Disease relevance of BL 194

• Prevention of experimental allergic encephalomyelitis via inhibition of IL-12 signaling and IL-12-mediated Th1 differentiation: an effect of the novel anti-inflammatory drug lisofylline [1].
• CONCLUSION/INTERPRETATION: Lisofylline prevents the onset of autoimmune diabetes in NOD mice by a mechanism that does not seem to enhance the function of regulatory T cells, but could be associated with suppression of proinflammatory cytokines and reduction of cellular infiltration in islets [2].
• The effects of lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine] (LSF), an inhibitor of de novo phosphatidic acid (PA) generation, on sepsis-induced acute lung injury was studied using Hanford minipigs weighing 18 to 25 kg [3].
• Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma [4].
• Treatment of newly diagnosed AML, RAEB-t or RAEB with lisofylline or placebo in addition to chemotherapy [5].

High impact information on BL 194

• Thus, LSF blocked IL-12-enhanced IFN-gamma production in anti-CD3-stimulated T cells and prevented IL-12-mediated repression of the transcription factor GATA-3 [6].
• We have previously shown that lisofylline (LSF) inhibits murine Th1-mediated disease in vivo by blocking IL-12-induced differentiation of Th1 cells [6].
• These findings were extended to show that LSF also inhibits IL-12-dependent responses in human T cells [6].
• We examined the effect of a novel anti-inflammatory drug, lisofylline (LSF), on EAE induced either by injection of mouse spinal cord homogenate or following transfer of myelin basic protein-reactive T cells [1].
• METHODS: Lisofylline was added to isolated NOD islets in vitro, with or without IL-1 beta [2].

Chemical compound and disease context of BL 194

• Effects of heparin and lisofylline on pulmonary function after smoke inhalation injury in an ovine model [7].

Biological context of BL 194

• RESULTS: In vitro, Lisofylline preserved beta-cell insulin secretion and inhibited DNA damage of islets in the presence of IL-1 beta [2].
• We decided to determine if cytotoxic therapies induce inflammatory cytokines with inhibitory effects on hematopoiesis and if lisofylline (LSF), a novel antiinflammatory compound, suppresses this induction [8].
• Platelet adhesiveness was not affected by lisofylline [9].
• Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans [10].
• Lisofylline (LSF), a novel anti-inflammatory compound that modulates stress-associated changes in lipid metabolism, is under development to modify toxicity for patients undergoing dose-intensive cytotoxic therapy for neoplasia and to prevent multiorgan failure and acute respiratory distress syndrome after oxidative injury [11].

Anatomical context of BL 194

• Effect in supralethally irradiated rats of granulocyte colony-stimulating factor and lisofylline on hematopoietic reconstitution by syngeneic bone marrow or whole organ passenger leukocytes [12].
• Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1 beta-induced inhibitory effects on insulin release [13].
• Lisofylline, a novel antiinflammatory agent, protects pancreatic beta-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism [13].
• Pretreatment of hepatic nonparenchymal cell donors with G-CSF, but not lisofylline, also resulted in striking improvement of recipient survival which was associated with an augmented subpopulation of donor stem cells [12].
• LSF also reduced monocyte/macrophage infiltration into the vessel wall and the activation of PSTAT4 [14].

Associations of BL 194 with other chemical compounds

• Group LH (n = 6) was treated with nebulized heparin and intravenous infusion of lisofylline (10 mg x kg(-1) x hr(-1)) for 48 hrs after a bolus injection (20 mg/kg) [7].
• Pentoxifylline is exclusively reduced to the optical antipode of lisofylline (S M-1) in human liver cytosol, whereas the reduction in microsomes is 85% stereoselective in favor of S M-1 formation [15].
• Clinical trials using corticosterolds, prostaglandins, nitric oxide, prostacyclin, surfactant, lisofylline, ketoconazole, N-acetylcystelne, and fish oil have been unable to show a statistically significant Improvement in patient mortality [16].
• The antioxidant and radical scavenging properties of 8-oxo derivatives of pentoxifylline, lisofylline, enprofylline (3-propyl xanthine), and 1,7-dimethyl enprofylline were studied in vitro [17].
• In cell lines lacking functional p53 (SKOV3, SKOV3 CDDP-resistant, OVCAR3, and OVCAR432) Lisofylline (20-100 microM) enhanced the cytotoxicity of CDDP by approximately 50% as measured by the Alamar blue vital dye indicator assay [18].

Gene context of BL 194

• We describe the kinetics of pentoxifylline formation from lisofylline in human liver microsomes using selective inhibitors of cytochrome P450 isozymes, correlation studies with specific isozyme activities, and cDNA-expressed human CYP1A2 and 2E1 [19].
• At 5 microM of lisofylline the CYP1A2 inhibitor, furafylline, inhibited pentoxifylline formation by 58.8%, and the nonspecific CYP2E1 inhibitor, diethyldithiocarbamate, inhibited pentoxifylline formation by 21.7% [19].
• Lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine; LSF] selectively inhibits generation of selected species of PA in P388 cells induced by TNF alpha, IL-1 beta or LPS [20].
• The formation of lisofylline 4,5-diol by these enzymes was confirmed with cDNA-expressed human CYP3A4 and CYP2A6 [21].
• Although hyperoxic exposure produced activation of both nuclear factor-kappaB and CREB in lung cell populations, only CREB activation was reduced in the mice treated with lisofylline [22].

Analytical, diagnostic and therapeutic context of BL 194

• The novel anti-inflammatory agent lisofylline prevents autoimmune diabetic recurrence after islet transplantation [23].
• Intestinal barrier function was prospectively examined in the course of a clinical trial evaluating the efficacy and safety of lisofylline for reducing cytotoxic therapy-induced intestinal epithelial damage-related infectious morbidity in patients receiving standard remission-induction therapy for acute myeloid leukaemia [24].
• Lisofylline (LSF), a water-soluble, nontoxic, selective inhibitor of the PA-1 alpha subspecies, which is stimulated by IL-1 beta and tumor necrosis factor-alpha, has been shown to prevent cytokine-induced cytotoxicity in in vivo animal models [25].
• DESIGN: Prospective, randomized, and blinded survival studies were performed with two lisofylline dosing regimens added to fluid resuscitation in a shock model [9].
• A randomized placebo-controlled trial of lisofylline in HLA-identical, sibling-donor, allogeneic bone marrow transplant recipients. The Lisofylline Marrow Transplant Study Group [26].

References