Protection of rat heart from damage due to ischemia-reperfusion during procurement and grafting by defibrotide.

We studied the efficacy of defibrotide, a prostacyclin-stimulating agent, in preventing ischemia reperfusion injury in Wistar rat heart by using three experimental models: (1) hearts from donors were perfused with the drug (32 mg/kg/hr) during 15, 30, 45, and 60 min of cold ischemia following 5, 10, and 15 min of warm ischemia; (2) hearts from donors treated with the drug were cold-stored for 12 or 24 hr; and (3) procured hearts perfused with the drug were isografted, after 30 or 60 min of warm ischemia, in recipient rats treated daily with defibrotide. Hearts perfused with saline and/or vehicle of the drug were used as controls. At the end of established ischemia times, and after 30 min, and 2, 4, 7 and 14 days from transplantation, hearts were rapidly cooled in liquid nitrogen. ATP, ADP, AMP, cAMP contents, and NAD+/NADH ratios were evaluated in prepared tissue extracts. Cardiac ATP and ADP levels and NAD+/NADH ratios were significantly higher in defibrotide-treated organs than in controls. Isografted defibrotide-treated hearts were also significantly preserved, with respect to controls, from the loss of ATP levels until rejection occurred. Our results demonstrate the protective activity of the drug against the myocardial metabolic damage due to ischemia-reperfusion.

Is carnitine essential in children?

Carnitine has a fundamental biological role as a long-chain fatty acid carrier across the mitochondrial membrane and in ketone body formation. Although the body normally synthesizes carnitine, in certain circumstances such as total parenteral nutrition and haemodialysis a dietary supplement may be needed to maintain adequate levels. Several considerations suggest that carnitine is a truly essential nutrient in infancy and in other situations where the energy requirement is particularly high, e.g. pregnancy and breast feeding. There are, for example, congenital deficit syndromes due to enzymatic inadequacies. There is also the possible role of carnitine in serious metabolic disorders such as organic acidaemias and, above all, it has multiple physiological functions in major metabolic pathways which are essential for development and growth.

The role of lipids in nutrition during the first months of life.

The most important functional components of dietary lipids (triglycerides, cholesterol esters and phospholipids) are fundamental to normal growth and development of infants. Fatty acids are classified according to their chain length and their degree of saturation. Each class of fatty acid is involved in specific metabolic reactions: short-chain fatty acids act as local growth factors in the colon; medium- and saturated long-chain fatty acids are a good source of energy; polysaturated long-chain fatty acids are involved in metabolic regulation; and very long-chain fatty acids are important structural components of membranes. The development of the central nervous system depends on the amount and the quality of the lipid supply in the last months of prenatal and the first months of postnatal life. Placental cord blood during foetal life and breast milk provide fatty acids in the correct amounts and ratios. Fats in breast milk provide half the infant's calorific needs and maternal dietary habits can influence the lipid composition of milk. The preparation of blends of fats for formulas is under investigation in order to improve the lipid quality and to make formulas more similar to breast milk. A major goal of current research is to define the nutritional and metabolic relationships between fatty acid groups and between fats and the other dietary sources of calories in order to improve the composition of infant formulas, in particular for premature babies.

Prostacyclin release from endothelial cells, induced by defibrotide treatment, favours the function of grafted rat hearts and kidneys.

Defibrotide, a single-stranded DNA fraction obtained from mammalian lungs and able to increase prostacyclin production by endothelial cells, has been shown to be efficient in protecting rat organs (heart, kidney and liver) from ischaemic damage. We studied the efficacy of the drug in preserving the function of rat heart and kidney submitted to isotransplantation. Defibrotide was administered to donor Wistar rats at the dose of 32 mg/kg in 1.5 ml of saline. Heart and kidney were isolated and cold-preserved in buffered phosphate medium and continuously infused with defibrotide (32 mg/h) through the innominate or renal artery. Recipient Wistar rats were treated with defibrotide before and after transplantation at the dose of 32 mg/kg/day. Controls were treated with the vehicle of the drug. The function of isografted organs was evaluated at 12 and 24 h and at 2, 4 and 7 days from grafting. Heart function was evaluated by studying creatinine phosphokinase (CPK) and lactic dehydrogenase (LDH) activities of myocardial tissue. Renal function was evaluated by studying serum creatinine and urea levels of kidney-grafted rats. CPK and LDH activities were found to be significantly higher in defibrotide-treated rats than in controls. Creatinine and urea levels remained significantly lower in defibrotide-treated rats than in the controls. The results of the present work indicate that defibrotide treatment is useful to maintain the functionality of grafted hearts and kidneys.

