Continual infusion of intrathecal baclofen (ITB): long-term effect on spasticity.

BACKGROUND: Spasticity is a disorder of muscular function causing muscular tightness or spasm which occurs when there is damage to the central nervous system whether it is of spinal cord or brain origin. This insult could be either pathological or traumatic. METHOD: Thirty-three patients had intrathecal Baclofen pumps implanted for severe spasticity. These patients either did not respond to or tolerate oral medications. RESULTS: All patients showed significant improvement in their spasms following the procedure. Improvement was noted not only in spasticity, but also in pain, management of sleep disturbance, activities of daily living, indoor and outdoor mobility and behavior. CONCLUSION: The number of complications was acceptable, and generally were not life-threatening. Infection was the significant complication in two patients and this led to explantation of their pumps. Patient satisfaction was very high and was related to improvement in the quality of life for the patients.

Correlation of serum L-carnitine and dehydro-epiandrosterone sulphate levels with age and sex in healthy adults.

OBJECTIVES: L-carnitine and dehydro-epiandrosterone (DHEA) independently promote mitochondrial energy metabolism. We therefore wondered if an age-related deficiency of L-carnitine or DHEA may account for the declining energy metabolism associated with age. METHODS: we evaluated serum levels of L-carnitine and the sulphated derivative of DHEA (DHEAS) in cross-sectional study of 216 healthy adults, aged 20-95. RESULTS: serum DHEAS levels declined, while total carnitine levels increased with age (P < 0.0001). Total and free carnitine and DHEAS levels were lower in women than men (P < 0.0001). Esterified/free (E/F) carnitine (inversely related to carnitine availability) increased with age in both sexes (P=0.012). CONCLUSION: reduced carnitine availability correlates with the age-related decline of DHEAS levels. These results are consistent with the hypothesis that decreased energy metabolism with age relates to DHEAS levels and carnitine availability.

Effect of dehydroepiandrosterone sulfate on carnitine acetyl transferase activity and L-carnitine levels in oophorectomized rats.

Alteration in energy metabolism of postmenopausal women might be related to the reduction of dehydroepiandrosterone sulfate (DHEAS). DHEA and DHEAS decline with age, leveling at their nadir near menopause. DHEA and DHEAS modulate fatty acid metabolism by regulating carnitine acyltransferases and CoA. The purpose of this study was to determine whether dietary supplementation with DHEAS would also increase tissue L-carnitine levels, carnitine acetyltransferase (CAT) activity and mitochondrial respiration in oophorectomized rats. Plasma L-carnitine levels rose following oophorectomy in all groups (P < 0.0001). Supplementation with DHEAS was not associated with further elevation of plasma L-carnitine levels, but with increased hepatic total and free L-carnitine (P = 0.021 and P < 0.0001, respectively) and cardiac total L-carnitine concentrations (P = 0.045). In addition, DHEAS supplementation increased both hepatic and cardiac CAT activities (P < 0.0001 and P = 0.05 respectively). CAT activity positively correlated with the total and free carnitine levels in both liver and heart (r = 0.764, r = 0.785 and r = 0.700, r = 0.519, respectively). Liver mitochondrial respiratory control ratio, ADP:O ratio and oxygen uptake were similar in both control and supplemented groups. These results demonstrate that in oophorectomized rats, dietary DHEAS supplementation increases the liver and heart L-carnitine levels and CAT activities. In conclusion, DHEAS may modulate L-carnitine level and CAT activity in estrogen deficient rats. The potential role of DHEAS in the regulation of fatty acid oxidation in postmenopausal women is worthy of investigation.

L-carnitine improvement of cardiac function is associated with a stimulation in glucose but not fatty acid metabolism in carnitine-deficient hearts.

OBJECTIVES: Increasing myocardial carnitine content can improve heart function in patients with carnitine deficiency. We were interested in determining the effects of L-carnitine on cardiac function and substrate metabolism in a rat model of carnitine deficiency. METHODS: Carnitine deficiency was induced in male Sprague-Dawley rats by supplementing the drinking water with 20 mM sodium pivalate. Control animals received an equimolar concentration of sodium bicarbonate. Following treatment, cardiac function and myocardial substrate utilization were determined in isolated working hearts perfused with glucose and relevant levels of fatty acids. To increase tissue levels of carnitine, hearts were perfused with 5 mM L-carnitine for a period of 60 min. RESULTS: Hearts from sodium pivalate-treated animals demonstrated a 60% reduction in total heart carnitine content, depressions in cardiac function and rates of palmitate oxidation, and elevated rates of glycolysis compared to control hearts. Treatment with L-carnitine increased total carnitine content and reversed the depression in cardiac function seen in carnitine-deficient hearts. However, this was not associated with any improvement in palmitate oxidation. Rates of glycolysis and glucose oxidation, on the other hand, were increased with L-carnitine. CONCLUSIONS: Our findings indicate that acute L-carnitine treatment is of benefit to cardiac function in this model of secondary carnitine deficiency by increasing overall glucose utilization rather than normalizing fatty acid metabolism.

