الفهرس 
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Abstract
The role of antidepressants in fatal poisoning has become increasingly important. It was apparent that antidepressant drugs exhibit a delay of several weeks before their therapeutic benefit is established. So, they constitute a great hazared because of their liability to toxic accumulation on prolonged intake. Furthermore, depressed patients have tendencies to suicidal acts or ideation and although these drugs designed to assist them in overcoming their condition, they well often use the antidepressants to attempt suicide. Besides, these drugs might occasionally cause fatalities due to acute overdose, either accidental or inten-tional for homicidal purposes.
This study was done to evaluate and compare the toxic potentialities of fluoxetine hydrochloride, amitriptyline hydrochloride and imipramine hydro-chloride drugs in adult albino rats by studying their effects on the chromosomal pattern, incidence of micronuclei in polychromatic erythrocytes, as well as their effects on the liver and kidney functions. In addition, their effects on the liver, kidney, heart and lung histopathology. Whether, the effects were reversible or not, also one of the objectives of the study.
This study was conducted on 160 normal adult albino rats of both sexes, weighting approximately 120-150 grams each. They were classified into four groups. The first, second and third groups were received daily oral doses equivalent to 1/10th LD50, amounted to the following values and expressed in mg/kg body weight:
452 mg/kg b.w. for fluoxetine HCL.
380 mg/kg b.w. for amitriptyline HCL.
490 mg/kg b.w. for imipramine HCL.
The 4th group served as parallel non-medicated control. This study was done throughout three periods {two and four weeks then 4 weeks after stopping
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Summary and Conclusion
the last dose of each drug}. 1. Chromosomal stud :-
v After 2 weeks of daily oral administration of single dose of 1/10th LD50 of each drug.
Fluoxetine treated group revealed, very highly significant increase (P < 0.0025) of chromatid gap, deletion and total structural anomalies, significant increase (P < 0.025) of chromatid break and fragments and non-significant in-
crease (P > 0.05) of chromatid separation, ring chromosome and polyploidy as compared with the control.
Amitriptyline treated group revealed, very highly significant increase (P < 0.0025) of chromatid gap, break, separation, fragments, deletion and total structural anomalies, as well as polyploidy. While, ring chromosome showed significant increase (P < 0.025) as compared with the control.
Imipramine treated group revealed, very highly significant increase (P <
0.0025) of both total structural and numerical anomalies as compared with the control.
Comparison between fluoxetine and amitriptyline treated groups reveled, very highly significant increase (P < 0.0025) of total structural anomalies, sig-nificant increase (P < 0.025) of chromatid gap and break and non-significant increase (P > 0.05) of chromatid separation, fragments, deletion and ring chro-
mosome in amitriptyline treated group as compared with fluoxetine treated group.
Comparison between fluoxetine and imipramine treated groups reveled, very highly significant increase (P < 0.0025) of chromatid gap and break, sepa-ration, fragments, deletion, total structural and numerical anomalies. While, ring chromosome showed significant increase (P < 0.025) in imipramine treated group as compared with fluoxetine treated group.
Comparison between amitriptyline and imipramine treated groups rev-eled, very highly significant increase (P < 0.0025) of total structural anomalies,
4261).
Summary and Conclusion
significant increase (P < 0.05) of chromatid deletion and polyploidy. While, chromatid gap, break, separation, fragments and ring chromosome showed non-significant increase (P > 0.05) in imipramine treated group as compared with amitriptyline treated group.
+ After 4 weeks of daily oral administration of single dose of 1110th LD50 of
each drug.
Fluoxetine treated group revealed, very highly significant increase (P <
0.0025) of chromatid gap, break, deletion and total structural anomalies. While, chromatid separation, fragments, ring chromosome and polyploidy showed significant increase (P < 0.05) as compared with the control.
Amitriptyline treated group revealed, very highly significant increase (P < 0.0025) of both total structural and numerical anomalies as compared with the
control.
Imipramine treated group revealed, very highly significant increase (P <
0.0025) of both total structural and numerical anomalies as compared with the
control.