Defibrotide, a stimulator of prostacyclin (PGI2) production, prevents the effects of ischaemic damage.

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, has been demonstrated to exert profibrinolytic and antithrombotic activity through stimulation of vascular prostacyclin (PGI2) production. We studied the effect of defibrotide administration in protecting liver and heart from ischaemic and postischaemic reperfusion damage. Defibrotide was administered as an i.v. bolus (30 mg/kg) at the beginning of liver ischaemia and at the same dose continuously during 60 min of postischaemic reperfusion. ATP levels were significantly improved in livers of defibrotide-treated rats as compared to those obtained in livers of rats treated with vehicle of the drug. Intrahepatic cytoplasmic and mitochondrial NAD+/NADH ratios were higher in defibrotide-treated than in vehicle-treated animals. The hearts, isolated from rats according to the transplantation procedure, were subjected to different times of warm + cold ischaemia. During ischaemia, the hearts were perfused continuously with 60 mg/kg of defibrotide or vehicle of the drug. The loss of creatine phosphokinase and lactate dehydrogenase activities due to an increased ischaemia time was limited in defibrotide-perfused hearts. Intracardiac ATP and ADP levels were significantly higher in defibrotide-treated organs than in controls. Our results demonstrate the efficacy of defibrotide in protecting liver and heart from ischaemia.

Are increased ATP blood levels responsible for PGI2 release from endothelium?

Defibrotide, a polydeoxyribonucleotide with profibrinolytic and antithrombotic properties obtained from mammalian lungs was shown capable of favoring the release of prostacyclin from endothelial cells. We previously evidenced that the use of defibrotide i.p. (32 mg/kg for 30 min) or orally (50 mg/kg for 1 h) induced a significant increase in 2,3-diphosphoglycerate (2,3-DPG) content of blood cells in rats. We tested the in-vivo capacity of defibrotide to modify over 90 min the blood content of ATP, cAMP and 2,3-DPG. Male Wistar rats were anaesthetized with pentobarbital (20 mg/kg) i.p.; the left carotid artery was cannulated with a polyethylene tube, from which 0.4 ml of blood was drawn at 0, 5, 10, 15, 20, 30, 40, 50, 60 and 90 min. At 0 min, defibrotide was administered i.p. or i.v. (through the femoral vein) at the dose of 1 ml containing 80 mg of drug or orally at the dose of 1 ml containing 160 mg of drug. The control rats employed received either the vehicle of the drug or physiologic saline. Our results demonstrated a significant drug-related increase with time (maximal levels were revealed about 20 min after i.v., i.p., or oral defibrotide treatment) of blood ATP content and a significant decrease in cAMP content as compared with the controls. Our data confirm the relation between increased drug-induced prostacyclin production and that of ATP of in blood.

[Defibrotide in the prevention of deep venous thrombosis in gynecologic surgery. A controlled study versus calcium heparin in 120 patients]. / Il defibrotide nella prevenzione della trombosi venosa profonda in chirurgia ginecologica. Studio controllato vs eparina calcica in 120 pazienti.

