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PubMed1991

Carnitine content of red blood cells of human subjects treated with pivampicillin and carnitine.

Total- and free carnitine content of washed pooled red blood cells collected from five children prior to and on the last day of combined pivampicillin and equal molar carnitine treatment were measured. On the last day of treatment (day 7) the level of total carnitine decreased from 47.5 +/- 3.39 to 37.5 +/- 2.48 nmol/ml, mean +/- SEM (p less than 0.05) with a concomitant decrease of free carnitine (from 19.2 +/- 0.97 to 15.5 +/- 0.99 nmol/ml, p less than 0.05) as compared with the pretreatment control day (day 0). The calculated amount of acid soluble carnitine esters also fell (from 28.2 +/- 3.38 to 21.9 +/- 1.78 nmol/ml). The same effects were found when the carnitine levels were referred to haemoglobin or water content of samples. These results demonstrate that in pivampicillin treatment the carnitine pool of erythrocytes also alters. In agreement with previous findings the data presented here suggest, that the administered carnitine was not sufficient to meet the enhanced needs of the organism caused by the pivalate load and that the organism utilized some of its stores for pivaloylcarnitine production. The decreased carnitine ester level of erythrocytes suggest, that the red blood cells do not participate in significant extent in pivaloylcarnitine transport or production.

Carnitine↗
PubMedDate not supplied

Free and total carnitine in human serum after oral ingestion of L-carnitine.

Twelve students with in apparent good health and fasting since the previous evening ingested 2 g of L-carnitine on one day and a placebo on another day in a single-blind trial. Six blood samples were taken during the 24 h following the ingestion. Their blood carnitine levels increased (the free form by 81%, and the total by 57%) to a maximum at about 3.5 h and then slowly decreased. Twenty-four hours after ingestion, blood carnitine concentrations had still not returned to their initial levels. In the time interval where the decay curve approximated a single exponential, the half-life of the carnitine appeared to be of the order of 15 h. During the 24 h after the administration of the 2 g of L-carnitine, 7% +/- 1% of it was eliminated in the urine. This work suggest that the daily administration during a long period, of 2 g of L-carnitine guarantee in a healthy subject blood carnitine concentrations superior to the normal levels. Its remains to determine if the dose is sufficient in the case where L-carnitine is given to ameliorate a primary or secondary lack of carnitine, or to lower a high level of lipids in blood.

Administration, Oral↗
PubMed1994

The effect of L-carnitine on the AZT-induced destruction of human myotubes. Part II: Treatment with L-carnitine improves the AZT-induced changes and prevents further destruction.

BACKGROUND: Zidovudine (AZT) as used in the treatment of AIDS causes a mitochondrial myopathy characterized by enzymatic defects in the respiratory chain system, accumulation of lipid droplets, and carnitine deficiency. Human myotubes treated with AZT demonstrate abnormal mitochondria, accumulation of lipid, and increased lysosomes. Because L-carnitine plays a major role in the transport of long chain fatty acids across the inner mitochondrial membrane and facilitates the beta-oxidation of fatty acids, we examined whether L-carnitine can enhance the recovery of the affected myotubes after withdrawal of AZT and can improve the structural changes of the myotubes while AZT treatment continues. EXPERIMENTAL DESIGN: Myotubes, prepared from human muscle biopsies, were exposed to 250 microM of AZT for 3 to 6 weeks. After 3 weeks of AZT treatment, the cultures were treated with L-carnitine or medium for 3 weeks, while AZT treatment was either withdrawn or continued for 3 more weeks. The cultures were evaluated with: (a) light microscopy; (b) immunocytochemistry, to count the number of myotubes stained with antibodies to Leu-19; (c) oil red O stain, to assess the lipid droplet accumulation; and (d) electron microscopy, to count all the organelles within representative sections of the myotubes, at x24,000, and to calculate the volumetric density (Vvi) of each organelle per unit volume of tissue. RESULTS: In the post-AZT-treated cultures, L-carnitine increased the number of Leu-19-positive myotubes from 3.83 +/- 1.23 to 23 +/- 1.5 per field, normalized their mitochondria, decreased the lipid droplets, and increased the Vvi of the myofibrils. In the cultures treated with 3 weeks of L-carnitine while AZT treatment continued for 3 more weeks, the number of myotubes increased from 3.3 +/- 0.74 to 6.87 +/- 1.35; the absolute number of the mitochondria increased from 1.65 +/- 0.35 to 9.02 +/- 1.11 and their Vvi from 3.67 +/- 0.83 to 6.57 +/- 0.78 (p < 0.05); the Vvi of the myofibrils increased from 2.50 +/- 0.52 to 5.37 +/- 0.76 (p < 0.05); and the Vvi of the lipid droplets decreased from 5.06 +/- 1.44 to 2.72 +/- 0.72 (p < 0.05). In the AZT-treated cultures that did not receive L-carnitine, the mitochondria demonstrated extensive vacuolation, abnormal cristae, and paracrystalline inclusions; in contrast, in the L-carnitine-treated cultures, the mitochondria had substantially improved in spite of continuation of AZT. CONCLUSIONS: L-carnitine enhances the pace and degree of recovery of the AZT-associated destruction of human myotubes, restores and preserves the structure of mitochondria, mobilizes the endomyotubular fat, and allows the regeneration of myofibrils, even if AZT treatment continues. The findings may have potential clinical implications in improving the myotoxicity of AZT in patients with AIDS when the administration of AZT treatment must continue.

