Omega-3 fatty acid-based lipid infusion in patients with chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter trial.

BACKGROUND: Profound changes in the metabolism of eicosanoids with increased concentrations of free arachidonic acid (AA) and its proinflammatory metabolites have been observed in psoriatic lesions. Free eicosapentaenoic acid (EPA) may compete with liberated AA and result in an antiinflammatory effect. OBJECTIVE: Our purpose was to assess the efficacy and safety of intravenously administered fish-oil-derived lipid emulsion on chronic plaque-type psoriasis. METHODS: A double-blind, randomized, parallel group study was performed in eight European centers. Eighty-three patients hospitalized for chronic plaque-type psoriasis with a severity score of at least 15 according to the Psoriasis Area and Severity Index (PASI) participated in a 14-day trial. They were randomly allocated to receive daily infusions with either a omega-3 fatty acid-based lipid emulsion (Omegavenous; 200 ml/day with 4.2 gm of both EPA and docosahexaenoic acid (DHA); 43 patients) or a conventional omega-6-lipid emulsion (Lipovenous; EPA+DHA < 0.1 gm/100 ml; 40 patients). The groups were well matched with respect to demographic data and psoriasis-specific medical history. Efficacy of therapy was evaluated by changes in PASI, in an overall assessment of psoriasis by the investigator, and a self-assessment by the patient. In one center neutrophil 4- versus 5-series leukotriene (LT) generation and platelet 2- versus 3- thromboxane generation were investigated and plasma-free fatty acids were determined. RESULTS: The total PASI score decreased by 11.2 +/- 9.8 in the omega-3 group and by 7.5 +/- 8.8 in the omega-6 group (p = 0.048). In addition, the omega-3 group was superior to the omega-6 group with respect to change in severity of psoriasis per body area, change in overall erythema, overall scaling and overall infiltration, as well as change in overall assessment by the investigator and self-assessment by the patient. Response (defined as decrease in total PASI of at least 50% between admission and last value) was seen in 16 of 43 patients (37%) receiving the omega-3 emulsion and 9 of 40 patients (23%) receiving omega-6 fatty acid-based lipid emulsion. No serious side effects were observed. Within the first few days of omega-3 lipid administration, but not in the omega-6 supplemented patients, a manifold increase in plasma-free EPA concentration, neutrophil leukotriene B5 and platelet thromboxane B3 generation occurred. CONCLUSION: Intravenous omega-3-fatty acid administration is effective in the treatment of chronic plaque-type psoriasis. This effect may be related to changes in inflammatory eicosanoid generation.

Triglyceride hydrolysis of soy oil vs fish oil emulsions.

BACKGROUND: Fish oil triglycerides (TG) are being considered for use in IV lipid emulsions, but the characteristics of their lipase-mediated clearance from plasma are largely unknown. METHODS: We compared the in vitro hydrolysis of soy oil long-chain triglyceride emulsions (LCT) and fish oil emulsions (omega-3) using lipoprotein (LPL) and hepatic (HL) lipases, omega-3 emulsions contained 18% and 28% of total TG fatty acid as eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), respectively. RESULTS: Under conditions of maximal hydrolysis, total free fatty acid (FFA) release was two- to threefold greater with LCT compared with omega-3 emulsions. Also, EPA and DHA together contributed proportionally much less than other fatty acids (< 20%) to FFA released from omega-3 emulsions. In mixtures of LCT emulsion with omega-3 emulsions, the presence of > 20% of omega-3 particles substantially inhibited LCT emulsion hydrolysis (by up to 50%). CONCLUSIONS: Our results suggest that, during infusion of omega-3 emulsions, EPA and DHA may enter cells as TG or partial glycerides within emulsion particles and not as FFA and that coinfusion of omega-3 emulsion with LCT emulsion at low omega-3:LCT emulsion ratios (up to 20% of total triglyceride as omega-3) will not substantially inhibit LCT hydrolysis.

Alteration of n-3 fatty acid composition in lung tissue after short-term infusion of fish oil emulsion attenuates inflammatory vascular reaction.

