Martin
MA, Gomez MA, Guillen F, Bornstein B, Campos Y, Rubio JC, de la Calzada CS,
Arenas J.
Carnitine
Back to the scientific study
index...
An excellent, all around primer on carnitine.
[5-38]
[needs to be cleaned up]
L-Carnitine: therapeutic applications of a conditionally-essential amino acid.
Kelly GS.
A trimethylated amino acid roughly similar in structure to choline, carnitine is a cofactor required for transformation of free long-chain fatty acids into acylcarnitines, and for their subsequent transport into the mitochondrial matrix, where they undergo beta-oxidation for cellular energy production. Mitochondrial fatty acid oxidation is the primary fuel source in heart and skeletal muscle, pointing to the relative importance of this nutrient for proper function in these tissues. Although L-carnitine deficiency is an infrequent problem in a healthy, well-nourished population consuming adequate protein, many individuals within the population appear to be somewhere along a continuum, characterized by mild deficiency at one extreme, and tissue pathology at the other. Conditions which seem to benefit from exogenous supplementation of L-carnitine include anorexia, chronic fatigue, coronary vascular disease, diphtheria, hypoglycemia, male infertility, muscular myopathies, and Rett syndrome. In addition, preterm infants, dialysis patients, and HIV+ individuals seem to be prone to a deficiency of L-carnitine, and benefit from supplementation. Although available data on L-carnitine as an ergogenic aid is not compelling, under some experimental conditions pretreatment has favored aerobic processes and resulted in improved endurance performance.
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A "call-to-arms" for more study on carnitines.
[5-59]
Carnitine metabolism and function in humans.
Rebouche CJ, Paulson DJ.
It is apparent from the foregoing discussion that carnitine plays an essential role in human intermediary metabolism. The question of a dietary requirement for carnitine, particularly for the human infant, is of significant theoretical and practical interest. Aberrant carnitine metabolism resulting from abnormal genetic or acquired conditions may have serious consequences for the affected individual. At present many of the treatment modalities for carnitine deficiency are empirical. Further clarification of the mechanisms by which carnitine depletion is manifest in these conditions is essential for designing treatment programs. Moreover, therapeutic use of carnitine in several human diseases not involving carnitine deficiency per se has been indicated. Before such treatment becomes generally accepted, we must determine precisely the role of this amino acid in the biochemical and physiological events that participate in the pathogenesis of each disease.
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This one focuses on the benefits of carnitine for ischemic (“oxygen starved”) heart disease. The result is more fuel available, better blood supply, fewer arrhythmias, and less free radical damage. Also shows how the propionyl-L-carnitine variety (included in CardioFuel) gets into heart cell mitochondria better.
[5-42]
Influence of L-carnitine and its derivatives on myocardial metabolism and function in ischemic heart disease and during cardiopulmonary bypass.
Lango R, Smolenski RT, Narkiewicz M, Suchorzewska J, Lysiak-Szydlowska W.
Chair and Department of Anesthesiology and Intensive Care, Medical University of Gdansk, Debinki 80-211, Gdansk, Poland. rlango@amg.gda.pl
Carnitine and its derivatives have recently been shown to protect cardiac metabolism and function in ischemic heart disease and other clinical conditions of myocardial ischemia. Potential mechanisms of this effect include an increase in glucose metabolism, a reduction of toxic effects of long-chain acyl-CoA and acyl-carnitine in myocytes, an increase in coronary blood flow and anti-arrhythmic effect. It has also been shown that propionyl-L-carnitine which penetrates faster than carnitine into myocytes is effective in inhibiting production of free radicals. Beneficial effects of carnitine supplementation have been demonstrated under a variety of clinical conditions such as acute cardiac ischemia, during extracorporeal circulation, in carnitine-dependent cardiomyopathy as well as in patients with chronic circulatory failure and in cardiogenic shock. However, further studies are required before carnitine administration could be recommended as a routine procedure in ischemic heart disease or before cardiopulmonary bypass.
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Like CoQ10 did in the previous studies, carnitine also helps the heart recover after it has been starved of oxygen.
[5-26]
Effects of propionyl-L-carnitine on isolated mitochondrial function in the reperfused diabetic rat heart.
Felix C, Gillis M, Driedzic WR, Paulson DJ, Broderick TL.
Department of Pharmacology, Faculty of Medicine, Dalhousie University, B3H 4H7, Halifax, NS, Canada.