Fatty acid oxidation and cardiac function in the sodium pivalate model of secondary carnitine deficiency.

Carnitine-deficiency syndromes are often associated with alterations in lipid metabolism and cardiac function. The present study was designed to determine whether this is also seen in an experimental model of carnitine deficiency. Carnitine deficiency was induced in male Sprague-Dawley rats supplemented with sodium pivalate for 26 to 28 weeks. This treatment resulted in nearly a 60% depletion of myocardial total carnitine content as compared with control hearts. When isolated working hearts from these animals were perfused with 5.5 mmol/L glucose and 1.2 mmol/L palmitate and subjected to incremental increases in left-atrial filling pressures, cardiac function remained dramatically depressed. The effects of carnitine deficiency on glucose and palmitate utilization were also assessed in hearts perfused at increased workload conditions. At this workload, function was depressed in carnitine-deficient hearts, as were rates of 1.2-mmol/L [U-14C]-palmitate oxidation, when compared with control hearts (544 +/- 37 vs 882 +/- 87 nmol/g dry weight.min, P < .05). However, glucose oxidation rates from 5.5 mmol/L [U-14C]-glucose were slightly increased in carnitine-deficient hearts. To determine whether the depressed fatty acid oxidation rates were a result of reduced mechanical function in carnitine-deficient hearts, the workload of hearts was reduced. Under these conditions, mechanical function was similar among control and carnitine-deficient hearts. Palmitate oxidation rates were also similar in these hearts (526 +/- 69 v 404 +/- 47 nmol/g dry weight.min for control and carnitine-deficient hearts, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

L-propionylcarnitine effects on cardiac carnitine content and function in secondary carnitine deficiency.

Long-term treatment with sodium pivalate, a compound conjugated to carnitine and excreted in the urine, results in carnitine deficiency and cardiac dysfunction. Since L-propionylcarnitine (LPC) is generally of benefit to cardiac function, it was of interest to determine whether it is effective in preventing the reductions in both heart carnitine content and function from occurring in carnitine deficiency. Secondary carnitine deficiency was induced in male Sprague-Dawley rats by supplementing the drinking water with 20 mM sodium pivalate for 26 weeks. Control animals received an equimolar concentration of sodium bicarbonate. At 13 weeks into treatment, a subgroup of control and sodium pivalate animals were given 80 mg/kg of LPC in their drinking water. Following treatment, isolated working hearts were perfused with buffer containing 11 mM glucose and 0.4 mM palmitate. Hearts from sodium pivalate treated animals demonstrated a severe reduction in tissue carnitine. When mechanical function was measured in these hearts, heart rate, rate-pressure product, and aortic flow were significantly depressed. Treatment with LPC, however, prevented the depletion in cardiac carnitine content and improved these cardiac parameters. Our results demonstrate that LPC treatment is beneficial in preventing the depression in cardiac function from occurring in this model of secondary carnitine deficiency.

Sodium pivalate reduces cardiac carnitine content and increases glucose oxidation without affecting cardiac functional capacity.

This study determined how selected functional, metabolic, and contractile properties were impacted by sodium pivalate, a compound which creates a secondary carnitine deficiency. Young male rats received either sodium pivalate (20 mM, PIV) or sodium bicarbonate (20 mM, CONTR) in their drinking water. After 11-12 weeks cardiac function and glucose oxidation rates were measured in isolated, perfused working heart preparations. Hearts were also analyzed for carnitine content, activities of hexokinase (HK), citrate synthase (CS), and B-hydroxyacyl CoA dehydrogenase (HOAD), and myosin isoenzyme distribution. Sodium pivalate treatment significantly reduced cardiac carnitine content and increased glucose oxidation but did not alter cardiac functional capacity. HK activity was increased in the PIV group (p < 0.05), and HOAD activity decreased (p < 0.05). CS activity and myosin isoform distribution (VI > 85%) remained unchanged. These results demonstrate that pivalate treatment of this duration and the accompanying carnitine deficiency shift cardiac substrate utilization without compromising cardiac functional capacity.

