الفهرس 
Material and methodsOnly 14 pages are availabe for public view
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Abstract
A causal relationship between excessive intake of
as the side effects of these agents are due to blockade of
NSAIDs namely: indomethacin, piroxicam, diclofenac sodium
the effect of chronic administration of some currently used
prostaglandin production. The present work aimed to stUdy
and pirprofen on the kidney. The effect of the preViously
mentioned
drugs was investigated on different
renal
function parameters including serum Na + ,
creatinine as well as the aSsociated renal
histopathological changes. In addition, an attempt was made
to clarify any correlation between the
an tirhellmatic
effects associated With their long term administration.
actiVities of these NSAIDs and the degree of renal adverse
The present work also, extended to stUdy the effect of
admi ni str·ation of indomethacin, piroxicam,
diclofenac sodium and pirprofen on the liver functions
(total serum bilirubin, SGOT and SGPT) as well as to
investigate the associated hepatic histopathological
changes.
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Finally,
r6Pvln’sibi1ity
kidn6PYs and
the present study also investigated
of NSAIDs induced adverse effects on
the
the
livers of the arthritic r-ats after
discontinuation of these drugs.
It is to be not6Pd that the pres6Pnt experiments were
conducted on normal as well as rats with adjuvant arthritis
which is the best available model of chronic inflammation
and the n6Parest experim6Pntal approximation to rheumatoid
arthritis in human being. The manifestations of arthritis
in the adjuvant inOCUlated rats became evident 16 days
after Freund’s adjuvant inoculation and there were a highly
significant increases in the mean values of paws thickness.
Treatment of the arthritic rats by
indomethacin,
piroXicam, diclofenac sodium or pirprofen significantly
inhibited the magnitude of paw thickness. The mean paw
thickness inhibited by indomethacin > piroxicam >
diclofenac sodium> pirprofen and these r6PsuIts refl6Pcted
the antiinflammatory actiVity of the tested drugs.
Interestingly, the same findings were proved by the
histopathological examination of the ankle joints of the
arthritic treated rats as the improv6Pment in the repair
process of the ankle joints of the arthritic rats was most
marked with indomethacin> piroxicam > diclofenac sodium >
pirprof6Pn.
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As regards the analgesic activity of the tested drugs,
indomethacin, piroxicam, diclofenac sodium or pirprofen
were significantly increased paw pressure threshold of the
arthritic rats. When recorded after 10 days therapy, the
analgesic actiVity of the tested drugs was more pronounced
by pirprofen > indomethacin> diclofenac sodium> piroxicam
whereas after 60 days term therapy the analgesic actiVity
of the tested drugs was in the sequence: pirprofen equal to
indomethacin > piroxicam > diclofenac sodium. The
variations in the sequence of the analgesic actiVity of the
tested drugs detected on days 10 and 60 of the term therapy
and the dissimilarity between the antiinflammatory activity
of the tested drugs and their analgesic effect recorded in
this work could be attributed to the fact that NSAIDs could
induce analgesic effect which is partly independent on
their antiinflammatory effect.
In the present study, no significant differences in the
mean values of serum Na+, K+, urea and creatinine as well
as no evident renal histopathological changes were observed
between the arthritic and non arthritic rats. On the other
hand, administration of indomethacin, piroxicam, diclofenac
sodium or pirprofen to the arthritic rats for 45 days led
to significant increase in s e r-um Na+, K+ , ur-e a and
creatinine and the increments in serum K, urea and
creatinine showed more increase with the prolongation of
,.£-”.,_”,:.!..,~ 1
- .. - .._~~
””’ ..
the term therapy- Moreover, when estimated one month after
discontinuation of the tested drugs, the increments in
serum urea and creatinine (the usual indices of renal
functions) induced by indomethacin and diclofenac sodium
reversed to become no longer significant while that induced
by piroxicam and pirprofen were still significant- These
results suggest that the increments in the serum urea and
creatinine induced by piroxicam or pirprofen may be
attributed to structural rather than functional
alterations- These res~llts were confirmed by the
histopathological examination of the kidneys of the
arthritic rats which revealed severe tubular necrosis and
degeneration as well as marked lymphocytic infiltrations in
the sections of the kidneys of the arthritic rats treated
by piroxicam or pirprofen for 60 days_
According to the levels of serum urea and creatinine
which are the usual indices of renal functions, the present
study revealed that the renal deleterious effects following
long term administration of NSAID were more pronounced by
piroxicam > pirprofen > diclofenac sodium> indomethacin-
As a consequence, the present work showed no correlation
between the potency of the drug as an antiinflammatory
agent and its hazardous effects on the kidney_ These
findings suggest that inhibition of prostaglandin synthesis
as a causal mechanism for renal damage is not the main
236
factor in the pathological changes at least with basal
conditions. A direct toxic effect of the drug or its
metabolites
participatlP.
or an idiosyncratic mechanism may also
ThlP rlPsults of thlP prlPsIPnt study also showlPd no
significant differences in the mean values of total serum
bilirubin, SGOT and SGPT as wlPII as
histopathological differences were observed
livers of the arthritic and non arthritic
no evidIPnt
between the
rats. On thlP
other hand, administration of indomethacin,
dicloflPnac sodium or pirprofen for 45 days
significant increase in total serum bilirubin,
SGPT and these increments showed progression
prolongation of the term therapy to 60 days.
piroxicam,
led to
SGOT and
with the
The transaminases showed increments with piroxicam >
pirprofen > indomethacin > diclofenac sodium and these
values in fact reflect the hepatocellular injury induced by
these drugs which was confirmed by the histopathological
findings. The variations in the hepatocellular injury may
be attributed to the variations in the half lifes of the
tested drugs. Drugs with prolonged half lifes may be
accumulated leading to direct toxic effects on the liver
ce11s.
2.37
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On the other hand, total serum bilirubin was increased
by priprofen > piroxicam > indomechacin > diclofenac
sodium. The relatively high total serum bilirubin induced
by pirprofen may be attributed to the pricipitation of
hepatitis of cholestatic type. This suggestion may be
confirmed by the histopathological study which illustrated
severe portal necrosis with marked lymphocytic
infiltrations and proliferation of bile ducts in the
sections of the livers of the arthritic rats treated by
pirprofen for 60 days.
The results of the present work also showed that the
discontinuation of the tested NSAIDs for one month had led
to return of the tested liver function parameters to the
normal Ieve 1s.
In conclusion:
1. The antiinflammatory activity of the tested drugs was in
the sequence I indomethacin> piroxicam > diclofenac
sodium> pirprofen.
2. Long term administration of the tested drugs led to
kidney
with
function impairments which were more
piroxicam > pirprofen > diclofenac
p ron o un c e d
sodium >
indomethacin.
3. No correlation between the potency of the NSAID as an
238
antiinflammatory agent and its hazardous effect on the
kidney.
4. Indomethacin and diclofenac sodium showed reversal of
their deleterious effects on the kidney after their
discontinuation.
5. Long term administration of piroxicam and pirprofen
induced kidney functions impairments which did not
reverse after their withdrawal.
6. Long term administration of indomethacin, piroxicam,
diclofenac
functions
sodium or pir’profen
impairments whi ch
ind~lced
reversed
hepatic
after’
discontinuation of these drugs.
7. Pirprofen may be participated in induction of hepatitis
of cholestatic type.
8. NSAIDs of prolonged half lifes may be accumulated
leading
liver.
to direct toxic effects on the kidney and
9. Frequent monitoring of kidney and liver functions for
patients receiving NSAIDs for long term are
recommended.
10. In patients with kidney or liver f~tnctions
impairments, the u s e of these drugs should be avoided.
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