Comparison between fluoxetine and amitriptyline treated groups reveled,
very highly significant increase (P < 0.0025) of total structural anomalies, highly significant increase (P < 0.005) of chromatid deletion. While, chromatid gaps, break fragments and polyploidy showed significant increase (P < 0.05) and chromatid separation and ring chromosome showed non-significant increase (P > 0.05) in amitriptyline treated group as compared with fluoxetine treated
group.
Comparison between fluoxetine and imipramine treated groups reveled,
very highly significant increase (P < 0.0025) of both total structural and nu-merical anomalies, except ring chromosome which, showed significant increase (P < 0.025) in imipramine treated group as compared with fluoxetine treated group.
Comparison between amitriptyline and imipramine treated groups rev-
4262)
Summary and Conclusion
eled, very highly significant increase (P < 0.0025) of total structural anomalies and polyploidy, highly significant increase (P < 0.005) of chromatid gap and break, significant increase of chromatid deletion and non-significant increase (P > 0.05) of chromatid separation, fragments and ring chromosome in imipramine treated group as compared with amitriptyline treated group.
+ Four weeks after stopping the last dose of each of test drugs.
Fluoxetine, amitriptyline and imipramine treated groups revealed non-significant increase (P > 0.05) in both total and structural chromosomal anoma-lies as compared with the control group.
The mechanisms of producing mutagenic effect of fluoxetine were attrib-uted to modification of preexisting protein, as well as its cytotoxic effect.
The mechanisms of producing mutagenic effect of amitriptyline were at-ributed its cytotoxic, clastogenic and mitotoxic effect as well as its ability to induce alternation in gene protein expression.
The mechanisms of producing mutagenic effect of imipramine were at-tributed to its ability to decrease DNA and RNA synthesis as well as direct
damage effect to DNA that interferes with normal functioning of the chromo-some and causing genotoxicity.
2. Micronucleus test-
+ After 2 and 4 weeks of daily oral administration of single dose of I/10th LD50 of each drug.
Fluoxetine treated group revealed significant increase in the incidence of MNPCEs (P < 0.025) at the end of 2 weeks and highly significant increase (P < 0.005) at the end of 4th week as compared with the control.
Amitriptyline treated group revealed very highly significant increase in
the incidence of MNPCEs (P < 0.0025) at the end of 2nd and 4th weeks as com-pared with the control.
Imipramine treated group revealed very highly significant increase in the
4263)
SUMMARY AND CUNCLUNIQN
incidence of MNPCEs (P < 0.0025) at the end of rd and 4th weeks as compared with the control.
Comparison between fluoxetine and amitriptyline treated groups revealed highly significant increase of MNPCEs (P < 0.01) at the end of 2nci week and very highly significant increase (P < 0.0025) at the end of 4th week in amitripty-line treated group as compared with fluoxetine treated group.
Comparison between fluoxetine and imipramine treated groups revealed very highly significant increase of MNPCEs (P < 0.0025) at the end of rd and 4th weeks in imipramine treated group as compared with fluoxetine treated group.
Comparison between amitriptyline and imipramine treated groups re-vealed very highly significant increase of MNPCEs (P < 0.0025) at the end of 2nd and 4th weeks in imipramine treated group as compared with amitriptyline treated group.
Four weeks after stopping the last dose of each of test drugs.
Fluoxetine, amitriptyline and imipramine treated groups revealed non-significant increase (P > 0.05) in MNPCEs as compared with the control group.
The mechanism of producing micronuclei in polychromatic erythrocytes for fluoxetine was attributed to its cytotoxic effect which affecting both mitotic and meiotic chromosome segregation.
The mechanism of producing micronuclei in polychromatic erythrocytes for amitriptyline was attributed to its clastogenic and/or spindle poison effect.
The mechanism of producing micronuclei in polychromatic erythrocytes for imipramine was attributed to the presence of N-atom at position 5 in the central ring of the drug molecule, which has a clastogenic effect.
3. Biochemical and histooathological changes:-
A) Liver functional changes: -
. After 2 and 4 weeks of daily oral administration of single dose of 1/10th
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Summary and Conclusion
LD50 of each drug.
