Cyclosporin A in fat emulsion carriers: studies on the immunosuppressive potential,using the heterotopic heart transplant model in rats

Cyclosporin A (CyA) is an extremely lipophilic drug that needs a solubilizing agent to become soluble in water. In the commercially available intravenous formulation-Sandimmun-Cremophor EL is used for this purpose. It is likely that Cremophor EL contributes to some of the side effects produced by i. v. Sandimmun. We have recently shown that if Cremophor EL is replaced by a soybean oil (SBO)-based fat emulsion carrier, the acute renal side effects following i. v. administration of CyA are avoided in a rat model. It is then important to ascertain whether the use of a fat emulsion carrier alters the immunosuppressive effect of CyA. Moreover, fatty acids can themselves influence the immune system, and both omega-3 and omega-6 fatty acids have been reported to possess immunosuppressive properties. In the present study, the effect on graft survival of i. v. CyA administered in five different formulations, using fat emulsions or liposomes as carriers, was compared to that of conventional Sandimmun infusion substance in the heterotopic heart transplant model in rats. The new formulations tested did not reduce the immunosuppressive effect of CyA. On the contrary, a small but significant increase in graft survival was noted in the groups given CyA in the SBO-based fat emulsion carrier (17.0±0.82 days) and CyA in liposomes (16.0±0.63 days) as compared to the results in the Sandimmun-treated group (15.0±0.58 days: P<0.01 and P<0.05, respectively).     

n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner

Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet-induced insulin resistance through peroxisome proliferator-activated receptor (PPAR)-alpha activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-alpha null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-alpha null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-alpha null safflower oil-fed mice). In PPAR-alpha null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet-induced hepatic insulin resistance in a PPAR-alpha-and diacylglycerol-dependent manner.     

Improved survival of heterotopic cardiac allografts in rats with dietary n-3 polyunsaturated fatty acids

A heterotopic cardiac transplant model, with male Fischer 344 rats as donors and Long Evans rats as recipients, was utilized to investigate the effect of dietary n-3 polyunsaturated fatty acids on acute rejection. Both donor and recipient rats were fed purified diets high in either n-3 polyunsaturated fatty acids (from concentrated n-3 ethyl esters [EE] or fish oil [FO]) or n-6 polyunsaturated fatty acids (from corn oil [CO]) for either 2-3 or 3-4 weeks before transplant. The recipient rats continued on their diets until rejection. The AIN-76A-based diets (with 30% of calories as fat) had adequate essential fatty acids and were balanced for sterols and antioxidants. Allograft survival was significantly increased by 45% when recipient rats were fed EE as compared to the control (CO diet fed to both donor and recipient), regardless of the diet fed to the donor. There was a slight but significant increase in allograft survival when only donor rats were fed the EE diet 2-3 weeks before transplant. With the FO diet (containing one third of the n-3 fatty acids in the EE diet), only the group fed FO to both donor and recipient (starting 2-3 weeks before transplant) showed a significant increase in allograft survival over the control. However, if the FO diets were fed for 3-4 weeks before transplant, increased survival was seen in groups fed FO to either the donor or recipient alone. In this case, allograft survival with FO feeding to both donor and recipient was not different from recipient treatment alone. In all the studies there was a significant and direct correlation between allograft survival and the donor heart phospholipid n-3/n-6 fatty acid ratio and the n-3 fatty acid content (at rejection). There was an indirect relationship with the n-6 fatty acid content. There was no detectable 20:3 (n-9) in the cardiac phospholipids, indicating the absence of essential fatty acid deficiency. Recipient diets were the strongest determinant of the fatty acid composition in the transplanted donor heart. The data indicate that providing dietary n-3 polyunsaturated fatty acids before and after cardiac transplant to recipient animals provides a significant protection against acute rejection.     

