The Experts below are selected from a list of 210 Experts worldwide ranked by ideXlab platform
Jerry L Nadler - One of the best experts on this subject based on the ideXlab platform.
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amelioration of type 1 diabetes following treatment of non obese diabetic mice with ingap and Lisofylline
PMC, 2012Co-Authors: Sarah A Tersey, Jeffery D Carter, Lawrence Rosenberg, David A Taylorfishwick, Raghavendra G Mirmira, Jerry L NadlerAbstract:Type 1 diabetes mellitus results from the autoimmune and inflammatory destruction of insulin-producing islet β cells, rendering individuals devoid of insulin production. Recent studies suggest that combination therapies consisting of anti-inflammatory agents and islet growth-promoting factors have the potential to cause sustained recovery of β cell mass, leading to amelioration or reversal of type 1 diabetes in mouse models. In this study, we hypothesized that the combination of the anti-inflammatory agent Lisofylline (LSF) with an active peptide fragment of islet neogenesis associated protein (INGAP peptide) would lead to remission of type 1 diabetes in the non-obese diabetic (NOD) mouse. We treated groups of spontaneously diabetic NOD mice with combinations of LSF, INGAP peptide, or control saline parenterally for up to 6 weeks. Our results demonstrate that the mice receiving combined treatment with LSF and INGAP peptide exhibited partial remission of diabetes with increased plasma insulin levels. Histologic assessment of pancreata in mice receiving combined therapy revealed the presence of islet insulin staining, increased β cell replication, and evidence of Pdx1-positivity in ductal cells. By contrast, diabetic animals showed severe insulitis with no detectible insulin or Pdx1 staining. We conclude that the novel combination treatment with LSF and INGAP peptide has the potential to ameliorate hyperglycemia in the setting of established type 1 diabetes via the recovery of endogenous β cells and warrant further studies.
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synthesis and biological evaluation of Lisofylline lsf analogs as a potential treatment for type 1 diabetes
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Peng Cui, Meng Chen, Timothy L Macdonald, Jerry L NadlerAbstract:Lisofylline (LSF, 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is an anti-inflammatory agent that protects beta-cells from Th1 cytokine-induced dysfunction and reduces the onset of Type 1 diabetes in non-obese diabetic (NOD) mice. Due to its low potency, poor oral bioavailability, and short half-life, the widespread clinical utility of LSF may be limited. Our goal has been to develop new agents based on the LSF structural motif that resolve the potency and pharmacokinetic liabilities of LSF. In this study, we have generated a focused library of LSF analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. This library includes the xanthine-like (5-aza-7-deazaxanthine), as well as non-xanthine-like skeletons. The LSF analogs were evaluated in a pancreatic beta-cell line for the effects on apoptosis protection and insulin release. The metabolic stability of selected compounds was also tested.
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combined treatment with Lisofylline and exendin 4 reverses autoimmune diabetes
Biochemical and Biophysical Research Communications, 2006Co-Authors: Zandong Yang, Meng Chen, Jeffrey D Carter, Craig S Nunemaker, James C Garmey, Sarah D Kimble, Jerry L NadlerAbstract:Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic β-cell destruction. New evidence suggests that β-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of β-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for β-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined Lisofylline to suppress autoimmunity and exendin-4 to enhance β-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved β-cell metabolism and insulin secretion, while reducing β-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.
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Lisofylline a potential lead for the treatment of diabetes
Biochemical Pharmacology, 2005Co-Authors: Zandong Yang, Meng Chen, Jerry L NadlerAbstract:Lisofylline (LSF), a synthetic modified methylxanthine, was originally designed and tested as an agent to reduce mortality during serious infections associated with cancer chemotherapy. Experimental studies and several clinical trials showed that LSF inhibited the generation of phosphatidic acid and free fatty acids. LSF also blocked the release of pro-inflammatory cytokines in oxidative tissue injury, in response to cancer chemotherapy and in experimental sepsis. Recent research has revealed a new potential to extend the therapeutic application of LSF especially for diabetes mellitus. These new studies demonstrate multiple actions of LSF in the regulation of immune cell function and autoimmune response by inhibition of IL-12 signalling and cytokine production. Supporting the new potential for LSF is the discovery of beneficial effects in protecting pancreatic β cells and in preventing autoimmunity. In this article, these new observations about LSF are reviewed and a strategy proposed for using this compound in new clinical applications. LSF may, thus, have therapeutic value in the prevention of autoimmune disorders, including Type 1 diabetes, and autoimmune recurrence following islet transplantation, and in preservation of β cell functional mass during islet isolation.