Carnitine↗
PubMed1996

Alterations of remnant liver carnitine and serum carnitine concentrations after partial hepatectomy in rats.

The role of carnitine in the early phase of liver regeneration after partial hepatectomy has been a controversial issue. The purpose for this study was to evaluate the alterations of remnant liver carnitine and serum carnitine concentrations in partial-hepatectomized rats. Partial hepatectomy, with resection of the median and left lateral lobes (67%), was done in 40 male Wistar rats weighing about 200 g. Another group of 40 rats underwent a sham-operation for comparison. All the rats underwent fasting for 4 hours before surgical procedure and 2 hours after surgery. They were killed at 6, 24, 48 or 72h after the operation, ten rats for each time. The serum carnitine concentration, remnant liver carnitine content, serum free fatty acid (FFA), acetoacetate (AA) and beta-hydroxybutyrate (BB) concentrations were measured. It was found that: (1) the serum carnitine concentration increased in the early posthepatectomized stage; (2) the carnitine content in the remnant liver increased in the early posthepatectomized stage; and (3) the serum FFA and its metabolites markedly increased with a depressed ketone body ratio noted in the early post-hepatectomized stage. These results supported the theory that regenerating liver utilized free fatty acids as an immediate main substrate. The utilization then decreased. Because of a marked increase of the carnitine concentration in the remnant liver and serum, it is suggested that the carnitine contents were sufficient for liver regeneration. There must be other reasons for the decreased utilization of free fatty acids.

3-Hydroxybutyric Acid↗
PubMed1996

[Influence of multiple-dose administration of cefetamet pivoxil on blood and urinary concentrations of carnitine and effects of simultaneous administration of carnitine with cefetamet pivoxil].

Cefetamet pivoxil (CEMT-PI), a drug of pivaloyloxymethyl group, was investigated for its impact on the carnitine blood homeostasis and renal excretion upon administering CEMT-PI alone, and CEMT-PI simultaneously with carnitine. 500 mg of CEMT-PI (group A) and 500 mg of CEMT-PI and an equimolar amount (200 mg of carnitine) of levocarnitine chloride (group B) were administered twice a day for 7 and 1/2 consecutive days to 5 healthy volunteers (group A) and 3 healthy volunteers (group B). No serious side effects nor abnormal values in physical and laboratory tests were observed throughout the study in both groups. During the treatment period, plasma total carnitine decreased slowly down to 25.5 microM (group A) and 38.8 microM (group B) and plasma free carnitine reached steady state levels at 17.7 microM (group A) and 29.2 microM (group B) on day 5. These concentrations represent 45 and 37% in group A, 66 and 58% in group B of the average pre-treatment baseline levels. Plasma pivaloylcarnitine quickly reached plateau levels of 6.12 microM (group A) and 4.05 microM (group B) on day 4. After treatment stop, plasma total and free carnitine returned to the pretreatment baseline level within 5 days (group A) and 3 days (group B), and plasma pivaloylcarnitine was detectable until day 7 of the treatment-free follow up in both groups. Although carnitine was given concurrently at a dose equimolar to the ingested amount of pivalic acid in group B, the plasma total and free carnitine exhibited a decrease. This was considered attributable to the fact that the bioavailability of carnitine is as low as 16% when administered orally, which is considerably less compared to the 55% bioavailability of cefetamet pivoxil.

Administration, Oral↗
PubMed1992

Elevated plasma carnitine in the hepatic form of carnitine palmitoyltransferase-1 deficiency.

