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L-carnitine and myopathy
L-carnitine and myopathy -- Posted by Zee on 01-03-05 18:18
myotoxicity, L-carnitine and statins:
ARDUINI, A., PESCHECHERA, A.,
GIANNESSI, F. & CARMINATI, P. (2004)
http://tinyurl.com/6rq7f
Improvement of statin-associated myotoxicity by L-carnitine.
Journal of Thrombosis and Haemostasis 2 (12)
To the Editor:
Although statins represent the mainstay therapy for the treatment of
hypercholesterolemia and have a positive tolerability and safety
profile,
the occurrence of statin-associated myopathy, an accepted class effect
of
these drugs, may be more common than originally thought. In this
regard, a
recent paper by Phillips and collegues on the myotoxic effect of statin
has been followed by a number of interesting letters and authors'
response addressing several issues of statin myotoxicity [1,2 ].
Among them, Toma reasoned that L-carnitine (LC ) treatment might have a
favourable impact on the incidence of statin-associated therapy [2 ].
We
have recently completed a study in young rodents treated with myotoxic
doses of simvastatin, a useful model for statin myotoxicity studies
[3],in
combination or not with LC and our results strengthen the Toma's
proposal in addressing the preventive or therapeutic effect of LC on
statin-asociated myopathy in human clinical trials.
Indeed, our study shows that, at the highest dose of simvastatin,
creatine kinase (C K ) plasmalevels were significantly elevated in
treated animals compared to controls and that carnitine
co-administration efficiently counteracted plasma C K levels in the
former group (Table).
Statin treatment at the two highest doses also caused a significant
elevation of glutamic oxalacetate transaminase (G O T ) and glutamic
pyruvate transaminase (G PT ),which may reflect both hepatic and muscle
insult.
LC administration did not lead to a significant correction of these two
enzymatic indexes in statin treated groups, though, at the highest dose
of simvastatin, LC seems to oppose G OT and G PT elevations (T able).
The beneficial effect of carnitine administration in the simvastatin
treated animals does not seem to be linked to an alteration of the
pharmacokinetic properties of the statin, since the
cholesterol-lowering effect observed at the highest dose of simvastatin
w as not affected by carnitine (Table).
Statin-treated animals were also treadmill-tested at a constant 15=B0
angle and a speed of 10m/min. As expected, their walking capacity was
severely impaired at the highest statin dose (9 0 % of rats fell more
than 3 times over a period of
5 min walking) compared to controls (no fallover a period of 5 min
walking). A marked improvement by adding carnitine to statin treatment
was
ob served (6 0 % of rats fell more than 3 times over a period of 5 min
walking
The majority of the specific myotoxic actions described in the
literature
seem to indicate that muscle membrane represents a common pathogenetic
target of statins' mode of action [4 ]. Since several cellular
functions
rely on the integrity of biological membranes (i.e.: ionic homeostasis,
signal transduction, complex lipid metabolism, etc),any intervention
affecting supramolecular organization of the membrane bilayer may lead
to
dramatic changes of those function/activities residing on muscle
membranes. LC is one of the major drivers of mitochondria based energy
production processes.
How ever, supraphysiological LC levels may altercellular integrity and
viability of cells exposed to a variety of adverse conditions by other
mechanisms mainly operating through a dual metabolic and biophysical
interventions on plasma membrane [5,6 ]. Statin treatment has also been
show n to cause a moderate muscle LC deficiency in rabbits [7 ],though
overt myotoxicity is only observed in much more severe LC deficiency
condition [8 ]. Irrespective of the precise nature of LC beneficial
action, our rodent study further supports the concept that human
studies should be performed to quantify the potential protective effect
of LC administration in statin-associated myotoxicity in man.
References
1=2EPhillips PS ,Haas R H ,Bannykh S ,Gray N L, Kimura B J, et al.
Statin-associated myopathy with normal creatine kinase levels. Ann.
Intern. Med. 2 0 0 2 ;137 :58 1-5.
2 Letters to the Editor and Authors' Response. Ann. Intern. Med . 2 0 0
3;138 :10 0 7-9 .
3=2EReijneveld JC , Koot R W , Bredman JJ, Joles JA , Bar PR .
Differential
effects of 3-hydroxymehyglutaryl-Coenzyme A reductase inhibitors on the
development of myopathy in young rats. Ped. R es. 19 9 6 ;39 :10 2
8-35.
4 Evans M , Rees A . Effects of H M G-Co A reductase inhibitors on
skeletal muscle. Drug Safety. 2 0 0 2 ;2 5:6 4 9-6 3.
5=2EArduini A , Holme S , Sweeney JD , Dottori S
,Sciarroni A F, et al. Addition of L-carnitine to additive
solution-suspended red cells stored at 4=B0C reduces in vitro hemolysis
and
improves in vivo viability. Transfusion. 1997;37:166-74.
6=2EGeorges B , Galland S ,Rigauls C, Le Borgne F,
Demarquoy J. Beneficial effects of L-carnitine in myoblastic C2C12
cells
interaction with zidovudine. Biochem. Pharmacol. 2003;65:1483-88.
7=2EBhuiyan J, Secombe D W . The effects of
3-hydroxymehyglutaryl-Co A reductase inhibition on tissue levels of
carnitine and carnitine acyltransferase activity in the rabbits.
Lipids.
1996;31:867-70.
8=2EPons R , De Vivo D C. Primary and secondary
carnitine deficiency syndromes. J. Child. Neurol. 1995;10(Suppl):2S
8-2S
24.
Table. Plasma G O T, G PT, CK and cholesterol levels in simvastatin and
simvastatin plus LC treated rats.
GO T U /L
GPT U /L
CK U /L
Cholesterol m g/dL
Control (14)
140 96-196
45 40-57
1056 477-1616
72.0+6.5
Simvastatin 70 m g/kg (10)
125 98-237
50 41-73
971 396-1754
69.9+14.2
Simvastatin 140 m g/kg (8)
190** 139-293.8
69** 40-98
1308 417-1836
60.9+13.7*
Simvastatin 210 m g/kg (9)
686** 172-5288
94* 35-495
1784* 880-4887
49.0+10.5**
Simvastatin 70 m g/kg plus LC 200 m g/kg b.i.d. (9)
123 100-204
50 38-77
709 442-1840
76.5+19.4
Simvastatin 140 m g/kg LC 200 m g/kg b.i.d. (9)
209 112-373
57 42-138
762* 350-1455
57.3+14.8
Simvastatin 210 m g/kg LC 200 m g/kg b.i.d. (9)
435 134-2422
78 52-495
741* 535-2425
45.2+14.1
Young male Wistar rats weighing 45-50 g (about 23 days of age) received
three different doses of simvastatin (70,140 and 210 mg/kg) alone and
in
combination with LC (200 mg/kg, bid) for 9 days. Twenty four hours
after
the last treatment, blood w as collected and plasma CK, GO T , GPT and
cholesterol levels were analyzed with Roche diagnostic kit. Since serum
enzymatic activities showed a highly skewed distribution, a
non-parametric Wilcoxon signed rank test w as used to evaluate
statistical
significance differences. Cholesterol data were evaluated with an
analysis
of variance follow ed by the Bonferroni t test. A p < 0 .05 w as the
criterion for statistical difference. Groups' comparison: control vs
simvastatin, and simvastatin vs simvastatin plus LC. *P < 0 .05;**p <
0=2E002. Data are expressed as median and range or mean +S D. Number of
animals between parenthesis.
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