The effects of propionyl-L-carnitine (PLC) on isolated mitochondrial respiration in the ischemic reperfused diabetic heart were studied. Oral PLC treatment of STZ-diabetic rats was initiated for a period of 6 weeks. After treatment, isolated working hearts from diabetic rats were perfused under aerobic conditions then subjected to 25 min of no-flow ischemia followed by 15 min of aerobic reperfusion. At the end of reperfusion, heart mitochondria was isolated using differential centrifugation and respiration measured in the presence of pyruvate, glutamate, and palmitoylcarnitine. Our results indicate that diabetes was characterized by a pronounced decrease in heart function under aerobic conditions as well as during reperfusion following ischemia. Treatment with PLC resulted in a significant improvement in heart function under these conditions. The depressions in state 3 mitochondrial respiration with both pyruvate and glutamate seen in reperfused hearts from diabetic rats were prevented by PLC. State 3 respiration in the presence of palmitoylcarnitine was also improved in the ischemic reperfused diabetic rat heart. Our results show that PLC improves recovery of mechanical function following ischemia in the diabetic rat heart. The beneficial effects of PLC are associated with enhanced mitochondrial oxidation of fuels.
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They put carnitine-fed rats on the treadmill for this one...
[5-40]
Exercise intolerance during post-MI heart failure in rats: prevention with supplemental dietary propionyl-L-carnitine.
Koh SG, Brenner DA, Korzick DH, Tickerhoof MM, Apstein CS, Saupe KW.
Cardiac Muscle Research Laboratory, Boston University School of Medicine, 650 Albany St, X720, Boston, MA 02118, USA.
Exercise capacity in patients with several types of cardiovascular disease can be improved with dietary carnitine, or carnitine derivatives. Mechanisms underlying this improvement remain largely unknown in part due to a lack of animal models of cardiac pathology in which carnitine derivatives improve exercise tolerance. Our goal was to evaluate the ability of propionyl-L-carnitine (PLC) to improve exercise tolerance in a rat model of exercise intolerance. Fischer 344 rats were followed after either a moderate size MI (n = 22) or sham MI surgery (n = 14). Starting 10 days post-surgery 10 of the MI and 7 of the sham rats received 100 mg/kg/day PLC in drinking water, which increased plasma and LV total l-carnitine concentrations 15-23% (p < 0.05). Rats were followed longitudinally until a statistically significant decrease in exercise capacity occurred in one of the groups, at which time all rats were sacrificed for study of the isolated perfused hearts. At 12-weeks post-MI exercise capacity had decreased 16 +/- 7% (p < 0.05) in the MI group, but remained within 3% of baseline in the MI group that received PLC and the sham groups. Both MI groups exhibited the same degree of LV dilation, decrease in fractional shortening, and blunting of the response to isoproterenol. We conclude that supplemental dietary PLC attenuates the exercise intolerance that occurs secondary to post-MI heart failure in rats, but that this beneficial effect is not attributable to altered LV remodeling, an improved response to beta-adrenergic stimulation, or increased skeletal muscle citrate synthase activity.
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This study supposes that part of why carnitine works so well is because it dilates arteries, thus increasing blood flow.
[5-18]
Propionyl-L-carnitine dilates human subcutaneous arteries through an endothelium-dependent mechanism.
Cipolla MJ, Nicoloff A, Rebello T, Amato A, Porter JM.
Department of Surgery, Division of Vascular Surgery, Oregon Health Sciences University, Portland 97201, USA.