In a boy with a defect in fatty acid oxidation due to the hepatic form of carnitine palmitoyltransferase-1 deficiency, plasma carnitine concentrations were found to be twice normal. The elevation in plasma carnitine levels was accompanied by an unusually high renal threshold for free carnitine, suggesting a secondary increase in carnitine transport. Similar to other fatty acid oxidation disorders involving the carnitine cycle, urinary dicarboxylic acids were not abnormally elevated during illnesses. The combination of elevated plasma carnitine levels and absence of dicarboxylic aciduria may help to distinguish the hepatic form of carnitine palmitoyltransferase-1 deficiency from other defects in fatty acid oxidation.

Blood Glucose↗
PubMed2001

Carnitine palmitoyltransferase I deficiency in neonate identified by dried blood spot free carnitine and acylcarnitine profile.

A neonate at risk for hepatic carnitine palmitoyltransferase I (L-CPT I) deficiency was investigated from birth. The free carnitine and acylcarnitine profile in dried whole blood filter paper samples collected at ages 1 and 4 days showed a markedly elevated concentration of free carnitine (141 and 142 micromol/L, respectively), normal concentrations of acetyl- and propionylcarnitine, with the near absence of all other species. The diagnosis was confirmed by in vitro fatty acid oxidation screening assays and enzyme assay in cultured skin fibroblasts. Retrospective study of the newborn whole blood sample of the index case showed a similar profile (free carnitine 181 micromol/L). The newborn population distribution of free carnitine (n = 143,981) showed that only three samples had free carnitine > 140 micromol/L (>99.9th centile), two were from L-CPT I-deficient neonates and one from a baby with sepsis. While there are other conditions that can cause elevated concentrations of free carnitine, an isolated elevation of free carnitine only in an apparently healthy term neonate warrants further investigation to exclude L-CPT I deficiency.

Carnitine↗
PubMed1983

Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat.

The requirement for carnitine and the malonyl-CoA sensitivity of carnitine palmitoyl-transferase I (EC 2.3.1.21) were measured in isolated mitochondria from eight tissues of animal or human origin using fixed concentrations of palmitoyl-CoA (50 microM) and albumin (147 microM). The Km for carnitine spanned a 20-fold range, rising from about 35 microM in adult rat and human foetal liver to 700 microM in dog heart. Intermediate values of increasing magnitude were found for rat heart, guinea pig liver and skeletal muscle of rat, dog and man. Conversely, the concentration of malonyl-CoA required for 50% suppression of enzyme activity fell from the region of 2-3 microM in human and rat liver to only 20 nM in tissues displaying the highest Km for carnitine. Thus, the requirement for carnitine and sensitivity to malonyl-CoA appeared to be inversely related. The Km of carnitine palmitoyltransferase I for palmitoyl-CoA was similar in tissues showing large differences in requirement for carnitine. Other experiments established that, in addition to liver, heart and skeletal muscle of fed rats contain significant quantities of malonyl-CoA and that in all three tissues the level falls with starvation. Although its intracellular location in heart and skeletal muscle is not known, the possibility is raised that malonyl-CoA (or a related compound) could, under certain circumstances, interact with carnitine palmitoyltransferase I in non-hepatic tissues and thereby exert control over long chain fatty acid oxidation.

Acyl Coenzyme A↗
PubMed1993

Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in patients with mitochondrial myopathy.

Plasma carnitine "insufficiency," (plasma esterified carnitine to free carnitine ratio above 0.25) was found in 21 of 48 (43.8%) patients with mitochondrial myopathy, of whom 4 also showed both total and free carnitine deficiencies in plasma. In addition, plasma levels of SCAC and LCAC were higher in patients with mitochondrial myopathy than in controls (P < 0.001 and P < 0.01, respectively). Patients diagnosed as having plasma carnitine insufficiency or deficiency were treated with L-carnitine (50-200 mg/kg per day in four daily doses). Muscle weakness improved in 19 of 20 patients, failure to thrive in 4 of 8, encephalopathy in 1 of 9, and cardiomyopathy in 8 of 8 patients. Plasma carnitine "insufficiency" provides an additional clue to the diagnosis of mitochondrial myopathy and an indication for L-carnitine therapy.