OBJECTIVES: To investigate whether modulation of the fatty acid profile can be achieved by the short-term infusion of a fish oil emulsion which may attenuate the pulmonary response to inflammatory stimulation. Changes of fatty acid pattern in-lung tissue and perfusate were analyzed and correlated with physiologic data after a 3-hr infusion of fish oil in comparison with a soybean oil preparation. DESIGN: Prospective, randomized, controlled trial. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Forty standard breed rabbits of either gender. INTERVENTIONS: Isolated lungs from anesthetized rabbits were ventilated and recirculation-perfused (200 mL/min) with 200 mL of cell-free buffer solution to which either 2 mL of saline (control, n = 6), 2 mL of a 10% soybean oil preparation (n = 6), or 2 mL of a 10% fish oil emulsion (n = 6) were added. Samples of perfusate and lung tissue were collected for analysis of fatty acid composition. Tissue and perfusate fatty acid composition were analyzed by capillary gas chromatography. To study metabolic alterations in states of inflammatory stimulation, lungs of each group were stimulated with small doses of the calcium ionophore, A23187 (10(-8) M), during the 180-min lipid perfusion period and again after washing out the lipids by exchanging the perfusion fluid. Pulmonary arterial pressure and lung weight gain were monitored, and eicosanoids were analyzed in the perfusate. MEASUREMENTS AND MAIN RESULTS: Free eicosapentaenoic acids increased several-fold in lung tissue and perfusate during a 3-hr infusion with fish oil. The intravenously administered n-3 fatty acids were rapidly hydrolyzed, as indicated by the appearance of substantial quantities of eicosapentaenoic acid in the perfusate free fatty acid fraction. This increase of perfusion levels of eicosapentaenoic acid was paralleled by an attenuated pressure increase and edema formation due to calcium ionophore challenge and an altered eicosanoid spectrum determined in the perfusate compared with soybean oil-treated lungs. CONCLUSION: Short-term n-3 lipid application (fish oil emulsion) exerts anti-inflammatory effects on lung vasculature, which may be due to the metabolism of eicosapentaenoic acid resulting in the generation of less potent inflammatory eicosanoids.

Modulation of pulmonary vascular resistance and edema formation by short-term infusion of a 10% fish oil emulsion.

BACKGROUND: The aim of this study was to investigate whether the pulmonary response to inflammatory stimulation, resulting in increased vascular resistance and permeability, could be attenuated by short-term infusion of triglycerides containing omega-3 fatty acids. With the concept of altering the composition of membrane phospholipids in such a manner that stimulation resulted in the release of less vasoconstrictive and permeability-enhancing metabolites of eicosapentaenoic acid instead of those of arachidonic acid (AA), the parenteral application of a lipid emulsion prepared from fish oil (Omegavenös) was tested in comparison with a soy oil preparation (Lipovenös). METHODS: Isolated lungs from anesthetized rabbits were ventilated and recirculatingly perfused (200 ml/min) with 200 ml cell-free buffer solution to which either 2 ml saline (controls, n = 6), 2 ml Lipovenös 10% (n = 6) or 2 ml Omegavenös 10% (n = 6) were added. To study the possible metabolic alterations in states of an enhanced AA turnover, lungs of each group were stimulated with smaller doses of A23187 (10(-8) M) during the 180-min lipid perfusion period, followed by a 10 times higher calcium ionophore A23187 (10(-7) M) challenge after washing out the lipids by exchange of perfusion fluid. Pulmonary artery pressure (PAP) and the lung weight gain indicating edema formation were monitored, and eicosanoids were analyzed in samples of the perfusate. RESULTS: Upon A23187 injection lung weight gain and PAP increase were significantly reduced (50%) in Omegavenös-perfused lungs in comparison with controls and Lipovenös treatment. The vascular reactions were accompanied by a shifting from LTC4 to LTC5 during and after Omegavenös perfusion. CONCLUSION: The data demonstrate that omega-3 fatty acids seem to be incorporated into the phospholipid pool of the pulmonary tissue, even after short-term infusion (3 h) resulting in an attenuated pressure reaction and edema formation due to an altered spectrum of metabolites in the case of inflammatory stimulation.

Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis.