PURPOSE: The vasoactive effects of propionyl-L-carnitine (PLC) on human arteries, including endothelial and smooth muscle cell influences, were studied. METHODS: Small (less than 200 microm) subcutaneous fat arteries (n = 19), obtained from human patients undergoing vascular surgery, were dissected and mounted in an arteriograph system that allowed measurement of lumen diameter and control of transmural pressure. To investigate the role of the endothelium, arteries were compared intact, intact and in the presence of either 0.3 mmol/L nitro-L-arginine (an inhibitor of nitric oxide synthesis) or 10 micromol/L indomethacin (an inhibitor of prostaglandin synthesis), or denuded of endothelium. After a 1-hour equilibration at a pressure of 50 mm Hg, arteries were precontracted 50% with an intermediate concentration of norepinephrine, and clinically relevant concentrations of PLC (0.1 to 100 micromol/L) were cumulatively added to the bath while the lumen diameter was continually measured. RESULTS: Intact arteries dose-dependently dilated to PLC, with the half maximal dilation occurring at 2.9 +/- 1.2 micromol/L, increasing diameter 91% +/- 5% at 100 micromol/L. In contrast, PLC had significantly less effect on deendothelialized arteries, increasing diameter only 24% +/- 11% at 100 micromol/L (P <.01 vs. intact). This indicates the endothelial dependency of this compound. Blockade of nitric oxide did not inhibit this vasodilation, with the half-maximal response occurring at 8.6 +/- 7 micromol/L, increasing diameter 85% +/- 8% at 100 micromol/L ( P >.O5 vs. intact). However, this vasodilation was significantly diminished in the presence of indomethacin, which dilated arteries only 53% +/- 18% at 100 micromol/L (P <.01 vs. intact; P >.O5 vs. denuded). CONCLUSION: PLC is an endothelium-dependent vasodilator, the mechanism of which is partially mediated by prostaglandin synthesis, not nitric oxide. The beneficial effects of this compound may, in part, be related to vasodilation and enhanced blood flow.
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Angina is chest pain from the heart. Stable angina is pain that is brought on by, and commensurate with, physical activity. Here carnitine reduced angina in a dozen test subjects on a treadmill, made them perform better, reduced their chest pain, and even made their EKG’s look better. A couple of them didn’t even complain of chest pain at all after taking carnitine!
[5-36]
Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris.
Kamikawa T, Suzuki Y, Kobayashi A, Hayashi H, Masumura Y, Nishihara K, Abe M, Yamazaki N.
The effects of L-carnitine (900 mg, p.o. daily) on exercise performance were studied in 12 patients with stable effort angina using a multistage treadmill exercise test. Exercise tests were performed at the end of the placebo period and after 4 and 12 weeks of carnitine therapy. While 12 patients experienced angina during treadmill tests in the placebo period, 2 patients were free of angina after treatment with carnitine. The mean exercise time was 11.4 +/- 0.7 min (mean +/- SE) in the placebo period. This increased significantly to 12.2 +/- 0.5 min (p less than 0.05) after 4 weeks and 12.8 +/- 0.5 min (p less than 0.01) after 12 weeks of treatment with carnitine. The time required for 1 mm ST depression to occur was 6.4 +/- 0.9 min in the placebo period. This increased significantly to 7.6 +/- 0.9 min (p less than 0.01) after 4 weeks and 8.8 +/- 1.0 min after 12 weeks of treatment with carnitine. There was significantly less ST segment depression during the same exercise load after 12 weeks of treatment as compared with that in the placebo period (p less than 0.05). The heart rate and the pressure rate product at the same work load showed no significant difference among the 3 testing periods. The results of this study suggest that L-carnitine may improve exercise tolerance in patients with effort angina.
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Men and women with congestive heart failure, when given the same dose of carnitine included in CardioFuel, lowered heart rate and water retention, and needed fewer drugs to strengthen the heart. It also improved their lipid profile. Most importantly, they felt better!
[5-28]
Evaluation of the therapeutic efficacy of L-carnitine in congestive heart failure.
Ghidini O, Azzurro M, Vita G, Sartori G.
Reparto Medicina Interna, Ospedale Bussolengo, Verona, Italy.
To evaluate the therapeutic efficacy of L-carnitine in elderly subjects suffering from heart failure, secondary to ischemic and/or hypertensive heart disease, 38 patients (22 men, 16 women) were studied, aged from 65 to 82 years. In addition to traditional therapy (digitalis, diuretics, antiarrhythmic agents) given in all cases, 21 patients received oral L-carnitine on the basis of a randomized protocol in 1-g doses twice daily for 45 days (the other 17 received placebo). In the group treated with L-carnitine, a distinct improvement was observed in both subjective and objective conditions; reduced heart rate, edema and dyspnea, increased diuresis and a marked reduction in daily digitalis consumption. L-carnitine treatment also induced a significant reduction in serum cholesterol and triglyceride levels. No adverse reactions attributable to L-carnitine administration were observed in any of the patients.
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Here live rat hearts were starved for nutrients. Carnitine not only improved intracellular energy supply, but also protected the hearts once they were reperfused--to the point of allowing four such starvation-reperfusion cycles. The hearts without carnitine couldn't survive the first one!
