Τόμος 14 (1996) – Τεύχος 1 – Άρθρο 1 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 14 (1996) – Issue 1 – Article 1 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

Από | | Άρθρο - Article, Πλήρες Κείμενο στα Ελληνικά - Full Text in Greek, Σταύρος Τ. Πλέσσας - Stavros T. Plessas, Χαράλαμπος Τ. Πλέσσας - Charalambos T. Plessas

 

Τίτλος – Title

L-Καρνιτίνη: Ο Ρόλος της στην Ιατρική. Σύγχρονη Θεώρηση της Φαρμακοκινητικής της, του Ρόλου της στο Μεταβολισμό των Λιπαρών Οξέων και της Χρησιμοποίησής της σε Ασθενείς με Πρωτοπαθείς και με Δευτεροπαθείς Ελλείψεις L-Καρνιτίνης, με Ισχαιμική Καρδιοπάθεια και σε Αιμοκάθαρση

L-Carnitine and its Role in Medicine: A Current Consideration of its Phar­ma­cokinetics, its Role in Fatty Acid Metabolism and its Use in Ischaemic Cardiac Disease and Primary and Secondary L-Carnitine Deficiencies
Συγγραφέας – Author

Σταύρος Τ. Πλέσσας1 και Χαράλαμπος Τ. Πλέσσας2

1 Εργαστήριο Φυσιολογίας, Τμήμα Νοσηλευτικής, Πανεπιστήμιο Αθηνών 2 Τμήμα Επιστημονικής Πληροφόρησης, ΦΑΡΜΑΚΟΝ-Τύπος, Αθήνα

S.T. Plessas1 and C.T. Plessas2

1 Laboratory of Physiology, Department of Nurs­ing, University of Athens, Athens, Greece 2 PHARMAKON-Press, Department of Scientific Informations, Athens, Greece
Παραπομπή – Citation

Πλέσσας,Σ.Τ., Πλέσσας,Χ.Τ. : L-Καρνιτίνη: Ο Ρόλος της στην Ιατρική. Σύγχρονη Θεώρηση της Φαρμακοκινητικής της, του Ρόλου της στο Μεταβολισμό των Λιπαρών Οξέων και της Χρησιμοποίησής της σε Ασθενείς με Πρωτοπαθείς και με Δευτεροπαθείς Ελλείψεις L-Καρνιτίνης, με Ισχαιμική Καρδιοπάθεια και σε Αιμοκάθαρση , Επιθεώρηση Κλιν. Φαρμακολ. Φαρμακοκινητ. 14 :  11-64 (1996)

Plessas,S.T., Plessas,C.T. : L-Carnitine and its Role in Medicine: A Current Consideration of its Phar­ma­cokinetics, its Role in Fatty Acid Metabolism and its Use in Ischaemic Cardiac Disease and Primary and Secondary L-Carnitine Deficiencies, Epitheorese Klin. Farmakol. Farmakokinet. 14 : 11-64 (1996)
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Λέξεις κλειδιά – Keywords

L-καρ­νι­τί­νη, προ­έ­λευ­ση, βιο­σύν­θε­ση, με­τα­βο­λι­σμός λι­παρών οξέων, κα­τα­βο­λι­σμός α­μι­νο­ξέ­ων, φυ­σιο­λο­γι­κός ρό­λος, μη­χα­νι­σμός δρά­σης, φαρ­μα­κο­κι­νη­τι­κή, ι­σχαι­μι­κή καρ­διο­πά­θει­α, στηθάγχη, έμφραγμα μυοκαρδίου, καρδιακή ανεπάρκεια, πρω­το­πα­θείς ελ­λεί­ψεις, μυο­πα­θο­λο­γι­κή έλ­λει­ψη, γενι­κευ­μέ­νη έλ­λει­ψη, ε­ξε­λι­κτι­κή μυο­καρ­διο­πά­θει­α, δευ­τε­ρο­πα­θείς ελ­λεί­ψεις, γε­νε­τι­κής αι­τιο­λο­γί­ας, νε­φρι­κό σύν­δρο­μο Fanconi και αι­μο­κά­θαρ­ση, βαλ­προ­ϊ­κό ο­ξύ, πι­βα­μπι­κιλ­λί­νη, ο­λι­κή πα­ρε­ντε­ρι­κή δια­τρο­φή, χρήση σε νεογνά, καρ­διο­το­ξι­κό­τη­τα α­πό αν­θρα­κυ­κλί­νες, δια­τα­ρα­χές λει­τουρ­γί­ας πνευ­μό­νων, πε­ρι­φε­ρια­κή αγ­γει­α­κή νό­σος, το­ξι­κό­τη­τα, α­νε­πι­θύ­μη­τες ε­νέρ­γει­ες, δο­σο­λο­γί­α