The efficacy of defibrotide and calcium heparin in the prevention of Deep Vein Thrombosis (DVT) in gynecological surgery were compared in a randomized study. Seventy patients candidate to gynecological surgery (for benign conditions) and 50 candidate to surgery for malignancies were randomly allocated either to defibrotide (400 mg b.i.d. IM from the day before operation to the 7th postoperative day, n = 60) or to calcium heparin (5000 IU t.i.d. SC from the operation to the 7th postoperative day, n = 70). The diagnosis of DVT was made with impedance plethysmography and if necessary confirmed with phlebography. No patient developed established DVT in either groups and no adverse reactions were observed. These results indicate that defibrotide may be considered as an alternative to heparin in the DVT prophylaxis in gynecological surgery.

[Fatty acid metabolism and requirements in childhood]. / Metabolismo e fabbisogno di acidi grassi in età pediatrica.

The metabolism of fatty acids (FA) has a profound impact on the development of the human being. In fact, the lipidic composition of membranes may be modulated by the relative concentrations of available FA. During the last months of the fetal life, an increasing concentration of polyunsaturated very long-chain (VLC) FA is observed from the umbilical cord to the liver and the central nervous system, where they contribute to the qualitative development of the nervous membranes. Therefore, the preterm baby is at particular risk of polyunsaturated VLCFA deficiency. Among polyunsaturated VLCFA, 20:4 n-6 and 22:6 n-3 carry on fundamental roles respectively for cellular growth and visual development. The accretion of VLCFA in the human body is intense also in the term infant during the first months of life. In the period of exclusive milk-feeding fat represents 50% of the daily caloric intake, and the ketonic bodies, resulting from the incremented beta-oxidation of FA, are readily utilized as source of energy by the developing brain. Weaning is now object of study to precise both metabolic needs and dietary intakes of FA families. Recent surveys have revealed that in this period the intakes of linoleic and linolenic acid are at the lower limits of the recommended levels. No upper limit for saturated FA is advisable for the first two years of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine-induced insulin release in rats is related to an increase in plasma lipid levels.

We studied the modifications of plasma lipid levels induced by cyclosporine (CsA), streptozocin (STZ) or both drugs in rats. Male Wistar rats (RT1y) were administered i.p. with CsA or STZ or both at the dosage of 15 mg/kg daily for 8 days and were sacrificed on day 9. Total lipid, triglyceride and total cholesterol plasma levels were measured. The plasma total lipid content was significantly increased in CsA-treated and in CsA + STZ-treated rats with respect to controls (662 +/- 29 and 632 +/- 32, respectively, vs 472 +/- 27 mg/dl). The triglyceride content was significantly higher in CsA-treated and in CsA + STZ-treated animals than in controls (137 +/- 8.7 and 188 +/- 14.1, respectively, vs 79 +/- 7.7 mg/dl). The total cholesterol level was not significantly different in CsA- and STZ-treated rats with respect to controls. CsA-treated and STZ-treated rats concomitantly revealed a significant impairment of glucose tolerance. In fact, 150 min after orogastric administration of 350 mg glucose, glycaemia was significantly more elevated in treated animals than in controls. We conclude that the increase in lipid levels induced by CsA treatment could be related to drug-induced damage to the pancreas islets, as shown by the early insulin release and fatty tissue degeneration.

Reduced plasma C-20 and C-22 polyunsaturated fatty acids in children with phenylketonuria during dietary intervention.

The fatty acid composition of plasma and erythrocyte lipids was analyzed in 15 children with phenylketonuria (aged 3 to 12 years) during dietary treatment aimed to maintain plasma phenylalanine levels at less than 8 mg/dl (485 mumol/L), and compared with those of 12 matched control subjects. The diet of children with phenylketonuria provided less protein, with a very low proportion of animal proteins, less fat, but a higher proportion of linoleic acid as a percentage of calories, and a higher carbohydrate content versus that in the diet of control subjects. The children with phenylketonuria had higher plasma levels of oleic acid but lower levels of arachidonic (n-6) and n-3 fatty acids. Linoleic and eicosatrienoic (n-9) acid levels were the same in both groups. These changes in patients with phenylketonuria resemble those observed in vegetarians and may be due to the absence of preformed arachidonic acid and long-chain n-3 fatty acids in the phenylketonuric diet.