[5-45]
Effects of L-carnitine and its acetyl and propionyl esters on ATP and PCr levels of isolated rat hearts perfused without fatty acids and investigated by means of 31P-NMR spectroscopy.
Loster H, Keller T, Grommisch J, Grunder W.
Institute of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Germany.
31P-NMR in vivo spectroscopy is a non-invasive and non-hazardous technique which investigates chemical composition and metabolism of living objects, for example by determining phosphocreatine (PCr) and ATP concentrations. In the present study we investigated the influence of L-carnitine, acetyl-L-carnitine and propionyl-L-carnitine on the energetic state of the Langendorff rat heart subjected to an ischemic period of 20 min followed by a reperfusion period of 60 min. To avoid an overlapping of the effects of fatty acids and glucose, the hearts were perfused with a Tyrode solution containing no fatty acids. Ischemia causes a rapid decrease in the PCr signal, followed by a decrease in the ATP signal after a prolonged period of ischemia. At the same time, a drastic increase in the Pi signal was observed. A partial recovery of the ATP and PCr signals was observed in the reperfusion period. With L-carnitine a markedly improved recovery of the high energy phosphates (e.g. increased PCr/P ratios) was found. With acetyl-L-carnitine this effect was enhanced in the first postischemic phase. It was followed, however, by a more rapid decrease in the PCr/Pi ratio in the late reperfusion period. The effect of propionyl-L-carnitine was not significantly improved in the first minutes of the reperfusion period, but during the whole reperfusion phase a stabilization of the PCr/Pi ratio was observed. Intracellular pH can be calculated from determination of the Pi-chemical shift. This shows that L-carnitine and its derivatives have a protective effect against intracellular pH decrease during ischemia. L-carnitine improves the energetic state of the heart, which leads to increased ischemia tolerance. Hearts under L-carnitine were able to tolerate up to four ischemia-reperfusion periods in succession, whereas the controls were not able to do so. These NMR results confirm the hypothesis that L-carnitine and its esters have a protective effect in the reperfusion period of the ischemic rat heart. This could be of importance for the treatment of ischemic cardiac diseases.
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How much the important left ventricle of the heart enlarges after a heart attack predicts how well--and how long--the patient will survive. Carnitine may decrease the amount of tissue which dies during the heart attack, as well as help the heart maintain its normal size later on. Other benefits are described as well, adding up to a recommendation that anyone who has had a heart attack should get on, and stay on, carnitine.
[5-19]
Myocardial infarction and left ventricular remodeling: results of the CEDIM trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico.
Colonna P, Iliceto S.
Institute of Cardiology, University of Cagliari, Italy.
Left ventricular dilatation after acute myocardial infarction (MI) is a powerful predictor of progressive functional deterioration, culminating in heart failure and death. The most important determinants of post-MI left ventricular remodeling are the size of the infarct, the degree of residual stenosis in the infarct-related artery, and the viability of the infarct zone. In addition to reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may represent a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function. Ongoing studies with early metabolic intervention with carnitine in the acute phase of infarction may prove successful in protecting the microcirculation against ischemic damage and enhancing its ability to respond to blood flow resumption. The results of the multicenter, randomized, double-blind Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial suggest that the early and long-term administration of L-carnitine attenuates progressive left ventricular dilatation after acute anterior MI. Results show significant, consistent reductions in end-diastolic volume and end-systolic volume in patients who received L-carnitine compared with placebo. The ongoing CEDIM-2 trial (projected 4000 patients with acute MI) will assess the efficacy of L-carnitine in reducing the combined incidence of death and heart failure at 6 months. In addition to standard reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may be a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function by limiting infarct size, decreasing residual stenosis in the infarct-related artery, and increasing viability of the infarct zone.
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This study shows how giving carnitine to those who have had a heart attack reduces heart rate, lowers blood pressure, decreases subsequent chest pain and improves cardiac output, as well as the lipid profile. Why is this not being recommended to everyone who has had an MI?
[5-21]
Controlled study on L-carnitine therapeutic efficacy in post-infarction.
Davini P, Bigalli A, Lamanna F, Boem A.
Department of Cardiovascular Medicine, Santa Chiara Hospital, U.S.L., Pisa, Italy.