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Lisofylline a novel anti inflammatory agent enhances glucose stimulated insulin secretion in vivo and in vitro studies in prediabetic and normal rats
Metabolism-clinical and Experimental, 2004Co-Authors: John S Striffler, Jerry L NadlerAbstract:Previous studies from this laboratory have shown that the novel anti-inflammatory agent, Lisofylline (LSF), improves oral glucose tolerance in streptozotocin (STZ) diabetic rats. Subsequent studies suggested that the improved glucose tolerance could be the result of enhanced β-cell functioning. The possibility that LSF enhancement of insulin release in these animals is the result of direct effects of this agent on a residual population of functionally normal β cells was further evaluated in these studies. In vivo studies: 6- to 8-week-old male rats were administered STZ (35 mg/kg body weight) intravenously. After 10 days, LSF administration (25 mg/kg body weight, twice daily) was initiated in the treated group (n = 11) for comparison with the vehicle-injected controls (n = 10). Body weight, food intake, and serum glucose and insulin levels were monitored weekly. Glucose and insulin responses to an oral glucose bolus were measured at 4 to 5 weeks as an index of LSF effects on impaired glucose tolerance. Glucose areas under curve (AUC) during the 2-hour tolerance tests in the LSF-treated rats (n = 11) were 23,390 ± 253 versus 29,390 ± 1,006 mg/dL × min (P < .0001) in the vehicle-injected rats (n = 10). Improved glucose tolerance was associated with increases in blood insulin levels in the LSF-treated rats, AUC (+LSF) = 6,564 ± 66 versus 5,127 ± 633 μU/mL × min in the vehicle-injected STZ-rats (not significant [NS]). These observations suggested that the improved glucose tolerance is the result of direct effects of LSF on glucose-induced release of insulin. In vitro studies: the validity of this hypothesis was subsequently tested using isolated perfused pancreas preparations from normal rats. In this series of experiments, 12-week-old animals were used, and pancreases were perfused in situ using single-pass technique. Three levels of LSF were directly infused into individual pancreas preparations and included 20 (n = 5), 40 (n = 4), and 60 (n = 4) μmol/L. First (minutes 3 to 10) and second (minutes 13 to 35) phase glucose-stimulated (300 mg/dL) insulin response areas (AUC) for the 2 phases measured in the LSF-infused pancreases were compared with AUC in vehicle-infused pancreases (n = 4). At LSF concentrations of 20 and 40 μmol/L, total insulin released during the first phase of glucose stimulation was more than twice that of the controls (3,919 ± 739 and 3,643 ± 630 μU, respectively v 1,481 ± 269 μU, P < .03). A total of 60 μmol/L LSF did not significantly enhance first phase glucose-induced insulin secretion. Second phase comparisons of total insulin released in the LSF-infused versus the controls showed differences of comparable magnitude (about 2-fold) with statistical significance (P < .03) observed at all 3 levels of LSF. These findings demonstrate that LSF enhances glucose-stimulated insulin release in vitro. Enhanced β-cell functioning by LSF likely represents an important factor underlying improved glucose tolerance in vivo. In addition, the in vitro observations in normal rat pancreas indicate that the LSF effect is not limited to β-cell dysfunction per se. These results support the conclusion that agents, such as LSF, may have therapeutic benefits in type 2 diabetes.
Meng Chen - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological evaluation of Lisofylline lsf analogs as a potential treatment for type 1 diabetes
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Peng Cui, Meng Chen, Timothy L Macdonald, Jerry L NadlerAbstract:Lisofylline (LSF, 1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine) is an anti-inflammatory agent that protects beta-cells from Th1 cytokine-induced dysfunction and reduces the onset of Type 1 diabetes in non-obese diabetic (NOD) mice. Due to its low potency, poor oral bioavailability, and short half-life, the widespread clinical utility of LSF may be limited. Our goal has been to develop new agents based on the LSF structural motif that resolve the potency and pharmacokinetic liabilities of LSF. In this study, we have generated a focused library of LSF analogs that maintain the side chain (5-R-hydroxyhexyl) constant, while substituting a variety of nitrogen-containing heterocyclic substructures for the xanthine moiety of LSF. This library includes the xanthine-like (5-aza-7-deazaxanthine), as well as non-xanthine-like skeletons. The LSF analogs were evaluated in a pancreatic beta-cell line for the effects on apoptosis protection and insulin release. The metabolic stability of selected compounds was also tested.
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combined treatment with Lisofylline and exendin 4 reverses autoimmune diabetes
Biochemical and Biophysical Research Communications, 2006Co-Authors: Zandong Yang, Meng Chen, Jeffrey D Carter, Craig S Nunemaker, James C Garmey, Sarah D Kimble, Jerry L NadlerAbstract:Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic β-cell destruction. New evidence suggests that β-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of β-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for β-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined Lisofylline to suppress autoimmunity and exendin-4 to enhance β-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved β-cell metabolism and insulin secretion, while reducing β-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.
