Doxorubicin is a widely used anthracycline antibiotic in cancer
chemotherapy, the most serious adverse effect being life-threatening heart
damage. It is commonly used in the treatment of a wide range of cancers,
including some leukemias and Hodgkin's lymphoma, as well as cancers
of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue
sarcoma, multiple myeloma, and others . Commonly used doxorubicincontaining
regimens are AC (Adriamycin, cyclophosphamide), TAC
(Taxotere, AC), ABVD (Adriamycin, bleomycin, vinblastine,
dacarbazine), and FAC (5-fluorouracil, adriamycin, cyclophosphamide) .
Nebivolol is a β1 receptor blocker with nitric oxide-potentiating
vasodilator effect used in treatment of hypertension and, also for left
ventricular failure .
L-Carnitine is a natural substance that helps the body turn fat into
energy. Our body makes it in the liver and kidneys and stores it in the
skeletal muscles, heart, brain, and sperm. Usually, our body can make all
the carnitine it needs. Some people, however, may not have enough
carnitine because their bodies cannot make enough or can’t transport it
into tissues so it can be used .
The present study was carried out to find out and compare the
protective effects of nebivolol and L-carnitine against doxorubicin
cardiotoxicity , hepatotoxicity and nephrotoxicity, also the in vitro studies
were done to investigate the effect of doxorubicin on contractility of
isolated normal mammalian heart and the effect of increasing doses of
isopernaline on contractility of hearts taken from another 5 groups of rats
given the same medications as the groups of the in-vivo experiment.
Summary and Conclusion
11 9
Rats were randomly divided into 5 groups (6 rats for each group).
control group received saline intraperitoneal in comparative volume to
the tested groups, Dox group received doxorubicin intraperitoneally every
other day for 12 days, Dox + Neb group received doxorubicin
intraperitoneally every other day for 12 days and nebivolol orally daily
for 12 days , Dox +L-car group received doxorubicin intraperitoneally
every other day for 12 days and L-Carnitine intraperitonially daily for 12
days and Dox + Neb +L-car group received doxorubicin intraperitoneally
every other day for 12 days nebivolol orally and L-Carnitine
intraperitonially daily for 12 days.
At the end of the study period, ECG, blood pressure, troponin I
,CPK, creatinine ,ALT, AST were measured and histopathololgical
examination of heart , liver and kidney was done .
It was found that doxorubicin administration caused significant
increase in T wave voltage, significant reduction in blood pressure and
significant elevation in troponin I ,CPK, ALT, AST, creatinine serum
levels and prominent histopathological changes compared to control
group . This study revealed that nebivolol and L-carnitine produced a
significant reduction in T wave voltage, significant elevation in blood
pressure and significant reduction in troponin I ,CPK, , ALT, AST,
creatinine serum levels and improved markedly histopathological changes
compared to Dox group .
Comparing the result of Dox+Neb +L- car group with that of Dox+
neb group and Dox + L-car group, adding L-carnitine to nebivolol was
not significantly more effective than nebivolol or L-carnitine alone in
reducing T wave voltage .
Comparing the result of Dox +Neb+L- car group with that of Dox+
neb group, adding L-carnitine to nebivolol was significantly more
effective than nebivolol alone in elevating systolic & mean blood
Summary and Conclusion
12 0
pressure and comparing the result of Dox+Neb+L- car group with that of
Dox + L-car group, adding nebivolol to L- carnitine was not significantly
more effective than nebivolol alone in elevating systolic blood pressure &
mean blood pressure also was found that comparing the result of
Dox+Neb+L- car group with that of Dox+Neb group and Dox + L-car
group adding L-carnitine to nebivolol was not significantly more
effective than nebivolol or L- carnitine alone in reducing the cardiac
enzymes.
Comparing the result of Dox +Neb + L_Car group with that of Dox +
Neb group and Dox + L-car group, adding nebivolol to L- carnitine was
not significantly more effective than nebivolol alone in reducing the liver
enzymes. Comparing the result of Dox+Neb + L- car group with that of
Dox + Neb group and Dox + L-car group, adding L-carnitine to nebivolol
was not significantly more effective than nebivolol alone in reducing the
creatinine level .
In-vitro study, It was noticed that isoprenaline in increasing doses
(2, 4 and 8 μg/bath) produced an increase in the force of spontaneous
contraction of isolated perfused rat’s heart in dose related manner.
In Dox group it was noticed that isoprenaline in increasing doses
(2 , 4 μg/bath) produced an non significant increase in the force of
spontaneous contraction of isolated perfused rabbit’s heart .This increase
of the force of spontaneous contractions of the isolated perfused rabbit’s
heart was significant with the dose of 8μg/bath. with percentage of
increase 59.1 % compared to preisoprenaline contraction
In Dox + Neb group it was noticed that isoprenaline in increasing
doses (4 and 8 μg/bath) produced an increase in the force of spontaneous
contraction of isolated perfused rat’s heart in dose related manner.
This increase of the force of spontaneous contractions of the
isolated perfused rat’s heart was not significant with the dose of 2μg/bath.
Summary and Conclusion
12 1
In Dox + L-car group it was noticed that isoprenaline in increasing
doses (4 and 8 μg/bath) produced an increase in the force of spontaneous
contraction of isolated perfused rabbit’s heart in dose related manner.
This increase of the force of spontaneous contractions of the
isolated perfused rabbit’s heart was not significant (P > 0.05) with the
dose of 2μg/bath .
In Dox + Neb +L- car group it was noticed that isoprenaline in
increasing doses (2 , 4 and 8 μg/bath) produced an increase in the force
of spontaneous contraction of isolated perfused rat’s heart in dose related
manner.
It was noticed that doxorubicin in a gradually increasing doses (1/2
, 1, 2 and 4 μg / bath) produced a decrease in the force of spontaneous
contraction of isolated perfused rabbit’s heart in dose related manner.
Also it was noticed that doxorubicin decrease the positive inotropic
effect of isoprenaline in a dose of 2 μg / bath on isolated perfused rabbit’s
heart .
In conclusion, doxorubicin can induce cardiotoxicity,
hepatotoxicity and nephrotoxicity which can be ameliorated by using
nebivolol and L-carnitine which are effective and may be recommended
for protection against doxorubicin cardiotoxicity, hepatotoxicity and
nephrotoxicity . |
