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| Introduction |
| Introduction: Foreword by Prof M. MARZILLI |
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Treatment of angina pectoris is expected to relieve symptoms and to reduce the risk of death and nonfatal myocardial infarction.
Given that ischemia is attributed to an imbalance between myocardial blood supply and metabolic demand, drugs active on cardiac work and/or blood flow are generally regarded as the mainstay in the treatment of this condition.
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These “hemodynamic” agents, including
β-blockers, Ca-channel blockers, and nitrates,
are expected to restore the balance between myocardial
metabolic demands and coronary blood flow when
it is altered by flow-limiting coronary obstructions.
Unfortunately, “hemodynamic” agents do not provide consistent control of symptoms, and do not assure effective protection from major coronary events, and many patients eventually need revascularization procedures because of persistence of chest pain despite “optimal” medical treatment. However, even after a successful revascularization, recent reports have documented that patients continue to experience angina and myocardial ischemia.
These observations underscore the need for an innovative approach in the management of ischemic heart disease, unrelated to modulation of heart rate, arterial blood pressure, and myocardial myocontractility, yet capable of exerting a protective action on cardiac cells against ischemia and reperfusion.
It has been recently demonstrated that, by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase, FLAVEDON MR modulates energy metabolism via inhibitory effects on fatty acid oxidation, and favors glucose oxidation. On the basis of this observation, FLAVEDON MR is regarded as the representative prototype of a new class of antianginal agents: the 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitors.
By shifting cardiac energy metabolism form fatty acid to glucose oxidation, FLAVEDON MR exerts a direct cardioprotective effect that has been documented in many experimental models and confirmed in man during percutaneous coronary angioplasty and in patients undergoing aorto-coronary bypass surgery. FLAVEDON MR is free of hemodynamic effects.
In randomized, prospective, multicenter trials, FLAVEDON MR has been shown to be beneficial in patients with a variety of ischemic syndromes, including chronic effort angina, acute myocardial infarction, post-ischemic left ventricular dysfunction, and idiopathic cardiomyopathy, in the absence of any interference with heart rate and blood pressure.
Given its particular mechanism of action, this agent offers a great opportunity for combination with classic hemodynamic agents, with greater patient benefit and improved clinical tolerance.
The new 35mg formulation of FLAVEDON MR is now available, with an optimized pharmacokinetic profile, allowing twice-daily administration, while assuring perfect bioequivalence with the previous three-times-a-day formulation.
The greater use of this new formulation in daily
practice offers an opportunity for improving patient’s
compliance and increasing the therapeutic benefits
of an innovative, effective, and well-tolerated
antianginal agent.
Prof. M Marzilli
Professor of Cardiology, University of Siena, Siena, Italy |
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| FLAVEDON
MR: a metabolic anti-ischemic
agent for all coronary patients |
| Cardiac
Metabolism under normal conditions |
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Like all muscles,
the heart needs ATP to work. Energy
is provided by the hydrolysis of ATP
and is converted into contractile
work, allowing the pump to perform
efficiently.
The two main sources of energy originate
from the metabolism of both carbohydrates
and fatty acids ; in normoxic conditions,
two thirds are derived from free fatty
acid (FFA) pathway, the remaining
one third being produced through glucose
(GLU) pathways.(1) Glucose metabolism
has two origins: glycolysis (anaerobic)
and glucose oxidation (requires oxygen). |
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During normal oxygen
supply, the ß-oxidation pathway is
predominant over glucose oxidation,
despite a better yield provided by
glucose oxidation (Table I). |
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O2 cost |
ATP
produced |
ATP/O2 |
| Glucose |
5 |
32 |
6.4 |
| Stearic
acid (18C) |
26 |
147 |
5.6 |
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| Table
I. O2 Cost of energy production. |
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| Cardiac
Metabolism under ischemic conditions |
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During ischemia,
due to a decrease in oxygen supply,
the oxidation of both substrates (FFA
and GLU) is limited.(2),(3) This has
three main consequences:
- an increase in glycolysis (which
does not require oxygene to produce
ATP);
- a decrease in glucose oxidation;
- a decrease in FFA oxidation
This leads to an
uncoupling between glycolysis and
glucose oxidation, a decrease in ATP
production, and an accumulation of
FFA. |
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- increase in glycolysis
=> increase in lactate
and proton production leading
to cell acidosis and calcium
overload.
- Accumulation of FFA =>
membrane damage
- Decrease in ATP production
=> contractile dysfunction
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| Cardiac
Metabolism: pharmacological intervention |
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Direct pharmacological
intervention of cardiac metabolism
has been proven to be an efficient
treatment of ischemic heart disease.
Metabolic agents act on the fuel of
the heart without any inotropic or
chronotropic effect, unlike hemodynamic
drugs which act on the flow.
These pharmacological tools interact
with cardiac metabolism as enzymatic
modulators |
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- FLAVEDON MR (trimetazidine)(4):
3-KAT (long-chain 3 ketoacyl CoA
thiolase) inhibitor (specific enzyme
inhibitor)
- Niacin and derivatives(5): act
on lipolysis
- Etomoxir(6), oxfenicine(7), perhexiline(8):
inhibitor of CPT1 (membrane carnitine
palmitoyl transferase)
- Ranolazine(9): partial fatty acid
oxidation inhibitor (non specific
enzyme inhibitor)
Among these drugs,
FLAVEDON MR is the first metabolic
agent widely used for first-line treatment
of all coronary patients. |
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| FLAVEDON
MR: a specific metabolic mechanism
of action |
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All the enzymes of
the FFA ß-oxidation cycle have been
tested with FLAVEDON MR. At cellular
level, FLAVEDON MR causes a potent
and selective inhibition of one enzyme
of ß-oxidation: the long-chain 3-ketoacyl
CoA thiolase (3 KAT) with an IC50 of 75 nmol/L(4). This results in a partial
inhibition of fatty acid oxidation
and a shift towards glucose oxidation.
This is true under aerobic conditions
as well as under ischemic conditions. |
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Thus, ATP production
is increased, leading to improved
cardiac function. The metabolic switch
from fatty acid oxidation to glucose
oxidation supports the anti-ischemic
properties of FLAVEDON MR. |
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| Attached
References: |
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1997;95:313-315.
- Stanley WC, Lopaschuk GD. Cardiovasc
Res. 1997;33:243-257.
- Olivier MF, Opie LH. Lancet 1994;343:155-158.
- Kantor PF, Lucien A, Kozak R, Lopaschuk GD. Circ Res. 2000;86:580-586.
- Lassers BW, Wahlqvist ML, Kaijser L, Carlson LA. J Appl Physiol.
1972;33:72-80.
- Lopaschuk GD, Wall SR, Olley PM,
Davies NJ. Circ Res. 1988;63:1036-1043.
- Drake-Holland AJ, Passingham JE.
Basic Res Cardiol. 1983;78:19-27.
- Horgan JH, O'Callaghan WG, Teo
KK. J Cardiovasc Pharmacol.
1981;3:566-572.
- Mc Cormack JG, Stanley WC, Wolff
AA. Gen Pharmacol. 1998;30:639-645.
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