L-carnitine, occurrence, biosynthesis, fatty acid metabolism, amino acid ca­tabolism, physiological role, mechanism of action, pharmacokinetics, ischaemic cardiac disease, angina pectoris, myocardial infarction, heart failure, primary carnitine deficien­cies, myopathic carnitine deficiencies, systemic carnitine deficiencies, progressive car­diomyopathy and systemic, secondary carnitine deficiencies, defects of intermediary me­tabolism, Fanconi syndrome and long term intermittent haemodialysis, valproic acid, pivampicillin, total parenteral nutrition, use in neonates, anthracycline-induced cardiotoxic­ity, lung disorders, peripheral vascular disease, toxicity, side effects, dosage and admini­stration
Λοιποί Όροι – Other Terms

Άρθρο

Article
Περίληψη – Summary

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L-Carnitine (L-β-hydroxy-4-N-trime-thylaminobutyric acid) is an essential nutrient in animals and humans, which is synthesised en­dogenously, mainly in liver and kidney, or ob­tained from diet, with principal sources red meat in adults and human milk in infants.L-Carnitine is a cofactor of several enzymes, including carnitine-acylcarnitine translocase em­bedded in the inner mitochondria membrane, and two acylcarnitine (palmitoyl) transferases I and II, located respectively in the outer and inner mi­to­chondrial membrane; these biomolecules are re­quired in mammalian tissues to transfer long-chain acyl CoAs across the inner membrane for β-oxi­dation in the matrix. Furthermore, intramitochon­drial L-carnitine and the matrix enzyme L-carnitine acetyltransferase can react with short- and me­dium-chain acyl CoAs to produce acylcarnitines, which can be shuttled out of mitochondria. Through this mechanism, L-carnitine is able to modulate the intracellular concentrations of free CoA and acetyl CoA via reversible formation of acetylcarnitine. Therefore, besides shuttling long-chain fatty acids into mitochondria, L-carnitine fa­cilitates the oxidation of pyruvate and branched-chain ketoacids and, by preventing their accumu­lation, it contributes to the protection of cells from the potentially membrane-destabilising acyl CoAs. In the absence of L-carnitine, the accumulation of free fatty acids in the cytoplasm produces a toxic effect on the cell, and an energy deficit arises from the unavailability of fatty acids within the mi­tochondria.L-Carnitine is present in tissues and biological fluids in free and esterified forms. In humans, acylcarnitine esters account for about 25% of to­tal L-carnitine in serum and for about 15% of total L-carnitine in liver and skeletal muscle. Total L-car­nitine concentration in human tissues is higher in the heart and skeletal muscle (3.5-6.0 and 2.0-4.6 μmol/g, respectively) than in the liver and the brain (1.0-1.9 and 0.5-1.0 μmol/g, respectively): these values reflect the higher rates of fatty acid oxida­tive metabolism in the former tissues.The pharmacokinetics of exogenously adminis­tered L-carnitine have not been completely de­scribed. In the case of L-carnitine preparations from Sigma Tau Pharmaceuticals, peak plasma concentrations of free L-carnitine of 25 and 91 μmol/l have been attained 3 and 3,5 hours follow­ing single oral 30 and 100 mg/kg doses, respec­tively. L-Carnitine is actively transported into tis­sues via a saturable system, although passive dif­fusion also occurs. The apparent volume of distri­bution is about 37 l. The compound is likely me­tabolised in humans by partial conversion to acyl­carnitine esters and therefore is eliminated through the kidneys. The portion of a dose of L-carnitine excreted in the urine within 24 hours de­pends on the route of administration; thus, after an intrave­nous dose 86% has been recovered, in contrast to 7% of a dose recovered within 24 hours after an oral dose. Faecal elimination ac­counts for less than 2% of a dose. In healthy vol­unteers, the bio­logical half-life of L-carnitine varies from 3 to 12 hours, depending the dosage sched­ule.Over the past decade many clinical trials have suggested that L-carnitine may be administered to patients with ischaemic cardiac disease. The ra­tionale for the use of L-carnitine in such patients initially originated from the findings that myocar­dial L-carnitine concentrations are lower in pa­tients with fatal myocardial infarction, due to an in­creased lactate production and decreased en­ergy output of cardiac muscle, than in those dying from non-cardiac causes. L-Carnitine has been shown to improve pyruvate metabolism, to reduce lactate production and acidosis and to act as a scavenger of toxic catabolic products of free fatty acids, which accumulate in the heart during is­chaemia. Also, there is evidence for skeletal muscle L-car­nitine deficiency in some patients with atheroscle­rotic vascular disease; therefore, L-carnitine sup­plementation may have potential to improve skele­tal muscle metabolic and mechani­cal function. This double effect in cardiac and skeletal muscle makes L-carnitine attractive for patients with is­chaemic heart disease; L-carnitine seems to play an important metabolic role, not only by enhancing carbohydrate utilisation, but