Adolescent↗
PubMed1994

Determination of carnitine and saturated-acyl group carnitines in human urine by high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic method was developed for the determination of carnitine and 11 acylcarnitines (acetyl-, propionyl-, butyryl-, isovaleryl-, hexanoyl-, octanoyl-, decanoyl-, lauroyl-, myristoyl-, palmitoyl-, and stearoylcarnitine) in human urine. Urine samples were treated with a disposable cation-exchange column to extract carnitine and acyl-carnitines using cyclopentanoylcarnitine as an internal standard. The extracted carnitine and acylcarnitines were reacted with 3-bromomethyl-6,7-dimethoxy-1-methyl-2(1H)-quinoxalinone as a fluorescence derivatization reagent and were separated and detected by high-performance liquid chromatography with gradient elution. Calibration curves gave good linearities at the individual assay range. Analytical recoveries were 70-76% for palmitoylcarnitine and stearoylcarnitine, and were more than 96% for carnitine and the 9 other acylcarnitines. The lower limits of quantitation were 103 nmol/ml for carnitine, 19 nmol/ml for acetylcarnitine, and 0.5-10.5 nmol/ml for other acetylcarnitines. Precision and accuracy including within- and between-run were < or = 19% and -17 approximately +13% at the lowest concentrations of the individual assay ranges. The coefficient of correlation between this method and the radioenzymatic method was found to be 0.988 for the measured concentration of carnitine. We concluded that the present method can be used to measure carnitine and acylcarnitines in human urine.

Acetylation↗
PubMed2001

Carnitine transport by organic cation transporters and systemic carnitine deficiency.

The intracellular homeostasis is controlled by different membrane transporters. Organic cation transporters function primarily in the elimination of cationic drugs, endogenous amines, and other xenobiotics in tissues such as the kidney, intestine, and liver. Among these molecules, carnitine is an endogenous amine which is an essential cofactor for mitochondrial beta-oxidation. Recently, a new family of transporters, named OCT (organic cation transporters) has been described. In this minireview, we present the recent knowledge about OCT and focus on carnitine transport, more particularly by the OCTN2. The importance of this sodium-dependent carnitine cotransporter, OCTN2, comes from various recently reported mutations in the gene which give rise to the primary systemic carnitine deficiency (SCD; OMIM 212140). The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia. Most of the OCTN2 mutations identified in humans with SCD result in loss of carnitine transport function. Identifying these mutations will allow an easy targeting of the SCD syndrome. The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described. These mice have a mutation in the gene encoding the mouse carnitine transporter octn2. Although various OCTN carnitine transporters have been identified and functionally characterized, their membrane localization and regulation are still unknown and must be investigated. This knowledge will also help in designing new drugs that regulate carnitine transport activity.

Animals↗
PubMed1998

Free carnitine and acetyl carnitine plasma levels and their relationship with body muscular mass in athletes.

The purpose of the present study was to investigate the relationship between plasma carnitine concentration and body composition variation in relation to muscular and fat masses since there is no experimentally proved correlation between plasma carnitine and body masses. We used bioelectric impedance analysis (BIA), to determine body composition and to have a complete physical fitness evaluation. The post-absorptive plasma free carnitine and acetyl carnitine plasma levels, body composition as Fat-Free Mass (FFM) and Fat Mass (FM) in kg, as well as in percent of body mass, were analysed in 33 healthy subjects. A significant negative correlation was found between plasma acetyl carnitine and FFM in weight (kg) as well as in percent of body mass (respectively p < 0.0001; p < 0.01); a significant positive correlation was found only between FM in percent and plasma acetyl carnitine (p < 0.01). The observed negative correlation between plasma acetyl carnitine and muscular mass variation might reflect an oxidative metabolic muscle improvement in relation to muscular fat free mass increment and might be evidence that muscle metabolism change is in relation to plasma acetyl carnitine concentration.

Acetylcarnitine↗
PubMed1990

Carnitine deficiency with cardiomyopathy presenting as neonatal hydrops: successful response to carnitine therapy.

A small-for-date infant presented at birth with severe non-immune hydrops, cardiac failure, metabolic acidosis and hypoglycaemia. Ultrasonography disclosed a cardiomyopathy. Initial therapy consisting of artificial ventilation, inotropes and diuretics resulted in partial disappearance of oedema without significant improvement in cardiac function. Episodes of hypoglycaemia recurred despite continuous glucose infusions. Total serum carnitine from cord blood was 1.65 nmoles/ml and was undetectable on day 20. Oral DL-carnitine supplements resulted in normoglycaemia, dramatic improvement in cardiac function and restoration of serum carnitine levels to normal values. The infant was thereafter maintained on carnitine therapy. Follow-up over 1 year showed moderate growth retardation and normal developmental milestones. In order to account for such a severe neonatal presentation of carnitine deficiency, a combination of defective pre- and postnatal carnitine supply with an inborn error of carnitine handling is considered. The present case illustrates the need for evaluation of carnitine status in fetuses and neonates presenting with hydrops associated with cardiac failure.