Evaluation of fat nutrition in the energy intake on low protein diets for patients with chronic renal failure]

Low protein diet has been proven to retard the progression of chronic renal failure. In this diet, the energy intake depends mainly on fats and carbohydrates instead of protein, and precautions should be taken against increasing risks of both lipid nephrotoxicity and atherosclerosis. In order to assess the adequacy of fat nutrition in a low protein diet for patients with chronic renal failure, we evaluated the total amounts of dietary fat intake, dietary individual fatty acid intake and serum individual fatty acid concentrations in 16 patients, whose mean creatinine clearance was 21.3 +/- 12.1 ml/m, serum creatinine 3.8 +/- 2.2 mg/dl and serum urea nitrogen 41.5 +/- 18.6 mg/dl. The percentage ratio of fat intake to total energy intake was 26.7 +/- 5.2%. The ratio of intake of saturated fatty acids, monounsaturated fatty acids and polyunsaturated fatty acids was 1:2:1.8, and n-6/n-3 was 8.5 +/- 9.3. These were significant correlations between dietary intake and the serum concentrations in both EPA and the ratio of EPA/AA. Consequently, it might be considered that polyunsaturated fatty acids intake should be lowered and patients with chronic renal failure on a low protein diet should be advised about the proper selection of foods containing animal protein and plant-derived oil. It may be beneficial to recommend the intake of more EPA and lowering the ratio of n-6/n-3 intake might be useful in improving the fat nutrition to adequate levels in these patients.     

Fatty acid intake and Kupffer cell function: fish oil alters eicosanoid and monokine production to endotoxin stimulation

Diets high in n-3 fatty acids appear to have an anti-inflammatory effect, which is thought to be due to decreased macrophage prostaglandin (PG) and thromboxane (Tx) production after incorporation of these fatty acids into cell membrane phospholipids. The effect of n-3 fatty acids incorporation on macrophage monokine release in response to septic stimuli is not well established. Kupffer cells, the fixed macrophages of the liver, were obtained from rats fed diets with fat sources derived from corn oil (CO, control), fish oil (FO, high in n-3 fatty acids), or safflower oil (SO, high in n-6 fatty acids) for 2 or 6 weeks. After exposure to bacterial lipopolysaccharide, Kupffer cells from rats fed FO for 2 or 6 weeks produced less PG and Tx than Kupffer cells from rats fed CO or SO. After 2 weeks of defined diets, interleukin-1 (IL-1) and tumor necrosis factor release were not affected by dietary fat source. In contrast, after 6 weeks of feeding, Kupffer cells from both the FO and the SO groups released less IL-1 and tumor necrosis factor when triggered by lipopolysaccharide than Kupffer's cells from animals fed the control diet that contained CO. These data suggest that altered monokine release from macrophages may contribute to the anti-inflammatory effect of diets high in n-3 fatty acids. Also shown in our results is that prolonged changes in membrane phospholipid content induced by dietary fat source can influence not only PG and Tx production but monokine release as well.     

Impact of dietary fatty acid supplementation on renal injury in obese Zucker rats

We previously reported that renal injury in hyperlipidemic, obese Zucker rats was associated with a relative deficiency of tissue polyunsaturated fatty acids (PUFA). In the present study 10-week-old obese Zucker rats were pair fed regular chow or chow containing either 20% sunflower oil rich in n-6 PUFA, fish oil rich in n-3 PUFA, coconut oil medium-chain saturated fatty acid, or beef tallow long-chain saturated fatty acid. At 34 weeks of age there were comparable reductions in albuminuria, mesangial matrix expansion, and glomerulosclerosis in the fish oil and sunflower oil groups. While both fish oil and sunflower oil reduced serum triglycerides, and improved the composition of triglyceride-enriched lipoproteins, only fish oil decreased serum cholesterol. The effect of the dietary fatty acid supplementation on fatty acid profiles were similar in isolated glomeruli and cortical tissue. In general, the amelioration in injury in the fish oil and sunflower oil fed rats was most closely linked to glomerular levels of PUFA, either n-6 or n-3. These data suggest that hyperlipidemia and abnormalities in tissue FA are closely linked, and that dietary supplementation with PUFA may ameliorate chronic, progressive renal injury.     

Dose response of fish oil versus safflower oil on graft arteriosclerosis in rabbit heterotopic cardiac allografts.

With the advent of cyclosporin A, accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil, the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2, 3, and 4 animals received a daily supplement of low- (0.25 mL/kg/day), medium- (0.75 mL/kg/day), and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL), respectively. Group 5, 6, and 7 animals were supplemented with equivalent dose of safflower oil (i.e., 0.25, 0.75, and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted, morphometric planimetry. When the animals were killed, cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages, fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals, there was a trend for more graft vessel disease with increasing fish oil dose, as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group, animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%, p less than 0.017) and intimal thickness (7.9 +/- 1.9 microns versus 34.0 +/- 13.0 microns, analysis of variance: p = 0.054). Low-dose safflower oil also had a slight, but nonsignificant, beneficial effect on graft vessel disease when compared to control rabbits. The same trends were observed in the degree of histologic rejection (0 = none to 3 = severe) in fish oil- and safflower oil-treated animals. Rejection score correlated weakly but significantly (p = 0.0001) with mean luminal occlusion (r = 0.52) and intimal thickness (r = 0.46). Therefore allograft coronary disease in this model appeared to exhibit an unfavorable, direct-dose response to fish oil and safflower oil, independent of effects on plasma lipids.(ABSTRACT TRUNCATED AT 400 WORDS)     