N-3 fatty acids were supplied to a 36-year-old female patient suffering from ulcerative colitis and severe steroid side-effects, in a sequence of parenteral and enteral administration. During a moderately active period of disease, 200 ml d-1 fish oil-derived lipid emulsion (eicosapentaenoic acid [EPA], 4.2 g; docosahexaenoic acid [DHA], 4.2 g) was infused for 9 days, in parallel with rapid tapering of the steroid dose. Disease activity declined rapidly, and the patient was subsequently provided with 16 fish oil capsules per day (EPA, 2.9 g; DHA, 1.9 g) for 2 months. At the end of this period of therapy, severe colitis recurred with intestinal and extraintestinal manifestations. The n-3 lipid emulsion was then used for intravenous alimentation (29 days, maximum dose 300 ml per day); during this time, marked improvement of the inflammatory bowel disease was noted. During both periods of parenteral n-3 lipid administration, total plasma EPA and DHA contents increased several-fold, surpassing that of arachidonic acid; this plasma n-3 fatty acid enrichment was only maintained to a minor extent during the intermediate period of dietary fish oil supplementation. The intravenously administered EPA-containing triglycerides were rapidly hydrolyzed, as evidenced by the appearance of substantial quantities of EPA in the plasma free fatty acid fraction. Platelet and neutrophil total membrane content of EPA and DHA as well as n-3 fatty acid/AA membrane ratios similarly increased during the periods of intravenous n-3 lipid administration and declined during oral fish oil uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis. Rapid improvement of clinical manifestations and changes in neutrophil leukotriene profile.

Twenty patients hospitalized for acute psoriasis guttata with a minimum 10% of body surface area involvement (range 10-90%) completed a 10-day trial in which they were randomly allocated to receive daily infusions with either an n-3 fatty acid based lipid emulsion [100 ml/day with 2.1 g eicosapentaenoic (EPA) and 21 g docosahexaenoic acid (DHA)] or a conventional n-6 lipid emulsion (EPA + DHA < 0.1 g/100 ml). The severity of disease was evaluated by scoring daily erythema, infiltration, and desquamation and by a subjective scoring of clinical manifestations offered by the patients. Leukotriene (LT) and platelet-activating factor (PAF) generation were investigated in ionophore-stimulated neutrophils obtained on days 0, 1, 3, 5, 10, and 40. Moderate improvement in clinical manifestations was noted in the n-6 group (changes in score systems between 16-25% from baseline within 10 days). In contrast, the severity of disease markedly decreased in all patients of the n-3 group, with improvements in all score systems ranging between 45% and 76% within 10 days (P < 0.05 for each variable). The difference in response to the two regimens was evident within 4-7 days after onset of lipid infusion. A more than ten fold increase in neutrophil EPA-derived 5-lipoxygenase product formation (LTB5, its omega-oxidation products, non-enzymatic degradation products of LTA5 and 5-hydroxyeicosapentaenoic acid) was noted in the n-3 group but not in the n-6 group. Neutrophil PAF generation increased in the n-6 group but decreased in the n-3 group. In conclusion, modulation of eicosanoid metabolism by intravenous n-3 fatty acid supplementation appears to exert a rapid beneficial effect on inflammatory skin lesions in acute guttate psoriasis.

Influence of a single parenteral application of a 10% fish oil emulsion on plasma fatty acid pattern and the function of thrombocytes in young adult men.

50 ml of a 10% fish oil emulsion (41% omega-3 fatty acids of total fatty acids) were infused for 1 h into the arm vein of young, healthy, male volunteers. The fatty acid composition of the plasma, aggregation of the blood platelets as well as the thromboxane synthesis, were measured before the beginning of infusion, 20, 60, 120, 360 and 1,440 min after the start of the fat infusion. In the first 60 min, the fatty acid composition of the plasma changed in correspondence with the supplied fatty acid pattern. At the end of the investigation it was again within the normal range. As a result of fat application thromboxane synthesis was reduced and the aggregation of the platelets was inhibited but it was normalized by the 1,440-min value. Fish oil emulsions might be beneficial for parenterally fed patients with a high risk of thrombosis. Therefore the performance of further investigations using a varying dosage and multiple application can be recommended.

[Elimination of fat emulsions of various concentrations from the blood. Observational study in the intravenous administration of Lipovenös 10% and 20% in premature infants with very low birth weight]. / Elimination von Fettemulsionen unterschiedlicher Konzentration aus dem Serum. Beobachtungsstudie zur parenteralen Gabe von Lipovenös 10% und Lipovenös 20% bei Frühgeborenen mit sehr niedrigem Geburtsgewicht.