also by reducing FFA toxicity and acting as a metabolic modulator in the hart. The available clinical trials include more than 2,000 patients where L-carnitine was administered either intra­venously or orally for up to 1 year and show some consistent findings: decrease in sig­nals of is­chaemia, such as ST segment depression during stress testing, improved clinical status, such as reduced frequency of anginal attacks, greater ex­ercise tolerance and reduction in consumption of cardiac drugs (p.ex. nitroglycerin). Since L-car­nitine does not have haemodynamic effects, its anti-ischaemic action may be additive to the anti-ischaemic action resulting from drugs with haemo­dynamic effects, such as nitrates, β-blockers and calcium antagonists.In patients with moderately impaired left ven­tricular function, the intravenously administration of L-carnitine (40 mg/kg) exerts a positive inotropic effect, since there is evidence that L-carnitine supplementation decreases the left ven­tricular dia­stolic pressure and the pre-ejection pe­riod/left ven­tricular ejection time ratio. These re­sults were confirmed in patients treated with L-carnitine 2 g intravenously daily for 10 days.The results of some interesting clinical trials suggest that L-carnitine exerts a benefit action in patients with acute myocardial infarction or ar­rhythmias.L-Carnitine concentrations are below normal in the skeletal muscle (but not in plasma, liver or heart) of patients with myopathic L-carnitine defi­ciencies (MCD) and in the plasma, liver, muscle and heart of those with the systemic form (SCD). These primary L-carnitine deficiencies are possi­bly due to impaired transport or biosynthesis of L-carnitine. In patients with the less debilitating MCD, there has been objective and subjective evidence of improved muscle strength within 1 week after oral L-carnitine administration of 2-6 g L-carnitine daily. Several cases of SCD have been treated with oral L-carnitine (up to 4 g per day): under treatment the metabolic attacks dis­ap­peared, muscle strength improved, and L-car­nitine content increased in the tissues of some of the patients reported.In organic acidurias and in defects of β-oxida­tion (secondary L-carnitine deficiencies), L-car­nitine supplementation was shown to have posi­tive metabolic effects, probably because exogenously administered L-carnitine was able to buffer the excess of acyl CoAs, which accumu­lates in mito­chondria as a consequence of specific metabolic blocks.A L-carnitine deficiency exists in the skeletal muscle and myocardium of patients undergoing chronic intermittent haemodialysis, showing that dialysis produces plasma L-carnitine losses that are not compensated for by its endogenous syn­thesis. In these patients total plasma L-carnitine concentrations are usually normal or elevated, free L-carnitine concentrations are significantly de­creased, and L-carnitine esters or acylcarnitine concentrations are markedly elevated. The oral and parenteral administration of L-carnitine to di­alysis patients increases plasma concentrations of both free L-carnitine and acylcarnitine and can de­crease the elevated plasma concentrations of tri­glycerides and total cholesterol. A few blind and non-blind clinical trials in small numbers of pa­tients with symptoms of the post-dialysis syn­drome sug­gest that intravenous L-carnitine ad­ministration appears to be associated with a de­crease in dia­lytic symptoms, an improvement in exercise ca­pacity, sense of well-being and certain serum chemistries and possibly an increase in muscle mass. The recommended dosage sched­ule is 20 mg/kg L-carnitine administered intrave­nously at the end of each dialysis treatment.In newborn infants receiving total parenteral nu­trition, the addition of L-carnitine increases plasma concentrations of total and free L-carnitine, which are lower than in infants fed by enteral methods; L-carnitine supplementation seems to result in bet­ter metabolism of intravenously administered fat emulsion, especially in premature infants.In patients who had received anthracycline in cumulative doses of less than 500 mg/m2, the orally or intravenously administered L-carnitine may decrease the severity of cardiotoxicity asso­ciated with doxorubicin administration.L-Carnitine, with LD50 values approximately equivalent to amino acids, is very well tolerated. At doses of up to 15 g/day few side effects have occurred, including infrequent dose-related diar­rhoea, gastralgia and nausea. A symptom similar to myasthenia gravis has been reported in pa­tients undergoing haemodialysis who were treated only with racemic carnitine.The recommended dose of L-carnitine in adults with primary or secondary L-carnitine deficiencies or ischaemic cardiomyopathies is 1 g given orally or parenterally 1 to 3 times per day. In patients with myocardial infarction and acute myocardial insufficiency, the suggested starting dose is 3 to 6 g/day given parenterally. In children with primary deficiencies, the usual dose is 50 to 100 mg/kg/day administered orally in 2 to 3 divided doses to a maximum of 3 g/day.

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