Cardiomyopathies↗
PubMed1991

Butyrobetaine is equal to L-carnitine in elevating L-carnitine levels in rats.

This work shows that butyrobetaine administered to rats in a single dose can be highly effective in elevating L-carnitine levels in all tissues. This ability of butyrobetaine was compared to that of L-carnitine. In an experiment with tracer dose of the compounds, 12 h following administration of [3H]butyrobetaine plasma and tissues contained radioactivity exclusively in L-carnitine and in similar amounts as in the other group of animals receiving L-[3H]carnitine. This was observed both after intraperitoneal and oral administration of the compounds. In the loading experiments 100 mumol [3H]butyrobetaine was administered orally to one group and 100 mumol L-[3H]carnitine to the other group of animals and 12 h later it was found that butyrobetaine caused the same increments in L-carnitine as L-carnitine administration. The increments in the organs of the butyrobetaine-treated group (in decreasing order) were as follows: kidney, 1227 nmol/g vs. 652 nmol/g; liver, 469 nmol/g vs. 258 nmol/g; muscle, 1043 nmol/g vs. 881 nmol/g; plasma, 79.4 nmol/ml vs. 39.3 nmol/ml. Butyrobetaine (100 mumol) caused similar increments when it was administered intraperitoneally. Based on these results butyrobetaine can be considered as a potential agent for L-carnitine supplementation therapy.

Administration, Oral↗
PubMed1991

Improved methodology to assay carnitine and levels of free and total carnitine in human plasma.

Carnitine, once known as vitamin Bt, is intrinsic to human tissue and is biochemically established as being acylated with fatty acids by Acyl-CoA to give Acyl-carnitines which then are transported to the inner mitochondrial membrane by a translocase. Carnitine is of increasing clinical interest and importance, and endomyocardial deficiencies of carnitine have been reported for patients in heart failure. Consequently, a reproducible and accurate analysis of human tissue specimens for levels of free carnitine and Acyl-carnitine to guide and to support continuing clinical studies of disease states is needed. We have devised an analytical method which utilizes 5,5'-dithiobis-2-nitro-benzoate and demonstrated recovery, reproducibility and precision. Hydrolysis of a specimen at 90 degrees C for 15 min, and control of pH below 6.0 are critical steps. The mean levels of free carnitine and total carnitine in 17 ordinary subjects were 50.6 +/- 9.7 nmol./ml and 62.6 +/- 11.7 nmol./ml. respectively.

Acetylcarnitine↗
PubMed1988

L-carnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentrations.

Persistent abnormalities of liver function tests occur in approximately 15% of home parenteral nutrition (HPN) patients and are associated with steatosis, steatohepatitis, and, rarely, fibrosis or cirrhosis. Approximately one-third of patients with gut failure on long-term HPN have low total and free plasma carnitine concentrations, and it has been suggested that a deficiency of L-carnitine may be responsible for the steatosis and steatohepatitis in HPN patients. To determine whether administration of L-carnitine is capable of reversing steatosis in HPN patients, 4 adult women on HPN for a mean of 53 mo (range 21-80 mo) were studied before and after 1 mo of intravenous L-carnitine supplementation (1 g/day). All patients had abnormalities in standard liver function tests and low total and free plasma carnitine values. The mean total and free plasma carnitine concentrations and the mean total hepatic carnitine concentration were reduced before supplementation and rose to normal values after treatment (27.4 +/- 2.3 to 35.5 +/- 3.1 nmol/ml, 19.4 +/- 2.8 to 25.7 +/- 2.5 nmol/ml, and 3.5 +/- 0.65 to 6.5 +/- 1.2 nmol/mg of noncollagen protein, respectively). However, there were no significant changes in mean serum aspartate aminotransferase and alkaline phosphatase levels (65 +/- 21 vs. 54 +/- 12 IU and 429 +/- 220 vs. 472 +/- 224 IU, respectively), plasma free fatty acids, plasma triglycerides, hepatic free fatty acid and triglyceride concentrations, or the grade of hepatic steatosis on light microscopy. These results suggest that carnitine deficiency is not a major cause of steatosis and steatohepatitis in patients receiving HPN.

Adult↗