A controlled study was carried out on 160 patients of both sexes (age between 39 and 86 years) discharged from the Cardiology Department of the Santa Chiara Hospital, Pisa, with a diagnosis of recent myocardial infarction. L-carnitine was randomly administered to 81 patients at an oral dose of g 4/die for 12 months, in addition to the pharmacological treatment generally used. For the whole period of 12 months, these patients showed, in comparison with the controls, an improvement in heart rate (p < 0.005), systolic arterial pressure (p < 0.005) and diastolic arterial pressure (NS); a decrease of anginal attacks (p < 0.005), of rhythm disorders (NS) and of clinical signs of impaired myocardial contractility (NS), and a clear improvement in the lipid pattern (p < 0.005). The above changes were accompanied by a lower mortality in the treated group (1.2%, p < 0.005), while in the control group there was a mortality of 12.5%. Furthermore, in the control group there was a definite prevalence of deaths caused by reinfarction and sudden death. On the basis of these results, it is concluded that L-carnitine represents an effective treatment in post-infarction ischaemic cardiopathy, since it can improve the clinical evolution of this pathological condition as well as the patient's quality of life and life expectancy.
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Here they sampled the hearts of those who received heart transplants--in other words, the worst cardiac tissue around. They found the several forms of carnitine were very deficient in these failed hearts, and in fact, on an almost molecule by molecule basis, the less carnitine, the less blood the heart could push out per beat.
[5-46]
Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure.
Martin
MA, Gomez MA, Guillen F, Bornstein B, Campos Y, Rubio JC, de la Calzada CS,
Arenas J.
Centro de Investigacion, Hospital Universitario 12 de Octubre, Madrid, Spain.
We studied myocardial tissue from 25 cardiac transplant recipients, who had end-stage congestive heart failure (CHF), and from 21 control donor hearts. Concentrations of total carnitine (TC), free carnitine (FC), short-chain acylcarnitines, long-chain acylcarnitines (LCAC) as well as carnitine palmitoyltransferase (CPT) activities were measured in myocardial tissue homogenates and referred to the concentration of non-collagen protein. Compared to controls, the concentrations of TC and FC as well as total CPT activities were significantly lower in patients. LCAC levels and the LCAC to FC ratio values were significantly greater in patients than in controls. While the malonyl-CoA sensitive fraction of CPT, which represents CPT I activity, was similar in patients and controls, the residual CPT activity after inhibition by malonyl-CoA, representing CPT II activity, was significantly reduced in patients compared to controls. Moreover, the activity of CPT in the presence of Triton X-100, which also represents the activity of CPT II, was significantly lower in patients than in controls. Malonyl-CoA concentrations required for half-maximal inhibition of CPT activity were significantly greater in patients than in controls. There was a linear relationship between ejection fraction (EF) values and concentrations of TC, FC, or total CPT activities. Values for LCAC and the LCAC to FC ratio were inversely related to EF values. We conclude that failing heart shows decreased total CPT and CPT II activities and carnitine deficiency that may be related to ventricle function.
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This study shows how sick hearts which require valve replacement have lower levels of carnitine. It also showed the actual heart tissue is using up the carnitine, as the carnitine concentration in the blood may still be normal.
[5-50]
Carnitine levels in patients with chronic rheumatic heart disease.
Narin F, Narin N, Andac H, Ergin A, Coskun A, Ustdal M, Ceyran H.
Erciyes University Medical Faculty, Department of Biochemistry, Kayseri, Turkiye.
OBJECTIVE: Carnitine, a small aminoacid derivative plays a major role in fatty acid oxidation. Myocardial carnitine deficiency may cause malfunction of the heart. Rheumatic valvular heart disease can be associated with myocardial dysfunction. We have investigated myocardial and plasma-free carnitine levels in patients with chronic rheumatic heart disease. MATERIAL AND METHODS: Eleven patients with chronic rheumatic heart disease requiring valve replacement were selected for study. Ten patients with no cardiac failure, myocardial wall motion abnormalities and myocardial infarction and for whom coronary bypass surgery was planned were selected as the control group. Carnitine levels of myocardial tissue obtained from the right atrium and plasma during the operation were evaluated using spectrophotometric method. Myocardial-free carnitine levels expressed as mumol/g (dry weight) were determined according to Ceberblad and Lindstedt technique. RESULTS: Myocardial-free carnitine levels in patients were found to be 0.72 +/- 0.37 mumol/g (dry weight) in comparison with 1.44 +/- 1.03 mumol/g (dry weight) in the control group. Myocardial-free carnitine levels in patients were statistically decreased when compared to control group. Plasma-free carnitine levels in patients were 80.91 +/- 28.22 mumol/L and 89.52 +/- 48.21 mumol/L in the control group, respectively. There was no significant difference between plasma-free carnitine levels of the groups. CONCLUSION: In our study, myocardial-free carnitine levels were decreased while plasma-free carnitine levels were normal in patient with chronic rheumatic heart disease.