Fluoxetine treated group revealed significant increase in GPT, GOT, ALP and BIL (P < 0.025) at the end of rd week and highly significant increase (P < 0.0025) at the end of 4th week as compared with control group.
Amitriptyline treated group revealed very highly significant increase in
GPT, GOT, ALP and BIL (P < 0.0005) at the end of 2” and 4th weeks as com-pared with control group.
Imipramine treated group revealed very highly significant increase in
GPT, GOT, ALP and BIL (P < 0.0005) at the end of 2” and 4th weeks as com-pared with control group.
Comparison between fluoxetine and amitriptyline revealed very highly significant increase of GPT, GOT, ALP and BIL (P < 0.0005) at the end of 2”
and 4th weeks, in amitriptyline treated group as compared with fluoxetine treated group.
Comparison between fluoxetine and imipramine revealed very highly significant increase of GPT, GOT, ALP and BIL (P < 0.0005) at the end of 211”
and 4th weeks, in imipramine treated group as compared with fluoxetine treated group.
Comparison between amitriptyline and amitriptyline revealed non-significant increase of GPT, GOT, ALP and BIL (P > 0.05) at the end of rd and
4th weeks, K in imipramine treated group as compared with amitriptyline treated group.
+ Four weeks after stopping the last dose of each of test drugs.
Fluoxetine, amitriptyline and imipramine treated groups revealed non-
significant increase (P > 0.05) in GPT, GOT, ALP and BIL as compared with the control group.
B) Liver histopathological changes:-
9 After 2 and 4 weeks of daily oral administration of single dose of 1110th
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Summary and Conclusion
LD50 of each drug.
Fluoxetine treated group revealed mild central venous congestion and dilatation of blood sinusoids with mild lymphocytic infiltrations, at the end of 2s week which, became pronounced at the end of 4th week.
The mechanisms of producing hepatic toxicity were attributed to its direct inhibitory effect on liver enzymes and mitochonderial toxic effect.
Amitriptyline and imipramine treated groups revealed moderate central venous congestion, dilatation of blood sinusoids with moderate lymphocytic infiltrations, mild fatty and severe hydropic degeneration with necrotic areas at the end of 2nd week which, become pronounced at the end of 4th week.
The mechanisms of producing hepatic toxicity were attributed to immu-nologic and/or idiosynecretic hypersensitivity effects. The presence of chlorine in imipramine molecule increases its hepatotoxic potentiallity.
v Liver histopathological changes for all treated groups {fluoxetine, ami-
triptyline and imipramine} which occurred at the end of 2’d and 4th weeks
were readily reversible as all affected parameters returned to normal in most
rats killed 4 weeks post dose drug-free recovery period.
C) Kidney functional changes:-
4. After 2 and 4 weeks of daily oral administration of single dose of 1/10th
LD50 of each drug.
Fluoxetine treated group revealed significant increase in BUN and CRI (P < 0.05) at the end of 2nd week and highly significant increase (P < 0.005) at the end of 4th week as compared with control group.
Amitriptyline treated group revealed very highly significant increase in BUN and CRI (P < 0.0005) at the end of rd and 4th weeks as compared with
control group.
Imipramine treated group revealed very highly significant increase in BUN and CRI (P < 0.0005) at the end of tad and 4th weeks as compared with
4266)
SUMMARY AND CONCLUSION
control group.
Comparison between fluoxetine and amitriptyline revealed very highly significant increase of BUN and CRI (P < 0.0005) at the end of rd and 4th weeks, in amitriptyline treated group as compared with fluoxetine treated group.
Comparison between fluoxetine and imipramine revealed very highly significant increase of BUN and CRI (P < 0.0005) at the end of 2nd and 4th weeks, in imipramine treated group as compared with fluoxetine treated group.
Comparison between amitriptyline and imipramine revealed non-significant increase of BUN (P > 0.10) and CRI (P > 0.20) at the end of rd while at the end of 4th week BUN (P > 0.20) and CRI (P > 0.25), in imipramine treated group as compared with amitriptyline treated group.
