Safety and efficacy of a new parenteral lipid emulsion (SMOFlipid) in surgical patients: a randomized, double-blind, multicenter study.

BACKGROUND/AIMS: A new lipid emulsion based on soybean oil, medium chain triglycerides, olive oil and fish oil (SMOFlipid) was tested for safety, tolerance, metabolic and clinical efficacy in surgical patients. METHODS: In a prospective, double-blind European multicenter study, postoperative patients (elective abdominal or thoracic surgery) were randomized to receive isonitrogenous, isoenergetic (30-35 kcal/kg) total parenteral nutrition over 5 postoperative days including either SMOFlipid 20% or standard soybean oil emulsion (Lipovenoes 20%) as lipid source (1.5 g kg(-1) day(-1)). Metabolic efficacy measurements included serum levels of triglycerides (AUC), phospholipids, and total cholesterol. Safety/tolerance parameters were: hematology; clinical chemistry; coagulation profile; clinical course (arterial blood pressure, heart rate, body temperature), and documentation of adverse events. Clinical efficacy was monitored by length of hospital stay and mortality. RESULTS: The 2 groups (per-protocol population: SMOFlipid n = 99, and Lipovenoes n = 100) were similar with respect to demographic characteristics and types of surgical intervention. Concentrations of serum triglycerides, phospholipids, and total cholesterol were comparable in both groups and within the expected ranges. Laboratory and clinical parameters were not different. A trend towards a reduced length of hospital stay was observed with SMOFlipid (15.7 +/- 6.3 vs. 17.8 +/- 13.2 days). CONCLUSIONS: SMOFlipid is clinically safe and well tolerated in postoperative patients. There are indications that SMOFlipid may be associated with a better liver tolerance and a shorter length of hospitalization.

Improved fatty acid and leukotriene pattern with a novel lipid emulsion in surgical patients.

OBJECTIVE: We assessed the effects of a novel lipid emulsion with reduced content of n-6 fatty acids (FA), increased share of MUFA and n-3 FA and supplemental vitamin E on fatty acid and leukotriene pattern in surgical patients. METHODS: In a double-blind, randomized study 33 patients received isonitrogenous, isocaloric TPN over 5 postoperative days following major abdominal surgery. 19 patients received the new SMOFlipid 20% and 14 patients a standard soybean oil emulsion (Lipovenoes 20%, both Fresenius Kabi), each 1.5 g fat/kg body weight (BW)/d. Routine lipid biochemistry, plasma tocopherol, fatty acid pattern in plasma phospholipids, as well as leukotriene (LT) release in leukocytes were assessed. Additionally, fatty acid pattern in leukocyte and platelet phospholipids were analysed, but results are not presented. RESULTS: On day 6, plasma alpha-tocopherol (34.2 +/- 10.3 vs. 17.6 +/- 2.9 micromol/L) and, in plasma PL, total n-3 FA were higher (11.1 +/- 1.9 vs. 4.9 +/- 0.9 mol%; p < 0.05) and total n-6 FA lower (23.8 +/- 2.2 vs. 31.8 +/- 1.7 mol%; P < 0.05); the ratio n-3/n-6 FA being elevated (0.5 +/- 0.1 vs. 0.2 +/- 0.0 p < 0.05) with SMOFlipid compared to the soybean oil emulsion. The shares of EPA (3.3+/-1.0 vs. 0.4+/-0.2 mol%; p<0.05) and DHA (6.9 +/- 1.8 vs. 3.7 +/- 0.8 mol%; p < 0.05) were highly increased but that of arachidonic acid (AA) was unchanged with SMOFlipid while the ratio EPA/AA was increased (0.7 +/- 0.2 vs. 0.1 +/- 0.0 p < 0.05). LTB(5) release was enhanced on day 6 (8.1 +/- 5.3 vs. 1.8 +/- 3.8 pmol/10(7) PMN, p < 0.05) and liberation of LTB(4) was lowered, yet not significantly with SMOFlipid (124.0 +/- 51.2 vs. 152.1 +/- 68.8 pmol/10(7) PMN). Length of hospital stay was significantly shorter with SMOFlipid (13.4 +/- 2.0 vs. 20.4 +/- 10.0 days, p < 0.05). CONCLUSION: Treatment with the new emulsion SMOFlipid is well tolerated and modulates FA and leukotriene pattern suggesting favourable anti-inflammatory effects and further clinical benefits.