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Another catch-all paper listing benefits of carnitine with respect to heart disease--including its ability to help clear cell toxins.
[5-57]
The therapeutic potential of carnitine in cardiovascular disorders.
Pepine CJ.
Division of Cardiology, University of Florida, Gainesville.
The naturally occurring compound L-carnitine plays an essential role in fatty acid metabolism. It is only by combining with carnitine that the activated long-chain fatty acyl coenzyme A esters in the cytosol are able to be transported to the mitochondrial matrix where beta-oxidation occurs. Carnitine also functions in the removal of compounds that are toxic to metabolic pathways. Clinical evidence indicates that carnitine may have a role in the management of a number of cardiovascular disorders. Supplemental administration of carnitine has been shown to reverse cardiomyopathy in patients with systemic carnitine deficiency. Experimental evidence obtained in laboratory animals and the initial clinical experience in man indicate that carnitine may also have potential in the management of both chronic and acute ischemic syndromes. Peripheral vascular disease, congestive heart failure, cardiac arrhythmias, and anthracycline-induced cardiotoxicity are other cardiovascular conditions that may benefit from carnitine administration, although at this time data on the use of carnitine for these indications are very preliminary.
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Claudication is terrible leg pain brought on by physical exercise, due to oxygen starvation because the blood supply of the legs is compromised. Carnitine here allowed people walk faster and longer on a treadmill, and therefore would improve their QOL (Quality of Life).
[5-32]
Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication.
Hiatt WR, Regensteiner JG, Creager MA, Hirsch AT, Cooke JP, Olin JW, Gorbunov GN, Isner J, Lukjanov YV, Tsitsiashvili MS, Zabelskaya TF, Amato A.
Department of Medicine, Section of Vascular Medicine, Divisions of Geriatrics and Cardiology, University of Colorado Health Sciences Center, Denver 80203, USA.
PURPOSE: We tested the hypothesis that propionyl-L-carnitine would improve peak walking time in patients with claudication. Secondary aims of the study were to evaluate the effects of propionyl-L-carnitine on claudication onset time, functional status, and safety. SUBJECTS AND METHODS: In this double-blind, randomized, placebo-controlled trial, 155 patients with disabling claudication from the United States (n = 72) or Russia (n = 83) received either placebo or propionyl-L-carnitine (2g/day orally) for 6 months. Subjects were evaluated at baseline and 3 and 6 months after randomization with a graded treadmill protocol at a constant speed of 2 miles per hour, beginning at 0% grade, with increments in the grade of 2% every 2 minutes until maximal symptoms of claudication forced cessation of exercise. Questionnaires were used to determine changes in functional status. RESULTS: At baseline, peak walking time was 331 +/- 171 seconds in the placebo group and 331 +/- 187 seconds in the propionyl-L-carnitine group. After 6 months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 +/- 222 seconds (a 54% increase) as compared with an improvement of 75 +/- 191 seconds (a 25% increase) for those on placebo (P <0.001). Similar improvements were observed for claudication onset time. Propionyl-L-carnitine treatment significantly improved walking distance and walking speed (by the Walking Impairment Questionnaire), and enhanced physical role functioning, reduced bodily pain, and resulted in a better health transition score (by the Medical Outcome Study SF-36 Questionnaire). The incidence of adverse events and study discontinuations were similar in the two treatment groups. CONCLUSIONS: Propionyl-L-carnitine safely improved treadmill exercise performance and enhanced functional status in patients with claudication.
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A study describing how carnitine may benefit the heart function of diabetics.
[5-13]
Propionyl-L-carnitine effects on postischemic recovery of heart function and substrate oxidation in the diabetic rat.
Broderick TL, Driedzic W, Paulson DJ.
Midwestern University, Department of Physiology, Glendale, Arizona 85308, USA.