Protection of mitochondrial and heart function by amino acids after ischemia and cardioplegia.

The effects of amino acids in protecting against ischemic/reperfusion injury were tested in two experimental models: the isolated perfused rat heart subjected to 21 min of zero flow ischemia (37 degrees) followed by 40 min of reperfusion and the isolated perfused rabbit heart subjected to 300 min of cardioplegic arrest (29 degrees) followed by 60 min of reperfusion. In both cases, the addition of amino acids to the perfusion medium significantly improved the recovery of cardiac contractile function. The protective effects of amino acids were associated with a preservation of mitochondrial respiratory activity. These findings suggest that amino acids by replenishing mitochondrial matrix levels of critical TCA cycle substrates, such as malate, stimulate mitochondrial respiration and thereby enhance the recovery of heart function.

Protection of the ischemic diabetic heart by L-propionylcarnitine therapy.

Diabetics suffer from an increased incidence of myocardial infarction and are less likely to survive an ischemic insult. Since L-propionylcarnitine (LPC) has been shown to protect against ischemic/reperfusion injury, we hypothesized that LPC may be of even greater benefit to the diabetic heart. Diabetes was induced by i.v. streptozotocin, 60 mg/kg; duration: 12 wks. The chronic effect of LPC was determined by daily i.p. injections (100 mg/kg) for 8 wks. The acute effects of LPC were determined by adding it to the perfusion medium (5 mM) of control and diabetic hearts. Initial cardiac contractile performance of isolated perfused working hearts was assessed by varying left atrial filling pressure. Hearts were then subjected to 90 min of low flow global ischemia followed by 30 min reperfusion. Chronic LPC treatment had no effect on initial cardiac performance in either control or diabetic hearts. Acute addition of LPC to the perfusion medium enhanced pump performance of control hearts, but had no effect in diabetic hearts. Both acute and chronic LPC significantly improved the ability of control and diabetic hearts to recover cardiac contractile performance after ischemia and reperfusion, however, chronic treatment was more effective in diabetic hearts.

The effect of enteral carnitine administration in humans.

We previously determined that the L-carnitine uptake by human duodenal tissue occurs by both active (KT 558 mumol/L) and passive mechanisms. The effects of enteral carnitine was studied in humans. A hamburger meal (345 mumol total carnitine) induced peak jejunal fluid free (unesterified) and short-chain acylcarnitine concentrations (SCAC) of 209 and 130 mumol/L, respectively. Plasma carnitine concentrations and the percent renal reabsorption remained unchanged. By contrast, a pharmacologic dose of free carnitine (25,298 mumol) raised peak intraluminal free and SCAC to 20,660 and 4204 mumol/L. Plasma total carnitine concentrations doubled to 93 mumol/L, and the percent renal reabsorption of free and SCAC declined to 76% and 52%, respectively. In triple-lumen perfusions, 200 mumol carnitine/L was absorbed at 484 nmol.min-1.30 cm-1 jejunum, a rate sufficient for prandial but not pharmacologic assimilation. Our findings indicate that absorption of physiologic and pharmacologic amounts of carnitine occurs predominantly by active transport and passive diffusion, respectively.

Protective effects of propionyl-L-carnitine during ischemia and reperfusion.

When cardiac function in isolated rat hearts was impaired by subjecting them to ischemia, subsequent perfusion with propionyl-L-carnitine and related compounds increased their rate of recovery. Thus at 11 mM, both propionyl-L-carnitine and, to a lesser extent, its taurine amide, and also acetyl-L-carnitine, significantly restored cardiac function in 15 minutes after 90 minutes of either low-flow or intermittent no-flow ischemia. Carnitine itself was ineffective. Propionyl-L-carnitine also increased tissue ATP and creatine phosphate compared with controls, but did not affect the levels of long-chain acyl carnitine and coenzyme. These esters also depleted fatty acid peroxidation, as shown with malonaldehyde, and were more effective than carnitine in preventing the production of superoxide. In myocytes, propionyl-L-carnitine alone stimulated palmitate oxidation, but in rat heart homogenates, both L-carnitine and propionyl-L-carnitine did so, while acetyl-L-carnitine was actually inhibitory. Possible mechanisms for the protective action of propionyl-L-carnitine against ischemia include an increased rate of cellular transport, stimulation of fatty acid oxidation, and a reduction of free radical formation.

Myocardial L-carnitine deficiency in a family of dogs with dilated cardiomyopathy.