High linoleic acid diets ameliorate diabetic nephropathy in rats

The value of high polyunsaturated fatty acid (PUFA) diets in preventing diabetic nephropathy in rats was studied. Diabetes was induced by intravenous injection of streptozotocin (SZ), 65 mg/kg. Rats were divided in four groups fed diets containing 11% fat for 38 weeks. Dietary fat derived from four sources: beef tallow (BT; rich in saturated fatty acids), evening primrose oil (EPO; rich in gamma linolenic [GLA] and linoleic acids [LA]), safflower oil (SO; rich in LA), and fish oil (FO; rich in eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids). Ultralente insulin was administered every other day to maintain the blood glucose levels between 11.1 and 22.2 mmol/L (200 and 400 mg/dL). The diets prepared with EPO and SO had a clear beneficial effect on proteinuria, glomerular sclerosis, and tubular abnormalities, as compared with BT. Both diets also increased the ratio of renal cortical production of 6-keto-PGF1 alpha to thromboxane B2 (TXB2), the stable metabolites of PGI2 and TXA2, respectively. They did not induce significant changes in plasma lipid composition. The FO diet did not have an effect on renal disease, but decreased plasma lipids and inhibited eicosanoid synthesis by platelets and kidney cortex. FO feeding was associated with a lowered 6-keto-PGF1 alpha/TXB2 ratio. It is concluded that high LA diets are protective in this model of diabetic nephropathy. The effect may be secondary to modifications of the eicosanoid balance. Diets containing FO have a beneficial effect on plasma lipids in this model.     

Improvement of Bone Quality in Gonad-Intact Middle-Aged Male Rats by Long-Chain n-3 Polyunsaturated Fatty Acid

The effect of long-chain n-3 polyunsaturated fatty acid (PUFA) on bone measurements was evaluated in gonad-intact middle-aged male rats. Seven rats were killed on day 0 of dietary intervention to determine bone parameters at baseline. Experimental rats (7/group) were fed one of the following lipid treatments (g/kg diet): 167 g safflower oil + 33 g menhaden oil (N6+N3 diet, control), 200 g safflower oil (N6 diet), or 190 menhaden oil + 10 g corn oil (N3 diet). After 20 weeks of dietary treatment, all groups had lower values for peak load and ultimate stiffness in femurs compared to baseline values. Rats fed the N3 diet had the highest values for peak load, ultimate stiffness, and Young’s modulus compared with those fed the N6 and control diets. Compared to baseline, all dietary treatment groups had significantly lower values for trabecular thickness and number in proximal tibia but higher values for trabecular separation and formation rate in proximal tibia and endocortical bone formation rate in tibial shaft. Compared with the control group, rats fed the N3 diet had lower values for formation rate, osteoclast number, and eroded surface in proximal tibia but higher values for periosteal mineral apposition and formation rates in tibia shaft. These findings indicate that a diet rich in long-chain n-3 PUFA mitigate aging-induced loss of bone integrity in intact middle-aged male rats through reducing bone turnover rate by suppressing both bone formation and resorption as a result of a larger net bone volume and modulating endocortical and cancellous bone compartments. Previously presented in part at the 26 th annual meeting of the American Society of Bone and Mineral Research, Seattle, Washington, USA, September 2004, and published in abstract form (Shen CL, Dunn DM, Yeh JK [2005] Dietary fish oil mitigates aging-induced bone loss in middle-aged male rats [abstract]. J Bone Miner Res 19(suppl 1):S205).     