• Four weeks after stopping the last dose of each of test drugs.
Fluoxetine, amitriptyline and imipramine treated groups revealed non-
significant increase (P > 0.05) in BUN and CRI as compared with the control group.
D) Kidney histopathological changes:-
v After 2 and 4 weeks of daily oral administration of single dose of We LD50 of each drug.
Fluoxetine treated group revealed mild congestion, loss of glomeruli, cloudy swelling and mild cellular infiltration, at the end of rd week which, became pronounced at the end of 4th week.
The mechanisms of producing nephrotoxicity were attributed to inappro-priate secretion of antidiuretic hormone or direct toxic effect of on the kidney.
Amitriptyline and imipramine treated groups revealed severe congestion and hypercelullarity of the glomeruli with lobulation, severe cloudy swelling
and tubular degeneration. These findings become pronounced at the end of 4th week.
The mechanisms of producing nephrotoxicity were attributed to their an-
4267)1
Summary and Conclusion
ticholinergic effects which lead to delayed micturation and urine retention as well as inappropriate secretion of antidiuretic hormone.
vKidney histopathological changes for all treated groups {fluoxetine, ami-triptyline and imipramine} which occurred at the end of 2nd and 4th weeks were readily reversible as all affected parameters returned to normal in most rats killed 4 weeks post dose drug-free recovery period.
E) Cardiac histopathological changes:-
C. After 2 and 4 weeks of daily oral administration of single dose of 1/10th LD50 of each drug.
Fluoxetine treated group revealed nearly normal heart.
Amitriptyline and imipramine treated groups revealed intramuscular oe-dema and diffuse perivascular haemorrhage, vascular congestion with perivas-cular lymphocytic infiltration. These findings become pronounced at the end of 4th week.
The mechanisms of producing cardiotoxicity were attributed to severe mitochonderial depression and cellular infiltration might be a part of the defence mechanism of the body against this new situation and/or increased permeability of the lining endothelium of blood vessels. In addition, quinidine like or mem-brane stabilizing properties {direct myocardial effects} of amitriptyline and
imipramine.
vCardiac histopathological changes for all treated groups {fluoxetine, ami-
triptyline and imipramine} which occurred at the end of ri and 4th weeks
were readily reversible as all affected parameters returned to normal in most
rats killed 4 weeks post dose drug-free recovery period.
F) Pulmonary histopathological changes:-
4. After 2 and 4 weeks of daily oral administration of single dose of 1/10th LD50 of each drug.
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Summary and Conclusion
Fluoxetine treated group revealed mild interstitial pneumonia with
haemorrhagic areas and congestion which become pronounced at the end of 4th week.
The mechanisms of producing pulmonary toxicity were attributed to the interaction between fluoxetine and/or norfluoxetine with phospholipids result-ing in phospholipidosis as well as direct toxic effect with consequance increased
pulmonary capillary leakage. In addition, fluoxetine may induced hypersensi-tivity reaction.
Amitriptyline and imipramine treated groups revealed severe oedema with degeneration and necrotic cell detachement, severe congestion and peri-
vascular lymphocytic infiltration. These findings become pronounced at the end of 4th week.
The mechanisms of producing pulmonary toxicity were attributed to res-
piratory depression, aspiration of gastric contents as well as hypersensitivity reaction.
v Pulmonary histopathological changes for all treated groups {fluoxetine,
amitriptyline and imipramine} which occurred at the end of 2’d and 4th weeks
were readily reversible as all affected parameters returned to normal in most
rats killed 4 weeks post dose drug-free recovery period.
Conclusion:-
from the results of the present study we can conclude that:-
1.Fluoxetine, amitriptyline and imipramine have reversible mutagenic ef-
fects when given in high doses or for long time, with fluoxetine has the least genotoxic effect and imipramine has the highest genotoxic effect.
2.Fluoxetine has the least incidence of micronucleated polychromatic eryth-rocytes and imipramine has the highest incidence.
3.Fluoxetine, amitriptyline and imipramine have reversible hepatotoxic.