Dilated cardiomyopathy in a family of dogs was found to be associated with decreased myocardial L-carnitine concentrations, when compared with those in control dogs. In 2 affected dogs, treatment with high doses of L-carnitine was associated with increased myocardial L-carnitine concentration and greatly improved health and myocardial function. Withdrawal of L-carnitine supplementation from these dogs resulted in development of myocardial dysfunction and clinical signs of dilated cardiomyopathy.

Plasma, tissue, and urine carnitine concentrations in healthy adult cats and kittens.

Mean carnitine concentrations [( carnitine]) were higher (P less than 0.05) in adult cats than in kittens for skeletal muscle (total and free carnitine), myocardium (free carnitine), and urine (total and free carnitine). The free/total carnitine ratio was lower (P less than 0.05) in kittens than in adults for liver, myocardium, and urine. Carnitine concentrations were similar between genders in kittens, but in adult cats, [carnitine] in plasma (total, free, and esterified carnitine) and liver (total and free carnitine) were higher (P less than 0.05) in female than in male cats. Total and free plasma [carnitine] were correlated to total and free liver [carnitine], respectively. Skeletal muscle [carnitine] was not correlated to plasma [carnitine]. Correlations in [carnitine] between plasma and myocardium, kidney, or urine were inconsistent.

Comparison of plasma, liver, and skeletal muscle carnitine concentrations in cats with idiopathic hepatic lipidosis and in healthy cats.

Concentrations of total, free, and esterified carnitine were determined in plasma, liver, and skeletal muscle from cats with idiopathic hepatic lipidosis and compared with values from healthy cats. The mean concentrations of plasma, liver, and skeletal muscle total carnitine; plasma and skeletal muscle free carnitine; and plasma and liver esterified carnitine were greater (P less than 0.05) in cats with idiopathic hepatic lipidosis than in control cats. The mean for the ratio of free/total carnitine in plasma and liver was lower (P less than 0.05) in cats with idiopathic hepatic lipidosis than in control cats. These data suggest that carnitine deficiency does not contribute to the pathogenesis of feline idiopathic hepatic lipidosis.

Metabolic alterations in end-stage and less severe heart failure--myocardial carnitine decrease.

Severe tissue carnitine deficiency impairs fatty acid oxidation. In explanted hearts from patients with end stage heart failure a 57% carnitine decrease was found in comparison with healthy donor hearts (p less than 0.05). The reduction of myocardial carnitine levels affected all areas of the explanted hearts to a comparable extent. Carnitine decreases in patients with dilated cardiomyopathy or coronary artery disease were similar. Endomyocardial biopsies from patients with less severe heart failure due to cardiomyopathy (n = 28) or other myocardial diseases (n = 8) showed a 42% decrease of total myocardial carnitine (in nmol/mg non-collagen protein) in comparison with biopsies from patients with normal cardiac function (controls) (heart failure: 5.7, confidence interval 4.2-7.0; controls 9.3, confidence interval 7.6-12.0, p less than 0.005). Free myocardial carnitine in heart failure was also different from controls (heart failure: 4.2, confidence interval 3.7-5.3; controls 10.3, confidence interval 7.5-12.2, p less than 0.001). The decrease of free and total myocardial carnitine was comparable in dilated cardiomyopathy and heart failure due to other diseases. Alterations in myocardial carnitine content represent therefore non-specific biochemical markers in heart failure with yet unknown consequences for myocardial function.

Defective myocardial carnitine metabolism in congestive heart failure secondary to dilated cardiomyopathy and to coronary, hypertensive and valvular heart diseases.

Reduced myocardial carnitine concentrations in the explanted heart and elevated plasma levels have been found in patients undergoing heart transplant for end-stage congestive heart failure (CHF). To evaluate a possible loss of myocardial carnitine in less severe stages of CHF, total myocardial carnitine levels were compared in right ventricular endomyocardial biopsies from 28 patients with mild, moderate and severe dilated cardiomyopathy, 8 patients with CHF of different origin and 13 normal control subjects. If possible, free myocardial carnitine and free and total plasma carnitine were also determined. For the first time, myocardial carnitine levels have been measured in endomyocardial biopsies from 13 normal human hearts (control values: 9.9 +/- 0.8 nmol/mg noncollagen protein). In comparison with these control values, total myocardial carnitine was significantly reduced in patients with dilated cardiomyopathy (6.1 +/- 0.5 nmol/mg noncollagen protein, p less than 0.0001), and CHF of other origins (6.6 +/- 1.1 nmol/mg noncollagen protein, p less than 0.02). Free myocardial carnitine concentrations in dilated cardiomyopathy (4.6 +/- 0.4 nmol/mg noncollagen protein) and CHF of different origin (4.4 +/- 0.5 nmol/mg noncollagen protein) were also significantly different from control values (control values: 9.7 +/- 0.7 nmol/mg noncollagen protein, p less than 0.0001 and p less than 0.005 for both groups). The loss of free and total myocardial carnitine was comparable in dilated cardiomyopathy and CHF due to other diseases. In contrast, plasma free and total carnitine levels in the CHF patients were significantly elevated (67 +/- 5.5 mumol/liter, control values 41 +/- 3.7 mumol/liter, p less than 0.005). Alterations in myocardial carnitine metabolism represent nonspecific biochemical markers in CHF with yet unknown consequences for myocardial function.