Within the scope of an observation study 40 premature low birth weight infants requiring parenteral nutrition received either 10% or 20% lipid emulsions (Lipovenös) for 7 days. The 10% lipid emulsion differs from the 20% lipid emulsion in the higher phospholipid/triglyceride-ratio (0.06 resp. 0.12). Lipid infusion was commenced at 0.5 g triglyceride/kg/24 hours and increased steadily to 2 g triglyceride/kg/24 hours. The aim of the study was to compare the effects of the two intravenously administered lipid emulsions on serum clearance. The serum concentrations of triglyceride and cholesterol did not change significantly during the infusion with 20% Lipovenös. Significant increases in the triglyceride and cholesterol content were observed only in the serum of the patients who were given the 10% Lipovenös. The reduced lipid serum clearance is attributable to the higher content of phospholipids in the 10% lipid emulsion. With regard to the risk of high cholesterol concentrations and an abnormal LPX serum accumulation, administration of 20% lipid emulsion is preferable to 10% lipid emulsion, also during the neonatal period.

Effects of high carnitine supplementation on substrate utilization in low-birth-weight infants receiving total parenteral nutrition.

Parenterally fed preterm neonates are known to be at risk for carnitine deficiency. We studied substrate utilization in low-birth-weight infants receiving total parenteral nutrition (TPN) with (A) and without (B) supplementation of 48 mg carnitine.kg-1.d-1 on days 4-7 (birth weights 1334 +/- 282 vs 1318 +/- 248 g, gestational age 32 +/- 2 vs 32 +/- 2 wk, A vs B, respectively). TPN consisted of 11 g glucose.kg-1.d-1 and 2.4 g.kg-1.d-1 of both protein and fat. Plasma carnitine concentrations at day 7 were for free carnitine 11.8 +/- 5.0 vs 164 +/- 56 mumol/L and for acyl carnitine 3.8 +/- 2.0 vs 33.9 +/- 15.4 mumol/L, respectively. Indirect calorimetry at day 7 showed a higher fat oxidation (0.21, -0.31 to +0.60 vs 1.18, 0.70 to 1.95 g. kg-1.d-1, respectively, P less than 0.02, median and interquartile range) in group B and a higher protein oxidation (0.37, 0.30-0.43 vs 0.63, 0.53-0.88 g.kg-1.d-1, P less than 0.001). The time to regain birth weight was also higher in group B (7, 5.5-9 vs 9, 7-14 d, P less than 0.05). Carnitine supplementation and calorie intake were the best explanatory variables for metabolic rate (R2 = 0.45, P less than 0.002). We conclude that carnitine supplementation of TPN in this dosage does not seem advisable.

Effects of an intravenous application of dl-alpha-tocopheryl acetate on tocopherol status in man.

The effects of intravenously administered dl-alpha-tocopheryl acetate on the plasma, erythrocyte and thrombocyte vitamin E levels were investigated in male subjects. 110 mg dl-alpha-tocopheryl acetate were applied as a single dose in the form of a rapid infusion. After 60 min, 89% of the dl-alpha-tocopheryl ester had been eliminated. The vitamin E ester injected was hydrolyzed and was detected in the plasma and the erythrocytes as free alpha-tocopherol. No significant change in the tocopherol concentration was observed in the thrombocytes. The results show that intravenously applied, esterified tocopherol is hydrolyzed relatively rapidly in the plasma, leading to an increase of free alpha-tocopherol content in the plasma and erythrocytes. The ratio of erythrocyte/plasma tocopherol 2 h after injection was 61% higher than the initial value; after 24 h the elevation was still 36%.

[Effect of various combinations of DL-alpha-tocopherol and acetylsalicylic acid on adjuvant arthritis in the rat]. / Einfluss verschiedener Kombinationen von DL-alpha-tocopherol und Acetylsalicylsäure auf die Adjuvansarthritis der Ratte.

