Cytoprotection by omega-3 fatty acids as a therapeutic drug vehicle when combined with nephrotoxic drugs in an intravenous emulsion: Effects on intraglomerular mesangial cells.

During therapeutic interventions, blood concentrations of intravenously applied drugs are higher, and their onset of pharmacological action is faster than with other routes of drug administration. However, acute drug therapy often produces nephrotoxic side effects, as commonly seen after treatment with Ketorolac or Gentamicin leading to questions about their use, especially for patients at risk for acute renal failure. Omega-6(n-6) and omega-3(n-3) polyunsaturated fatty acids (PUFA) affect eicosanoid metabolism, which plays a role in the regulation of inflammation. Eicosanoids derived from n-6 FA have proinflammatory and immunoactive functions, whereas eicosanoids derived from n-3 PUFA have anti-inflammatory and cytoprotective properties. We hypothesized that providing such injectable drugs with nephrotoxic potential in combination with n3-PUFAs from the outset, might afford rapid cytoprotection of renal cells, given the recent evidence that intravenously administered n3-PUFAs are rapidly incorporated into cell membranes. We used intraglomerular mesangial cells (MES13) that are sensitive to treatment with Ketorolac or Gentamicin instead of proximal tubular cells which do not respond to Ketorolac. We found a significant inhibition of Ketorolac (0.25, 0.5, 1 mM) or Gentamicin (2.5, 5 mM) induced cytotoxicity after pretreatment of MES13 cells with 0.01% of 20%w/v LipOmega-3 Emulsion 9/1, containing 90:10 wt/wt mixture of fish oil derived triglycerides to medium chain triglycerides.

Practical recommendations for immune-enhancing diets.

Immune-enhancing diets contain nutrients that have putative benefits, including arginine, (n-3) fats, glutamine, nucleotides, and structured lipids. Although under most circumstances the systemic inflammatory response is beneficial to the host, improving the eventual outcome of injury, infection, or inflammation, excessive proinflammation (leading to cardiac, hepatic, and mitochondrial dysfunction) or excessive counterinflammation (leading to immune depression) can worsen outcome. In critically ill septic patients, the synthesis of arginine can be exceeded by its catabolism to nitric oxide (NO) and urea, rendering arginine conditionally essential. In patients with sepsis, increased production of NO increases serum nitrite and nitrate levels, whereas levels in patients with trauma and trauma with sepsis are lower than in controls. In septic patients, supplemental arginine might further increase NO levels and be potentially harmful through excessive proinflammation. However, administration of increased amounts of arginine might improve immune function in surgical and trauma patients by increasing NO production in macrophages. When the diet provides at least 1 g of the (n-3) fatty acids eicosapentaenoic and docosahexaenoic acid combined, 2-series eicosanoids (prostaglandins, prostacyclins, thromboxanes) are replaced partially by 3-series eicosanoids, and 4-series leukotrienes are replaced partially by 5-series leukotrienes that are less proinflammatory. Thus, the effects of arginine and (n-3)-fat supplementation might be expected to be complementary-arginine might improve cytokine and NO production in patients with immunodepression, whereas (n-3) fats might be beneficial when there is excessive proinflammation, particularly when supplemental arginine is supplied, by reducing cytokine-induced eicosanoid production.