Previous studies have shown that propionyl-L-carnitine (PLC) can exert cardiac antiischemic effects in models of diabetes. In the nonischemic diabetic rat heart, PLC improves ventricular function secondary to stimulation in the oxidation of glucose and palmitate. Whether this increase in the oxidation of these substrates can explain the beneficial effects of PLC in the ischemic reperfused diabetic rat heart has yet to be determined. Diabetes was induced in male Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). Treatment was initiated by supplementing the drinking water with propionyl-L-carnitine at the concentration of 1 g/L. After a 6-week treatment period, exogenous substrate oxidation and recovery of mechanical function following ischemia were determined in isolated working hearts. In aerobically perfused diabetic hearts, compared with those of controls, rates of glucose oxidation were lower, but those of palmitate oxidation were similar. Diabetes was also characterized by a pronounced decrease in heart function. Following treatment with by propionyl-L-carnitine, however, there was a marked increase in rates at which glucose and palmitate were oxidized by diabetic hearts and a significant improvement in heart performance. Postischemic recovery of function in diabetic hearts was also improved with PLC. This improvement in contractile function was accompanied by an increase in both glucose and palmitate oxidation. Our findings show that postischemic diabetic rat heart function can be improved following chronic PLC treatment. This beneficial effect of propionyl-L-carnitine can be explained, in part, by an improvement in the oxidation of glucose and palmitate.
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The bottom line of this study is that carnitine is so important for the body, the kidneys are able to recover it back from the urine.
[5-56]
Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsorption.
Pace
S, Longo A, Toon S, Rolan P, Evans AM.
Sigma Tau Industrie Farmaceutiche Riunite s.p.a., Pomezia, Rome, Italy.
AIMS: Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. METHODS: This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. I.e. RESULTS: All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 I h-1 and a volume of distribution of 18.3 +/-2.4 I. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/-0.38 I h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 I h-1 at a dose of 1 g to 5.55 +/- 1.50 I h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. CONCLUSIONS: Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.
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Since carnitine is made in the kidney, those with kidney disease benefit from supplementing it.
[5-11]
Carnitine nutriture of dialysis patients.
Borum PR, Taggart EM.
Hemodialysis patients often experience muscle weakness, cardiac arrhythmias, and hypertriglyceridemia, along with other conditions that may lead to atherosclerosis and coronary heart disease. A contributing factor in the etiology of the symptoms may be carnitine deficiency. Patients undergoing renal dialysis treatment are at risk for developing a carnitine deficiency. The small carnitine molecule can be easily lost into the dialysate. A diseased kidney may lead to a decrease in the endogenous supply of carnitine since the kidney is a major site of carnitine biosynthesis. The diet of dialysis patients may be limiting in preformed carnitine as well as in the precursors and micronutrients required for carnitine biosynthesis. Both oral and intravenous supplementation of L-carnitine have been shown to alleviate muscle weakness, reduce the incidence and severity of arrhythmias, and decrease plasma triglyceride levels, along with alleviating other complications noted in dialysis patients. Health care professionals must be aware of the possible benefits of providing carnitine supplementation for renal dialysis patients.
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Carnitine is approved by the FDA for treatment of those who have kidney disease.
[5-41]
[we need to clean this up]
Carnitine is an endogenous molecule that serves as a carrier in the transport of long-chain fatty acids across the inner mitochrondrial membrane, facilitating oxidation and energy production. Dialytic losses, combined with reduced renal synthesis and reduced intake of meat and dairy products, can cause carnitine deficiency in end stage renal disease (ESRD) patients. Levocarnitine injection has been approved by the Food and Drug Administration (FDA) for the "prevention and treatment of carnitine deficiency in ESRD patients who are undergoing dialysis. Levocarnitine injection was first approved by the in FDA 1992. The FDA approved the drug's indication for ESRD patients on December 15, 1999. Given inconsistencies among the fiscal intermediaries' local coverage policies for this drug, the Centers for Medicare and Medicaid Services (CMS) believes a national review is appropriate. Among other issues, CMS plans to examine, in this review, the clinical significance of carnitine deficiency and the issue of intravenous administration of carnitine supplementation versus oral administration.
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The actual mechanism in which carnitine and CoQ10 work together in Energy Synergy.
[let's get a copy of the full text so I can be up on it]
[5-9]
Carnitine and coenzyme Q10: biochemical properties and functions, synergism and complementary action.
Bertelli A, Ronca G.
Department of Pharmacology, University of Milan, Italy.