3-Deazaadenosine prevents leukocyte invasion by suppression of adhesion molecule expression during acute cardiac allograft rejection: involvement of apoptotic cell death.

BACKGROUND: In the initial phase after cardiac transplantation, mononuclear cells infiltrate the graft, initiating a relevant impulse for rejection. 3-Deazaadenosine (c3Ado), an analog of adenosine, has proven anti-inflammatory properties both in vitro and in vivo. We hypothesized that c3Ado can serve as a therapeutic tool to reduce cellular infiltration in cardiac allograft transplantation. METHODS: Using the Wistar-Furth-to-Lewis rat cardiac allograft model, animals were treated with 5 mg c3Ado subcutaneously twice per day. Allografts of untreated animals served as controls. Grafts were harvested on Days 1, 3 and 6 after transplantation for further examination (n = 4 per group and timepoint). RESULTS: Immunohistochemical examination of c3Ado-treated grafts revealed up to 80% reduction of infiltrating major histocompatability complex (MHC) II-positive cells and T-cell-receptor-positive cells (R73) as well as ED1-positive monocytes and macrophages at Days 3 and 6 after transplantation. Adhesion molecule (ICAM-1 and VCAM-1) expression at Days 1 and 3 was almost completely abolished in c3Ado-treated grafts. However, c3Ado treatment did not prevent apoptotic cell death (TUNEL assay, DNA laddering) at Day 6, nor did it prolong allograft survival. As in controls, grafts were rejected at Day 7. CONCLUSION: c3Ado significantly reduces graft infiltration by preventing leukocyte invasion, most likely through suppression of adhesion molecule expression. Although graft survival was not prolonged, treatment with c3Ado may still serve as a strategy to protect hearts from early damage after transplantation. Further studies will show whether peri-operative use of c3Ado can bridge the critical phase after transplantation when standard immunosuppression is not yet completely efficacious.

Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients.

BACKGROUND: It has been suggested that increased monocyte responses might play a role in chronic allograft rejection. METHODS: We investigated in vitro monokine responses in 112 patients with long-term stable kidney graft function (ST patients; n=80, non-mycophenolate mofetil [MMF]; n=32, MMF) and 25 patients with chronic renal transplant rejection (CR patients; non-MMF). Interleukin 10 and tumor necrosis factor (TNF)-alpha promoter gene polymorphisms were tested by polymerase chain reaction and sequence-specific primers; antigen-presenting capacity (AC) of monocytes was tested by incubation with staphylococcal superantigens (SEA, SEE, SED). RESULTS: Although non-MMF-based immunosuppression in ST patients did not result in compromised AC or lipopolysaccharide (LPS)-stimulated monokine responses compared with healthy controls, we found MMF therapy to be associated with significantly reduced TNF-R1 expression on monocytes (P<0.001), suppressed AC (P<0.02, SED), and suppressed LPS-stimulated IL-1 beta, IL-10, and TNF-alpha secretion (P<0.01). Coinciding with a significantly higher steroid dosage in CR patients, IL-6 receptor and TNF-R1 expression on monocytes were down-regulated (P< or =0.02) and AC was suppressed in CR compared with ST (non-MMF) patients (P<0.01, SED; P<0.05, SEE). However, LPS-stimulated monokine secretion was not decreased or even enhanced (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]; P<0.05). Enhanced in vitro IL-10 responses (>500 pg/mL) were found predominantly in non-MMF-treated patients with the IL-10 genotype GCC (GCC: 23/62 [37%], non-GCC: 2/27 [7%], P<0.005; GCC and non-MMF: 22/47 [47%], GCC and MMF: 1/15 [7%], P<0.005]. CONCLUSION: Steroids and azathioprine did not sufficiently suppress monokine responses, whereas MMF treatment might inhibit chronic graft rejection because of suppression of TNF-R1 expression and vigorous inhibition of monokine secretion. MMF treatment may especially be indicated in patients with the IL-10 "high-producer" genotype GCC.

