الفهرس 
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Abstract
One aspect that has caused much controversy involves the com-bined use of monoamine oxidase inhibitors ( MAOIs) with tricyclics. This combined MAOI-tricyclic treatment has gained a reputation for unusual toxicity and unusual efficacy. Some have claimed it effective when all else failed, whereas others have warned of fatal reactions even to modest doses.
So, this research work was designed to asses whether combined MAGI-TCA treatment ( tranylcypromine - amitriptyline ) and (tranyl cypromine - imipramine ) has any pronounced advantages or disadvan-tages compared with MAOI ( tranylcypromine ) used alone on adult albinorats. Also we compare the safety of amitriptyline versus imi-pramine when combined with tranylcypromine.
Experimental procedures employed in the present work had been classified into the following two categories: Acute toxicity studies and short term chronic toxicity studies.
(I) Acute toxicity studies :
One hundred and forty adult normal albino rats of both sexes with a weight of 120 - 150 gm were classified into four groups for evaluation of the toxic effects which might occur from the acute overdoses of tranylcypromine ( TCP ), amitriptyline ( AMT ) and imipramine ( IMP ). The first three groups received the isolated
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drugs orally, while the fourth group used as control one, kept under the same environmental and dietary conditions. Median lethal dose ”LD50” as well as lethal dose 16 ”LD16” and the lethal dose 84
”LD84” for each drug were calculated, where oral LD50 of TCP was 32.5 mg/kg, LD50 of AMT was 415 mg/kg and that of IMP was 600 mg/kg.
Behavioral and clinical observations were observed in each group, while postmortem examination of the dead rats were carried out after death, with special emphasis on the naked eye appearance of the internal organs and viscera. Microscopical study had been carried out on the following organs: liver, heart, kidney, lung and brain. But a special attention has been drawn to the histopatho-logical findings in the mentioned organs of the dead rats, receiving varying doses exceeding the LD50 of each drug with the purpose of detection of the most probable cause of death and the most affected organs by each drug.
Intoxicated rats with lethal doses of AMT and IMP showed nearly similar behavioral changes. They showed gradual loss of spon-taneous motility and responses to external stimuli with evidence of C.N.S. depression. They also showed initial acceleration of spontaneous respiration but it eventually slowed down and then became gasping in character, and ended with death.
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On the other hand, lethally intoxicated rats with TCP showed minor behavioral changes in the form of hyperactivity to noise and muscle twitches, finally the rats showed progressive weakness, inability to
walk, slowing of respiratory and heart beats and death.
Histopathological examination revealed the following results : Severe hepatic lesions were observed due to toxic doses of TCP where most of the hepatocytes were enlarged and showed severe hydropic degeneration, necrosis and disturbed architecture. Also the lungs showed depressed alveoli with severe oedema and haemorrhage, others areas showed emphysema. While the brain showed vacuolation of most of the neurons with diffuse neuronal degeneration. On the other hand, the cardiac and renal lesions were mild. Post-mortem examination of the toxicated rats with AMT revealed severe degeneration of the cardiac muscle fibers, with congestion. Also the lungs showed oedema, congestion and patchy haemorrhagic spots. The kidneys revealed hyd-ropic degeneration with cortical infarction in half of the AMT toxic-ated rats. Severe shrinkage of the nerve cells with reduction in the number of the neurons and congestion were observed due to acute intoxication with AMT, while the liver lesions were mild.
Rats received lethal doses of impramine showed nearly similar patho-logical lesions as those of amitriptyline where the heart showed severe degenerated muscle fibers with severe congestion and haemo-rrhage. Also there were severe oedema with interstitial infiltration
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shrinkage of the nerve cells with reduction in the number of the neurons and blood vessels, were severely congested. The kidnyes showed cortical infarction, hydropic degeneration and interstitial haemorrhage in half of the toxicated rats while mild hepatic lesions were detected in the form of mild cloudy swelling with congestion.
(II) Short term chronic toxicity studies :
Two hundred adult normal albino rats of both sexes varying from 120 - 150 gm in weight were divided into four groups, each comprising 50 rats. Daily oral doses equivalent to 10% LD50 of trany-lcypromine ( TCP ) were given to the 1st group. The 2nd group recieved daily oral doses equivalent to 10% LD50 of tranylcypromine combined with 10% LD50 of amitriptyline ( TCP + AM T ), while the 3rd group received daily oral doses equivalent to 10% LD50 tranylcypr-omine with 10% LD50 of imipramine ( TCP + IMP ). Lastly the fourth group served as parallel non-medicated control received distilled water. In this work, the drug administration was limited to a period of one month, it is short term chronic study which is equivalent to 24 monthes i.e. two years in human being.
All groups were carefully observed for any toxic manifesta-tions, body weight changes, as well as any mortalities that might
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occur as a result of drug administration. Venous blood samples were obtained by means of capillary glass tubing from retro-orbital plexus under light either anaesthesia, for quantitative determination of serum GOT, GPT, Aik. Ph., bilirubin, creatinine and blood urea levels for assesment of liver and kidney functions. Histopathological examination of liver, heart, kidney and brain were done at the end of every week.