Fatty acid levels and risk of asthma in young adults

BACKGROUND: There is current interest in the possible protective effect of long chain (n-3) fatty acids from fish in chronic lung diseases such as asthma. The aim of this community based cross sectional study was to determine whether plasma long chain (n-3) fatty acids, as a measure of dietary intake, differed between 1601 young adults with and without asthma. METHODS: Subjects of mean (SD) age 34.6 (7.1) years completed a detailed respiratory questionnaire, food frequency questionnaire, skin prick testing, and lung function tests including methacholine challenge test for bronchial hyperreactivity (BHR) and had venous blood taken for analysis of plasma fatty acids. Plasma fatty acid levels (%) were analysed using multiple logistic regression with alternative definitions of asthma and atopy as the outcomes. RESULTS: Atopy was not associated with any plasma fatty acid. The n-3 polyunsaturated fatty acids and n-6:n-3 ratio were not consistently associated with asthma or atopy. The n-6 polyunsaturated fatty acid dihomo gamma-linolenic acid (DHGLA) was positively associated with current asthma (OR=1.30, 95% CI 1.06 to 1.60), asthma (OR=1.34, 95% CI 1.13 to 1.60), and doctor diagnosed asthma (OR=1.25, 95% CI 1.06 to 1.48). CONCLUSION: Plasma n-3 fatty acids are not associated with a reduced risk of asthma or atopy among young adults. The association of DHGLA with asthma warrants further research to determine a cause-effect relationship.     

Disorders of serum omega-3 fatty acid composition in dialyzed patients,and their associations with fat mass

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular mortality. Lipid disorders, a constant feature of CKD, might contribute to this state. The aim of this study was to evaluate n-3 polyunsaturated fatty acids (PUFA) composition in CKD patients treated with dialysis, in comparison to the general population and to assess possible associations between the n-3 PUFA profile and anthropometric variables. Thirty-three prevalent dialysis patients were studied and compared with an age- and sex-adjusted control group of 22 patients. Fatty acid composition in serum was analyzed by gas chromatography with a mass spectrometer detector (GC-MS) and anthropometric measures were assessed by bioimpedance spectroscopy. The fatty acid profile of dialyzed patients was characterized by a significantly lower percentage content of n-3 PUFA. For α-linolenic acid (ALA), it was 0.21?±?0.09% in dialysis patients versus 0.33?±?0.11% in the control group (p?p?p?r?=?.48 (p?r?=?.40 (p?相似文献   

Inhibition of accelerated cardiac allograft arteriosclerosis by fish oil

Accelerated coronary arteriosclerosis remains the most important factor limiting long-term survival of heart transplant recipients, and dietary fish oil supplementation with omega-3 polyunsaturated fatty acids has been suggested to have a protective effect against coronary disease in epidemiologic studies and to inhibit arteriosclerosis in animal experiments. Therefore we tested the hypothesis that fish oil administration inhibits the development of allograft coronary arteriosclerosis by using a heterotopic heart transplant model. Three groups of Lewis rats (n = 10 each) received heterotopic heart transplants from Brown-Norway donors and were treated with cyclosporine intraperitoneally on a tapering schedule. Group 1 received fish oil daily by gavage (2 ml/kg/day; Emulsified Super MaxEpa, Twin Labs, Ronkonkona, N.Y.). Group 2 received an equal amount of safflower oil, as well as aspirin (1 mg/kg/day) and dipyridamole (3 mg/kg/day). Group 3 received safflower oil only. All rats were put to death 110 days later, at which time there was no statistically significant difference in graft function as assessed by palpation (scale 0 to 4, mean = 3.7 +/- 0.5 [+/- standard deviation]; analysis of variance: p = 0.72) or in microscopic grade of rejection (scale, 0 = none to 3 = severe, mean 2.1 +/- 0.6; analysis of variance: p = 0.68) between any of the groups. The coronary arteries were histologically scored for the degree of arteriosclerosis (scale, 0 = normal to 3 = occluded), and a mean grade of coronary disease was calculated for each heart. The fish oil-treated group had significantly less severe allograft coronary arteriosclerosis (analysis of variance: p = 0.005) than did groups 2 and 3 (mean grade 0.23 +/- 0.22 versus 1.04 +/- 0.75 and 0.96 +/- 0.55 (p less than 0.05, Scheffe F test), whereas groups 2 and 3 had similar degrees of coronary disease (p = no significant difference). These data demonstrate that fish oil supplementation inhibited accelerated coronary arteriosclerosis in this cyclosporine-treated heart allograft rat model, whereas antiplatelet agents in these doses were ineffective. Although the mechanism of this protective effect remains incompletely understood, it does not appear to involve enhanced immunosuppression. Fish oil and specific omega-3 polyunsaturated fatty acids should be further investigated as potentially useful agents to ameliorate accelerated allograft coronary arteriosclerosis in other animal species and perhaps eventually in man.     