The influence of per os application of different combinations of DL-alpha-tocopherol (TOC) and acetylsalicylic acid (ASS) on adjuvant-induced arthritis was tested in male Wistar rats (body weight 227 +/- 18 g; 8 groups, n = 8). One group (control) was without adjuvans arthritis and received no treatment, another group was also not treated in spite of adjuvans arthritis. Further, six groups of adjuvans arthritis were treated with the following combinations: ASS/TOC (mg/kg BW/d each) 250/-, 250/250, 167/250, 83/250, 167/167 and 167/83. During the course of the experiment (21 d), body weights, food intake, and the swelling of injected and noninjected paws, and (at the end of the test period) relative weight of spleen and the albumin-globulin-ratio in plasma were recorded. With the ASS/TOC combination of 250 mg/kg BW each, the highest antiinflammatory effect could be reached, as compared with all treated groups. The reduction of acetylsalicylic acid does by one-third to 167 mg/kg BW in combination with 250 mg DL-alpha-tocopherol/kg BW seem to have the same antiphlogistic effect as acetylsalicylic acid alone at 250 mg/kg BW. This positive effect could be confirmed by the partially normalized relative spleen weight and albumin-globulin-ratio. The results allow the conclusion: --main antiphologistic effect of the combination is due to acetylsalicylic acid; --when combined with 250 mg DL-alpha-tocopherol/kg BW acetylsalicylic acid dosage can be reduced by one-third to 167 mg/kg BW and still have the same effect as ASS alone (250 mg/kg BW); --further reductions of ASS and/or DL-alpha-tocopherol dosage minimize the antiinflammatory effect.

[Effect of vitamin E on experimental inflammation in rats]. / Untersuchungen über den Einfluss von Vitamin E auf eine experimentelle Entzündung an Ratten.

Besides other mediators like prostaglandins, kinins and histamine, oxygen radicals potentiate inflammations. Vitamin E as natural antioxidant could scavenge radicals produced during an inflammation and therefore reduce the inflammatory response. In experiments with male Wistar rats maintained on a diet deficient in or supplemented with vitamin E for 6 weeks the influence of the administration of DL-alpha-tocopherol on the inflammation of the right hind paw was tested. The irritation produced by injection of Freund's complete adjuvants was observed for 21 days. Measuring the thickness of the paw and the activity of acid phosphatase in the paw tissue there was no difference in the intensity of inflammation among the control and the vitamin-E-deficient diet groups. The supplementation with a pharmacological dose of tocopherol (324 mg DL-alpha-tocopherol/100 g food) had no effect on the inflammation of animals with different vitamin E supplements. Differences in the antioxidant status (contents of tocopherol and malondialdehyde in several organs, activity of creatine kinase in plasma) among the groups were mainly linked to the various tocopherol supplies. The irritation increased the lipid peroxidation in liver mitochondria and the activity of creatine kinase in the plasma. The data show no influence of vitamin E on this kind of inflammation.

[Effect of linoleic acid administration on plasma- and liver lipids. Determination of linoleic acid requirements]. / Einfluss der Linolsäurezufuhr auf Plasma- und Leberlipide. Ein Beitrag zur Ermittlung des Linolsäurebedarfs.

In order to estimate the linoleic acid requirement of the rat, four groups of weanling male Wistar-Rats, 18 animals each, were fed isoenergetic semi-synthetic diets containing 14 cal% fat. The linoleic acid content (as linoleic acid methyl ester) amounted to 0; 0.5; 1.3 and 4.0% of total energy intake. The experiment lasted 14 weeks. The parameters analysed were the concentrations of total lipids (TL), free cholesterol (Ch), cholesterol esters (ChE), triglycerides (TG) and phospholipids (PL) in plasma and liver. - Clinical signs of linoleic acid deficiency were only found in the rats fed the linoleic acid free diet. With 0.5 cal% linoleic acid in the diet no deficiency symptoms were observed. - In plasma of the linoleic acid deficient animals the concentrations of TL, Ch, ChE and TG were decreased. Plasma PL contents were insignificantly altered. - While the contents of TL, TG and ChE in the liver of the deficient rats increased significantly, those of PL and Ch were hardly affected. The results show that a linoleic acid supply of 0.5 cal% prevents nearly all alterations of plasma and liver lipid concentrations noticed in linoleic acid deficiency. The effect of this dose was as good as that of 1.3 cal% linoleic acid. Therefore we assume that the minimum requirement of male young rats for linoleic acid is markedly less than 1,3% of total energy intake.