The mechanisms by which carnitine and coenzyme QIO intervene in the energetic metabolism are described. In particular, the metabolic stages in which the action of carnitine is complementary to the action of coenzyme QIO are illustrated. The synergism of the pharmacological and therapeutic actions that is found when these compounds are administered together is explained on the basis of their biochemical and metabolic complementarity.
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Carnitine even can help treat Ulcerative Colitis, as when it was applied directly to the tissues involved in this study.
[5-27]
Effects of propionyl-L-carnitine topical irrigation in distal ulcerative colitis: a preliminary report.
Gasbarrini G, Mingrone G, Giancaterini A, De Gaetano A, Scarfone A, Capristo E, Calvani M, Caso V, Greco AV.
Institute of Internal Medicine, Catholic University-Policlinico A. Gemelli Largo Gemelli, 8-00168 Roma, Italy, ggasbarrini@rm.unicatt.it
BACKGROUND/AIMS: To study the tolerability of propionyl-L-carnitine administered as rectal irrigation and its efficacy in improving the clinical picture of distal ulcerative colitis. METHODOLOGY: Ten male subjects (aged 18 to 55 years, with a body mass index ranging from 21 to 25 Kg/m2) with distal ulcerative colitis were treated with propionyl-L-carnitine enemas (6 g in 200 mL physiological solution) twice a day over 120 minutes each. All subjects had a disease activity index from 0 to 1. A clinical, laboratory, endoscopy and biopsy evaluation was performed at baseline and 14 days after treatment. Serum tumor necrosis factor-alpha and interleukin-2 concentration was measured. RESULTS: No side effects were reported by the entire patient population and the clinical conditions remained constant throughout the study period. The disease activity index improved significantly between the beginning and the end of the study in 80% of the patients. Histologic features (mucosal erosion, distortion of crypt architecture, inflammation and lamina propria gap) significantly improved in all treated patients. Serum interleukin-2 levels did not change significantly after propionyl-L-carnitine treatment (respectively: 14.7 +/- 15.8 before vs. 9.9 +/- 13.2 pg/mL), while tumor necrosis factor-alpha levels were undetectable both before and after propionyl-L-carnitine administration. CONCLUSIONS: The topical treatment with a new formulation containing propionyl-L-carnitine seems to be safe and effective in improving the histologic features in patients with inactive or mild ulcerative colitis, as an alternative to conventional therapy.
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[Get that study of carnitine and Leydig cell production.]
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Peyronie's Disease is a condition where the penis becomes curved and painful due to untoward tissue deposition. Carnitine was shown to be useful in treating this condition.
[5-15]
Oral propionyl-l-carnitine and intraplaque verapamil in the therapy of advanced and resistant Peyronie's disease.
Cavallini G, Biagiotti G, Koverech A, Vitali G.
Medicine Reproductive Unit, Societa Italiana Studi di Medicina della Riproduzione (SISMER), Bologna, Italy, giorgiocavallini@libero.it
OBJECTIVE: To ascertain whether oral propionyl-l-carnitine combined with intraplaque verapamil is a useful therapy for advanced or resistant Peyronie's disease. PATIENTS AND METHODS: The combined drugs were assessed in two studies. In the first, 60 patients with advanced Peyronie's disease, diagnosed using accepted definitions, were randomized in two subgroups treated with verapamil intraplaque infiltration (10 mg weekly for 10 weeks) plus a 3-month administration of propionyl-l-carnitine (2 g/day), or verapamil infiltration plus oral tamoxifen (40 mg/day) for 3 months. In the second study, 15 patients with resistant Peyronie's disease (progression despite previous therapy) received verapamil plus propionyl-l-carnitine. The differences between subgroups or between the variables before and after therapy were compared using analysis of variance or the chi-squared test. RESULTS: In the first study, the reduction in pain was the same in both subgroups. Propionyl-l-carnitine plus verapamil significantly reduced penile curvature, plaque size, cavernosal artery end-diastolic velocity, the need for surgery and disease progression, and increased the International Index of Erectile Function score and resistivity index of the cavernosal arteries. Tamoxifen plus verapamil had none of these effects. No drug combination affected the peak systolic velocity. Patients receiving verapamil had no side-effects but those taking tamoxifen did. In the second study propionyl-l-carnitine and verapamil modified the disease patterns as in the first and no patient had side-effects. CONCLUSION: The combination of propionyl-l-carnitine and verapamil can be considered the therapy of choice for advanced and resistant Peyronie's disease.
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