Modulation of Kupffer cell membrane phospholipid function by n-3 polyunsaturated fatty acids

Dietary n-3 polyunsaturated fatty acids (PUFAs) have been reported to improve clinical outcome in a number of inflammatory diseases including burns and sepsis. One mechanism contributing to the anti-inflammatory effect is the incorporation of n-3 PUFAs into membrane phospholipids which decreases macrophage eicosanoid production. We hypothesize that an additional mechanism for their effects is an alteration of membrane signal transduction that decreases macrophage responsiveness to inflammatory stimuli. Kupffer cells, the fixed macrophages of the liver, were obtained from rats pair fed diets for 6 weeks with 15% of calories supplied as menhaden (high n-3), corn (control), or safflower (high n-6) oils. The effects of the dietary oils on Kupffer cell membrane signal transduction and eicosanoid production were assessed by measuring inositol phospholipid (PI) metabolism, intracellular calcium responses, and prostaglandin E2 (PGE2) production to the inflammatory signals endotoxin (LPS) and platelet activating factor (PAF). The menhaden oil diet resulted in significant incorporation of n-3 PUFAs into total cellular PUFAs compared to corn and safflower oil. (total n-3 PUFAs, 28.1% menhaden vs 2.1% corn vs 1.2% safflower, P less than 0.03). This incorporation altered signal transduction of PAF as both PI turnover (65% +/- 10% of corn oil) and calcium response (0.6-fold vs 5.0-fold for corn oil) were significantly reduced in the menhaden oil group. (P less than 0.05) The menhaden oil diet also reduced significantly PGE2 production in response to PAF and LPS (corn, 348 +/- 23 pg/ml; menhaden, 48 +/- 6 pg/ml, P less than 0.01). We conclude that, in addition to modulating eicosanoid production, n-3 PUFAs can also alter macrophage membrane signal transduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined effects of soy isoflavone and fish oil on ovariectomy-induced bone loss in mice

Both soy isoflavone and n-3 polyunsaturated fatty acids are known to reduce the levels of bone-resorbing cytokines; however, the synergistic effects of these food ingredients have not been examined yet. This study was performed to elucidate the effect of concomitant intake of soy isoflavone and fish oil on bone mass in ovariectomized mice. Eight-week-old ddY female mice were subjected to ovariectomy (OVX) or sham surgery, and then fed an AIN-93G with safflower oil (So) as a control lipid source, isoflavone-supplemented safflower oil (So + I), fish oil instead of safflower oil (Fo) or isoflavone-supplemented fish oil (Fo + I) for 4 weeks. Femoral bone mineral density was significantly decreased by OVX; however, this decrease was inhibited by the intake of isoflavone and/or fish oil. Histomorphometric analyses showed that bone volume and trabecular thickness in the distal femoral trabecular bone were significantly lower in the So group than in the sham group, but those were restored in the Fo + I groups. The number of osteoclasts was significantly decreased by isoflavone intake. The increased rate of bone resorption after OVX was inhibited by isoflavone and/or fish oil. The serum concentration of tumor necrosis factor alpha was increased after OVX, but was significantly lower with the combination of isoflavone with fish oil than isoflavone or fish oil alone. The results of this study indicated that the intakes of soy isoflavone and/or fish oil might have ameliorating effects on bone loss due to OVX. Further, the concomitant intake of soy isoflavone and fish oil at a low dose showed better effects on cytokines related with bone resorption.     

Advances in Intravenous Lipid Emulsions

Abstract Over the past decade, our views have considerably evolved with respect to the metabolism of intravenous lipid emulsions and their composition. Substantial progress has been made in understanding the metabolic pathways of emulsion particles and the delivery of their various components (fatty acids and vitamins) to specific tissues or cells. Although soybean long-chain triglycerides represent a valuable source of energy, concerns have been raised about their high content of polyunsaturated fatty acids (mainly n-6 essential fatty acids), which may adversely affect immune functions and antioxidant status. Introduction of medium-chain triglycerides or olive oil to lipid emulsions can largely help bypass these disadvantages. Recently, incorporation of n-3 fatty acids in lipid preparations was suggested to have potential application in several chronic and acute diseases because of their ability to reduce inflammatory and thrombotic responses and cell sensitivity to various stimuli. Hence lipid emulsions should no longer be considered only as a means of providing energy substrates; they also modulate key metabolic functions. Such improved knowledge may lead to optimizing the metabolic care of certain patients. E-pub: 31 October 2000     

Supplementation with n-3 and n-6 polyunsaturated fatty acids: effects on lipoxygenase activity and clinical symptoms of pruritus in hemodialysis patients.