Tumor M2-pyruvate kinase in lung cancer patients: immunohistochemical detection and disease monitoring.

BACKGROUND: Lung cancer is one of the main causes for cancer death. A reliable diagnosis and follow-up of patients is important support for a successful therapy. The diagnostic efficiency of a new marker Tumor M2-pyruvate kinase (Tumor M2-PK) is evaluated. MATERIALS AND METHODS: In this report immunohistochemical detection of pyruvate kinase M2 in tissue sections of lung cancer specimens is presented. Furthermore Tumor M2-PK was quantified in EDTA plasma of lung cancer patients in order to monitor the disease, especially under chemotherapy. RESULTS: Immunohistochemical detection of pyruvate kinase M2 in tissue sections of lung cancer specimens showed selective staining of tumor cells, independent of the histological classification of the tumor. In EDTA plasma of lung cancer patients, the marker concentrations correlated well with the tumor load during follow-up, showing significantly increasing concentrations with progressive tumor stages and decreased concentrations during tumor remission. Again, this effect was independent of the histological tumor type. CONCLUSION: The present data indicate that Tumor M2-PK in EDTA-plasma could be a valuable tumor marker for monitoring lung cancer.

Inmunosupresión de las emulsiones lipídicas parenterales en un modelo de inmunoestimulación definida / Immunosuppresion by parenteral lipid emulsions in a model of defined immunostimulation

En el modelo del alotransplante de corazón en ratas se investigó el efecto inmunosupresivo de emulsiones grasas i.v. con una combinación diferente de ácidos grasos n-3 y n-6. Emulsiones de un 20 por ciento de aceite de cardo (n-3/n-6=1/370), de pescado (7,6/1), de soja (1/6,5), y una mezcla 1:1 de aceite de cardo y de pescado (1/2,1; como grupo control de aceite) fueron infundidos continuamente después del trasplante hasta el rechazo (9g de grasa/Kg peso corporal diario, n=10 por grupo). Fueron analizados el tiempo de supervivencia del trasplante, las subpoblaciones del infiltrado de células inmunocompetentes o circulantes y la secreción de interleuquina-6 de células mononucleares circulantes. En el grupo de aceite de cardo, de pescado y de soja, el tiempo de supervivencia del trasplante fue alargado hasta 13,3; 12,3 y 10,4 días en comparación a los 6,7 días en el grupo de aceite respectivamente y de 7,8 días en el grupo control de NaCL (p<0,01). En los dos grupos con la prolongación de supervivencia más alta se redujo el número de células en el infiltrado hasta un 50 por ciento y la producción de interleuquina-6 de células monocelulares hasta un 45 por ciento. Además se observó una disminución de las células-T circulantes en el grupo aceite de pescado. Las emulciones grasas i.v provocan, dependiendo de la relación de ácidos grasos de n-3/n-6, diferentes reacciones inmunomodulantes. Tanto los ácidos grasos de n-6 como los n-3 causan su efecto inmunosupresor mediante la reducción de la infiltración, la movilización y la producción de citocinas de células inmunocompetentes. El aceite de soja, con la relación de ácidos grasos n-3/n-6 más ponderada que el aceite de cardo, es significativamente menos inmunosupresivo, y las emulsiones grasas con una relación n-3/n-6 1.2 son inmunológicamente neutrales