In the TCP group, increased activity of the rats was noticed only at the beginning of the last two days of the third week and during the fourth week of treatment, while animals treated with TCP + IMP and TCP + AMT showed hyperactivity from the start in the form of tremors, hypersalivation and biting.
In the current study, all the rats in the three treated groups showed an increase in the body weight. Weight gain was greatest in TCP + AMT group ( + 22.2% at the end of the 1st week and reached + 52.1% at the end of the 4th week ), followed by TCP + IMP group ( + 20.1% at the end of the 1st week and reached 39.3% at the end of the 3rd week ), while TCP group showed a slight increase in the body weight ( + 12.8% at the end of the 1st week reached 37.3% at the end of the fourth week ) in comparison with the control
group.
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Hepato toxicity was the main prominent toxicity induced by TCP in the present study. Monitoring of serum levels of GOT, GPT and AIK. ph. yielded significant increase beyond the corresponding normal values graduated from the second week till the end of the fourth week, where there was a very highly significant increase ( P< 0.0005 ) in the three enzymes levels. Confirmatory evidence for our biochemical changes was provided by the non significant patho-logical changes detected at the end of the first week ( where the liver showed a very mild degenerative changes in the hepatic cells ) and then accentuation of hepatocellular damage by the lapse of time, which graduated from the 2nd week till the end of the fourth week where the incidence of the pathological lesions were markedly increases in the form of severe hydropic degeneration, lymphocytic infiltration and congestion.
Rats received TCP-AMT showed progressive elevation in the three serum enzymes ( GOT, GPT and AIK.ph. ) beyond the corresponding control non-treated rats but with insignificant difference from TCP- treated group throughout the period of the study.
At the same time there were no apparent differences in the histo-pathological findings in TCP-AM T treated group in comparison with the TCP treated group throughout the four weeks of treatment.
On the other hand, in TCP-IMP treated group, there was gradual very highly significant increase ( P < 0.0005 ) in the three serum
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enzymatic activity (GOT, OPT and Alk. Ph.) beyond the corresponding normal values and beyond the TCP and TCP-AMT treated groups in the three successive weeks. All the rats in TCP-IMP group died after the end of the 3rd week and before the end of the 4th week. Con-
firmatory evidence for the biochemical results was provided by the
very highly incidence of hepatotoxic lesions detected in the liver during the three weeks of TCP-IMP medication starting from moderate degree of cloudy swelling and hydropic degeneration at the end of the first week to severe degeneration and disturbed architecture of the end of the third week.
In the current study, the incidence of the cardiac toxicity in each group was indicated by the pathological changes in the heart and the elevation of serum level of GOT. Our results revealed that the cardiotoxicity was greatest in TCP-IMP group (where half of the animals showed cloudy swelling at the end of the 1st week while at the end of the 3rd week all the toxicated rats showed necrosis with leucocytic infiltration while vacuolar degeneration with interestitial haemorrhage were seen in 83.33%), followed by TCP-AMT group (where at the end of the study, the cardiac muscle fibers showed vacuolar degeneration in half of the animals, necrosis and interestitial haemo-rrhage in 66.67% and leucocytic infiltration in 83.33% of the toxicated rats ) and lastly the TCP group where the TCP-toxicated rats showed necrotic cardiac muscle fibers in half of the animals, interestitial haemorrhage and leucocytic infiltration in 66.67% and vacuolar dege-neration in 33.33% of the toxicated rats at the end of the 4th week.
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The brain lesions detected in TCP-treated group were time correlated graduated from mild necrosis, congestion and vacuolation
of the neurons at the end of the 1st week to severe vacuolar dege- neration, congestion and necrosis at the end of the 4th week. Similar
brain lesions were detected in both TCP-IMP and TCP-AMT-treated groups with non significant differences between them and the TCP-group.
The renal toxicity of this study showed that the TCP-induced a significant increase in blood urea and serum creatinine levels in rats and this increase was time correlated. Study of nephro toxicity due to MAOI-TCA combined thrapy revealed non significant difference between the incidence and severity of renal toxicity induced by the administration of TCP alone and in combination with AMT ( after four weeks, the TCP toxicited rats showed severe cloudy swelling in 66.67% and hydropic degeneration in half of the animals while the TCP-AMT toxicated rats showed necrotic tubules, periglomular oedema and hydropic degeneration in 66.67% ). On the other hand, the TCP-IMP treated rats showed a significant increase in the incidence and severity of renal toxicity from the corresponding TCP treated rats manifested by the very highly significant rise in serum creatinine and blood urea levels ( P < 0.0005 ) and the severity of the kidney
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lesions detected at the end of the 3rd week ( where most of the tubules showed hydropic degeneration in E13.33’ro of the animals ).
On the light of this study we can conclude that :
•The side effects of tranylcypromine-amitriptyline combination are
similar in nature, frequency and magnitude to those experienced with tranylcypromine alone.
•Tricyclic of choic3 for such combination was amitriptyline while
imipramine appeared more toxic than amitriptyline when used with tranylcypromine, thus imipramine if used in the combination might warrant extracaution.
•The relative safety of combined MAOI-TCA treatment when used according to specific guidelines.
•The MAOI-TCA combination would assume place among the ranks of suggested combination antidepressant treatment