OBJECTIVE: To investigate the effect of supplementation with different sources of oils rich in long chain fatty acids, ie, fish oil (FO) and safflower oil (SO), on the production of leukotriene B4 (LTB4) by polymorphonuclear leukocytes (PMNLs) in hemodialysis patients and the consequent effects on the symptoms of pruritus. DESIGN: Randomized, prospective, double-blind study for 2 treatment groups. SETTING: Three Medical Center-affiliated units. PATIENTS: Twenty-two patients on maintenance hemodialysis, of both sexes, age > or = 20 years with complaint of dry and/or itchy skin. INTERVENTION: Two groups of patients receiving daily supplements of 6 g ethyl ester of FO or SO for 16 weeks. MAIN OUTCOME MEASURES: Red blood cell (RBC) fatty acid profile, LTB 4 production by PMNLs, and pruritus symptoms at baseline and after supplementation. RESULTS: After supplementation, the FO group had a higher RBC 22:6n3, total n-3 fatty acids, and ratio of total n-3 to total n-6 fatty acids (P < .05) than the SO group. The change in LTB4 production (pg/mL) from baseline to week 16 was 240.7 +/- 200.2 to 29.2 +/- 14.6 in the FO group and from 171.1 +/- 121.7 to 31.9 +/- 14.7 in the SO group. The overall pruritus score change was 16.7 +/- 11.4 to 8.9 +/- 9.2 in the FO group and from 17.5 +/- 8.8 to 13.1 +/- 5.6 in the SO group. FO supplementation did not result in a significant specific effect on LTB4 production by the PMNLs. There was a nonsignificant decrease in the pruritus scores that could be clinically significant and important to patients suffering with this condition. CONCLUSION: Supplementation with FO results in significant incorporation of n-3 fatty acids in the RBCs. Intervention with both FO and SO resulted in a nonsignificant improvement of clinical symptoms of pruritus and a nonsignificant reduction in LTB 4 production by PMNLs in the hemodialysis patients. The percent decrease in total puritus score was greater for the FO group compared with the SO group.     

Fatty acid composition and arachidonic acid concentrations in alveolar bone of rats fed diets with different lipids

Summary The purpose of the present study was to determine if the type of dietary fat can modify the fatty acid composition and arachidonic acid levels in the alveolar bone phospholipids. Three groups of rats were fed nutritionally adequate semipurified diets containing different lipids: 10% corn oil (control, group 1, rich in n-6 fatty acids); 9% butter + 1% corn oil (experimental, group 11, rich in saturated fatty acids); and 9% ethyl ester concentrate of n-3 fatty acids + 1% corn oil (experimental, group 111, rich in n-3 fatty acids). After 10 weeks of feeding the various diets, rats were killed, maxillae and mandibles were dissected out, and the soft tissue was removed. Bone was frozen in liquid nitrogen and pulverized. Powdered bone was extracted for total lipids, and phospholipids were isolated by column chromatography. The fatty acid composition and arachidonic acid concentrations were determined in total phospholipids after the addition of an internal standard, octadecatetraenoic acid (18: 4n-3), and subsequent gas chromatography. The type of dietary lipids had a profound influence on the fatty acid composition of bone lipids. Arachidonic acid concentrations were significantly lower in total phospholipids of mandibles and maxillae of rats fed the experimental diets than in those fed the control diet. Because arachidonic acid is a precursor of prostaglandin E₂ and leukotriene C₄, a significant reduction in its concentration may result in reduced levels of these eicosanoids in the alveolar bone.Presented in part at the International Association for Dental Research Meeting, Glasgow, Scotland, July 1–4, 1992     

Dietary supplementation with fish oil modifies renal reserve filtration capacity in postoperative,cyclosporin A-treated renal transplant recipients

