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Abstract - 275 - 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 - 276 - 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 - 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 - 277 - 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. ------- -~- - 278 - 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- . 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 - 279 - 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 - 280 - 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 - 281 - 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 --- ----------- - 282 - 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 - 283 - 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. - 284 - 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•. -~--~- -~-- -- - 285 - 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. |