Fatal rhabdomyolysis following influenza infection in a girl with familial carnitine palmityl transferase deficiency.

Severe rhabdomyolysis following an influenza B infection developed in a previously well 13-year-old girl. There was no history of trauma. Her course was complicated by episodes of severe hyperkalemia, hypocalcemia, hyperphosphatemia, and myoglobinuria. Renal failure, hypertension, and life-threatening arrhythmias developed; she died. Muscle biopsy revealed that this girl had carnitine palmityl transferase deficiency. An asymptomatic sister was demonstrated to have the same disorder. Although carnitine palmityl transferase deficiency is usually associated with mild bouts of rhabdomyolysis that become apparent only in adulthood, severe forms of this disorder may be seen in children. Life-threatening rhabdomyolysis and myoglobinuria may follow any infection associated with decreased intake. If carnitine palmityl transferase deficiency is diagnosed in a proband, other siblings should be evaluated so that proper preventative measures can be undertaken to help prevent the development of symptoms in susceptible individuals who have not been recognized to have the disease.

The effects of caffeine on the ultrastructure and mitochondrial function of the embryonic chick heart.

Results from this study indicate that caffeine (at an embryotoxic dose equal to the LD40 administered to 3-day chick embryos produced both ultrastructural and functional abnormalities in embryonic cardiac mitochondria. The principal effects of caffeine on the ultrastructure of embryonic myocardial cells were clearly suggestive of cellular injury and included: (1) a marked disruption of mitochondrial cristae with formation of intramitochondrial myelin-like figures and (2) intracellular edema. A biochemical analysis of mitochondrial function revealed that caffeine inhibited the capacity of mitochondria to oxidize succinate. However, when pyruvate and malate were employed as substrates for isolated mitochondria, caffeine did not significantly alter mitochondrial function. Interference with embryonic cardiac mitochondrial succinate oxidation and/or fragmentation of mitochondrial membranes are suggested as possible events in the pathogenesis of caffeine-induced cardiac cell injury which, in turn, may lead to the embryonic death of the chick.

Ketogenic effects of carnitine in patients with muscular dystrophy and cytochrome oxidase deficiency.

The effects of a single oral dose of carnitine on fasting-induced ketosis was investigated in four normal individuals, five patients with muscular dystrophy, and one patient with a generalized cytochrome c oxidase deficiency. Plasma carnitine, free fatty acids, glucose, insulin, and glucagon were also measured. Normal individuals showed an average 0.09 mM increase in blood beta-hydroxybutyrate concentration during a 12- to 18-hr period of fasting and carnitine administration did not affect this response (average: 0.12 mM). Muscular dystrophy patients showed a greater fasting-induced elevation in beta-hydroxybutyrate (average 0.29 mM) and carnitine administration greatly enhanced this ketogenic response (average 0.84 mM). The cytochrome c oxidase deficient patient showed an even larger increase in beta-hydroxybutyrate with fasting (1.67 mM) and carnitine further augmented this ketotic effect (3.78 mM). Plasma free fatty acids were also elevated in patients that showed enhanced ketosis. Plasma glucagon concentration did not change, but insulin levels decreased during the 12- to 18-hr period of fasting; no major differences were found between controls and patients. These results indicate that some patients with muscular dystrophy and cytochrome c oxidase deficiency are more prone to develop ketosis than normal individuals and that carnitine administration enhances this response. Since both muscular dystrophy patients and the patient with cytochrome c oxidase deficiency had similar ketogenic responses, the data suggest that ketone body utilization may be impaired in these patients. The ability of L-carnitine to be ketogenic should be considered in the treatment of these patients.