The effect of a daily supplementation of 6 g fish oil (30% C20:5 omega-3=EPA and 20% C22:6 omega-3=DHA) for 1 month on renal function variables was investigated in a placebo-controlled (6 g coconut oil), prospective, randomized, double-blind study in acute postoperative cyclosporin A (CyA)-treated renal transplant recipients. Seventeen patients ingested placebo capsules (EPA-) and 14 patients fish oil (EPA+). Renal function tests were performed using the simultaneous determination of 125 I-iothalamate and 131 I-hippuran clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively. Renal reserve filtration capacity was assessed by dopamine infusion, amino acid infusion, and a combination of both stimuli. After 1 month there were no significant differences in rejection episodes, CyA dose, or CyA levels. In contrast to our earlier observations, serum creatinine, creatinine clearance, GFR, and ERPF did not differ between the EPA- and EPA+ groups. Filtration fraction (FF) differed significantly, being 0.21 in the EPA- group versus 0.26 in the EPA+ group. To exclude the possible influence of a rejection episode, the nonrejecting patients were analyzed separately, creating the subgroups EPA+ re- and EPA-re-. These two groups were comparable in age, donor age, and GFR. The EPA+ re-group had a significantly lower ERPF (164 ml/min per 1.73 m²) than the EPA-re- group (262 ml/min per 1.73 m²). FF was significantly higher in the EPA+re-group (0.26) than in the EPA-re- group (0.21). Following dopamine, no significant differences in the percentage increase of GFR and ERPF between both groups were observed, while FF fell to the same extent in both groups. Following amino acids, the fish oil-treated patients had a significantly better response on GFR (EPA+re- 15.3 versus EPA-re- 10.6%; P<0.05). The near-normal FF and the better response on amino acid infusion strongly suggest that at 1 month postoperatively, the CyA- and fish oil-treated patients have more balanced renal hemodynamics than the CyA- and coconut oil-treated patients.     

Oral fish oil supplementation raises blood omega-3 levels and lowers C-reactive protein in haemodialysis patients--a pilot study.

BACKGROUND: We previously reported that haemodialysis patients have suboptimal blood levels of the cardioprotective omega-3 polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. In the present pilot study, we tested the hypothesis that supplementing haemodialysis patients for 12 weeks with the American Heart Association (AHA)-recommended fish oil dose would be well tolerated and efficacious in boosting blood n-3 PUFA levels and improving cardiovascular risk biomarkers. METHODS: Twenty-seven subjects were randomized in a 2 : 1 ratio to either 1.3 g of EPA + DHA daily or placebo. RESULTS: At baseline, 83% of subjects consumed inadequate dietary fish and had the following erythrocyte n-3 PUFA levels (mean +/- SD,% weight)-EPA: 0.3 +/- 0.2, DHA: 2.9 +/- 2.0, and ratio of n-6/n-3 PUFA: 4.2 +/- 1.3. Supplementation induced large increases in mean blood EPA and DHA levels (% increase, P-value vs placebo group): erythrocyte-EPA: +400%, P = 0.0018, DHA: +205%, P < 0.0001; plasma-EPA: +275%, P = 0.0003, DHA: +69%, P = 0.0352. Levels in the placebo group remained relatively unchanged. The omega-3 index, a value correlating with the level of cardioprotection, increased significantly in the fish oil group. A reduction in mean C-reactive protein levels (-3.3 +/- 8.1 mg/l, P = 0.0282) and a trend towards lower triglyceride levels (-24 +/- 74 mg/dl, P = 0.0783) were also observed in the active vs placebo group. Minimal side effects were noted. CONCLUSIONS: Our preliminary observations that the AHA-recommended fish oil dose is well tolerated, efficacious and may improve surrogate markers of cardiovascular disease in haemodialysis patients paves the way for larger clinical trials to confirm a clinical benefit.     

n-3 Fatty acids and their role in nephrologic practice

During the past year, a newly reported clinical trial has strengthened the argument for recommending daily treatment with n-3 polyunsaturated fatty acids in patients with immunoglobulin A nephropathy (the most common form of primary glomerulonephritis in the world) who are at high risk for progression of renal disease. Studies are underway that involve a combination of cyclosporine A, a commonly prescribed immunosuppressive agent in solid-organ transplantation, with a high-potency n-3 polyunsaturated fatty acid to reduce cyclosporine toxicity. Two studies reported during the past year show promise that dietary supplementation with n-3 polyunsaturated fatty acids will substantially decrease vascular access graft thrombosis in patients receiving maintenance hemodialysis, and may reduce hypercalciuria in patients who suffer from kidney stones.