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l-Carnitine1occurs naturally as an essential cofactor of fatty acid metabolism which is synthesised endogenously or obtained from dietary sources. In patients with primary carnitine deficiencies, which may be life-threatening, and some secondary deficiencies such as organic acidurias, the exogenously administered compound is clearly beneficial: by abolishing hypotonia, motor skills are improved, as are muscle weakness and wasting. In preliminary clinical trials in patients with ischaemic cardiac disease, therapy with l-carnitine has shown beneficial effects on myocardial function and metabolism and has improved exercise tolerance in patients with angina pectoris — findings which require further substantiation in larger controlled studies. Moreover, while some interesting evidence suggests that l-carnitine may find potential use in such diverse conditions as carnitine deficiencies secondary to prolonged total parenteral nutrition supplementation or chronic haemodialysis, hyperlipidaemias and the prevention of toxicity induced by anthracyclines and valproate, such findings must be regarded as preliminary. Exogenously administered l-carnitinine is very well tolerated.
Thus, while its role in primary deficiencies is established, with its profile of negligible toxicity l-carnitine is worthy of further investigation to more clearly define its therapeutic applications in a variety of conditions which may be indirectly related to alterations in fatty acid metabolism.
Role of l-Carnitine in Fatty Acid Metabolism
l-Carnitine is a cofactor of several enzymes (carnitine translocase, acylcarnitine transferases I and II) necessary for the transformation of free long chain fatty acids to acylcarnitines, and their transport into the mitochondrial matrix. β-Oxidation of these compounds precedes their entry into the Krebs cycle, where energy production occurs. 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.
The pharmacokinetic properties of exogenously administered l-carnitine have not been thoroughly described. Peak plasma concentrations of free carnitine of 48.5 and 69 µmol/L have been attained 3.5 to 5 hours following single oral 500mg and 2g doses, respectively. l-Carnitine is actively transported into tissues via a saturable system, although passive diffusion also occurs. The volume of distribution is about 26% of bodyweight. The compound is likely not metabolised in humans (other than by partial conversion to acylcarnitine esters) and thus is eliminated via the kidneys. The portion of a dose of l-carnitine excreted in the urine within 24 hours varies depending on the route of administration. Thus, following an intravenous dose 80% has been recovered, in contrast to 7% of a dose recovered within 24 hours following an oral dose. Faecal elimination accounts for less than 2% of a dose. In healthy volunteers, the half-life of l-carnitine ranges from 2 to 15 hours.
Use in Patients with Ischaemic Cardiac Disease
The rationale for the use of l-carnitine in patients with ischaemic heart disease relates to the premise that increased lactate production and decreased energy output of cardiac muscle in such patients result in part from decreased l-carnitine concentrations in heart muscle, which has been demonstrated at necropsy in the necrotic area and the infarct border tissue of patients who died of myocardial infarction. In single dose studies in patients with ischaemic heart disease, l-carnitine 40 or 140 mg/kg intravenously or 1g daily orally, and dl-carnitine 20 or 40 mg/kg intravenously, decreased lactate production and increased the free fatty acid extraction ratio in the myocardium. Orally administered l-carnitine decreased the release of creatine kinase isoenzyme MB fraction in patients with acute myocardial infarction.
In patients with moderately impaired left ventricular function, intravenously administered l-carnitine 40 mg/kg exerted a positive inotropic effect as evidenced by a decrease in the left ventricular diastolic pressure and the pre-ejection period/left ventricular ejection time ratio. These effects were confirmed in patients treated with l-carnitine 2g intravenously daily for 10 days.
Preliminary trials in patients with chronic stable angina pectoris have indicated that orally administered l-carnitine 900 to 2000mg daily improved exercise tolerance, lessened the extent of ST segment depression, decreased the frequency of anginal attacks and reduced glyceryl trinitrate (nitroglycerin) consumption. These findings are supported by the results of an open multicentre study in more than 1000 patients with angina pectoris, which demonstrated that a reduction was obtained in the consumption of traditional antianginal drug therapies and the frequency of anginal attacks during the 12-month period of supplementation with oral l-carnitine 2g daily.
While some interesting evidence suggests that l-carnitine may be of benefit in the treatment of patients with acute myocardial infarction or arrhythmias, its role as an adjuvant in therapy of these conditions awaits definition in further studies.
Effects of l-Carnitine in Primary Deficiency
Concentrations of l-carnitine are below normal in the plasma, liver and muscle of patients with systemic carnitine deficiencies (SCD), and in the muscle of those with the myopathic form, possibly because of impaired transport or biosynthesis of l-carnitine. Replacement therapy with the drug in regimens of up to 4g daily reverses such clinical symptoms as severe muscular weakness, hypoglycaemia and intellectual retardation seen in patients more severely afflicted with SCD, and can be life-saving in some instances. Similarly, in patients with the less debilitating myopathic deficiency there has been objective and subjective evidence of improved muscle strength within 1 week of the commencement of l-carnitine therapy.
Use in Secondary Deficiencies
l-Carnitine has been shown to be of benefit in children with defects of intermediary metabolism (organic acidurias) who display impaired motor skills and low plasma concentrations of carnitine.
There is some evidence to indicate that the elevated plasma concentrations of triglycerides and total cholesterol in patients undergoing chronic intermittent haemodialysis can be decreased by l-carnitine supplementation, whether administered orally, intravenously or added to the dialysate. However, results of those studies that have included a placebo control have varied, and in view of the paradoxical increase in plasma triglycerides associated with high oral doses of l-carnitine (3g daily) in 1 trial, further studies are required to determine the optimum dose in these patients.
A few blind and non-blind studies in small numbers of patients with symptoms of the ‘post-dialysis syndrome’ have demonstrated symptomatic improvement after 2 or more months’ treatment with l-carnitine 990 to 2000mg daily, although objective measurements in one study did not alter significantly.
The addition of l-carnitine to total parenteral nutrition regimens in neonates has increased plasma concentrations of total and free carnitine which are lower than in infants fed by enterai methods. Some evidence indicates that carnitine supplementation results in better metabolism of intravenously administered fat emulsion, especially in premature infants.
A few uncontrolled studies in patients who had received anthracycline therapy in cumulative doses of less than 500 mg/m2, suggest that orally or intravenously administered l-carnitine may decrease the severity of cardiotoxicity associated with daunorubicin or doxorubicin administration.
l-Carnitine is very well tolerated; at doses of up to 15g daily no side effects have occurred other than infrequent diarrhoea, gastralgia and nausea. A symptom similar to myasthenia gravis which has been reported with the administration of dl-carnitine has not been seen with l-carnitine therapy.
The usual dose of l-carnitine in adults with primary or secondary carnitine deficiencies or ischaemic cardiomyopathies is 1g given orally or parenterally 1 to 3 times daily. Children should receive 50 to 100 mg/kg daily in 2 to 3 divided doses.
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