decrease of the hepatotxicity as compared to that induced by ACT alone, manifested by lowered biochemical values (SGOT, SGPT, and alkaline phosphatase) and the diminished incidence of hepatic lesions lesions (Mild centrilobular necrosis and central vein congestion). These changes became more evident after 20 and 30 days than after 10 days of experimentation.
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The renal biochemical and histopathological results showed a non - significant changes in comparison to those induced by ACT alone after 10, 20, and 30 days.
Gastric histopathological examination revealed a marked reduction of the gastric affection in comparison to ASA - induced gastric lesions, measured by lowered gastric congestion and the few areas of focal simple ulceration, which even disappeared after 30 days of oral administration.
5)Acetaminophen and Phenobarbital (ACT + PB) group :
Simultaneous oral daily administration of acetaminophen and phenobarbital induced a very highly significant (P < 0.0005) increase of hepatic and renal biochemical values (SCOT, SGPT, ALK. ph., Blood Urea, and Serum Creatinine) as compared to those values induced by ACT alone. These results were confirmed histopthologically by the higher incidence of hepatic damage (sever centrilobular necrosis, bile duct proliferation, and lymphocytic infiltration) as well as renal changes (sever tubular necrosis, glomerular loss, and cast formation) . All these changes were more prevalent after 20 and 30 days of the experiment.
No significant pathological changes were detected in the heart or the stomach in comparison to those changes induced by ACT alone.
6)Acetaminophen, Aspirin, and Phenobarbital (ACT + ASA + PB) group :
Concomitant daily administration of the three drugs resulted in a very highly significant (P < 0.0005) decrease of the hepatotoxicity induced by ACT alone measured by reduced values of SCOT. SGPT, and serum alkaline phosphatase and lowered incidence of histopathological changes in the liver (mild central necrosis after 10 days and disappeared after 20 and 30 days). Renal changes (biochemical
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and histopathological) showed a non significant difference from those results induced by acetaminophen alone.
Histopathological findings in the stomach revealed the absence of any gastric damage, idicating the protective effect of acetaminophen against aspirin - induced gastric damage. This protective effect was attributed to ACT blocking of the inhibitory effect of ASA over gastric prostaglandin biosynthesis.
- 214 - RECOMMENDATION
On the light of the results of the present study we recommend the following guidelines : -
1)It is so essential for every physician to get a considerable knowledge about the harmful side effects prescribing paracetamole in high doses or for long periods to avoid its hepatotoxic effect.
2)At present we would urge physicians to exercise extreme caution in prescribing a plenty of drugs in the same prescription for the sake of possible dangerous drug interactions as in case of describing paracetamole for an epileptic patient receiving phenobarbital regularly as it would markedly enhance the hepatotoxic effect of paracetamole.
3)Combination of paracetamole and aspirin may have potential use in the development of saver analgesic combination as aspirin do protect against paracetamole hepatotoxicity. While, paracetamole can protect against aspirin -induced gastric damage.
4)Availability of aspirin and paracetamole should be controlled as any other drug to avoid the high risk of using them without medical supervision.
5)We recommend more experimental researches about the effects of aspirin -paracetamole combination on the kidneys, as our results proved to be contradictory to many other researches.