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Lisofylline a potential lead for the treatment of diabetes
Biochemical Pharmacology, 2005Co-Authors: Zandong Yang, Meng Chen, Jerry L NadlerAbstract:Lisofylline (LSF), a synthetic modified methylxanthine, was originally designed and tested as an agent to reduce mortality during serious infections associated with cancer chemotherapy. Experimental studies and several clinical trials showed that LSF inhibited the generation of phosphatidic acid and free fatty acids. LSF also blocked the release of pro-inflammatory cytokines in oxidative tissue injury, in response to cancer chemotherapy and in experimental sepsis. Recent research has revealed a new potential to extend the therapeutic application of LSF especially for diabetes mellitus. These new studies demonstrate multiple actions of LSF in the regulation of immune cell function and autoimmune response by inhibition of IL-12 signalling and cytokine production. Supporting the new potential for LSF is the discovery of beneficial effects in protecting pancreatic β cells and in preventing autoimmunity. In this article, these new observations about LSF are reviewed and a strategy proposed for using this compound in new clinical applications. LSF may, thus, have therapeutic value in the prevention of autoimmune disorders, including Type 1 diabetes, and autoimmune recurrence following islet transplantation, and in preservation of β cell functional mass during islet isolation.
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the novel anti inflammatory agent Lisofylline prevents autoimmune diabetic recurrence after islet transplantation
Transplantation, 2004Co-Authors: Zandong Yang, Meng Chen, Lawrence B Fialkow, Justin D Ellett, Jeffrey D Carter, Jerry L NadlerAbstract:BACKGROUND Pancreatic islet transplantation has become a promising treatment for type 1 diabetes. However, autoimmune reactivity destroys engrafted islets in type 1 diabetic recipients. The authors' previous studies demonstrated that a novel anti-inflammatory agent, Lisofylline (LSF), suppressed autoimmune reactivity and protected nonobese diabetic (NOD) mice from diabetes. In this study, the authors investigated the potential of LSF in preventing autoimmune diabetes recurrence after islet transplantation. METHODS Spontaneously diabetic NOD mice received NOD severe combined immunodeficiency islet transplants and were treated with daily LSF injections at 50 mg/kg for 3 weeks. Blood glucose levels were monitored. Serum cytokine levels were measured at 1 and 3 weeks after engraftment. Nephrectomy of the islet-implanted kidney was performed in LSF-treated recipients. Histology of islet grafts was assessed at the end of the study. The effect of LSF on beta-cell function was studied in vitro. RESULTS Without immunosuppressants and insulin, the LSF-treated recipient mice maintained euglycemia significantly longer than the saline-treated recipients (mean, >65 days in the LSF-treated group vs. 6 days in saline controls; P=0.0004). Serum levels of interferon-gamma were markedly reduced in LSF-treated recipients at 1 and 3 weeks posttransplant. Diabetes recurred in the LSF-treated recipients after removing the islet-implanted kidneys. Immunohistochemistry showed retention of insulin-positive cells in the grafts of the LSF-treated recipients. LSF preserved beta-cell insulin secretory function in the presence of inflammatory cytokines in vitro. CONCLUSIONS This study demonstrates that autoimmune diabetes recurrence after islet transplantation could be prevented by treatment with LSF. LSF and its analogues may have the potential to prevent islet autoimmune destruction in clinical transplantation.
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the novel anti inflammatory compound Lisofylline prevents diabetes in multiple low dose streptozotocin treated mice
Pancreas, 2003Co-Authors: Zandong Yang, Meng Chen, Lawrence B Fialkow, Justin D Ellett, Jerry L NadlerAbstract:IntroductionProinflammatory cytokines play an important role in the development of type 1 diabetes. Lisofylline (LSF) is a novel anti-inflammatory compound that specifically inhibits proinflammatory cytokine production and action.AimTo investigate the effect of LSF on diabetes prevention.Methodology
Zandong Yang - One of the best experts on this subject based on the ideXlab platform.
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combined treatment with Lisofylline and exendin 4 reverses autoimmune diabetes
Biochemical and Biophysical Research Communications, 2006Co-Authors: Zandong Yang, Meng Chen, Jeffrey D Carter, Craig S Nunemaker, James C Garmey, Sarah D Kimble, Jerry L NadlerAbstract:Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic β-cell destruction. New evidence suggests that β-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of β-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for β-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined Lisofylline to suppress autoimmunity and exendin-4 to enhance β-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved β-cell metabolism and insulin secretion, while reducing β-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.
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Lisofylline a potential lead for the treatment of diabetes
Biochemical Pharmacology, 2005Co-Authors: Zandong Yang, Meng Chen, Jerry L NadlerAbstract:Lisofylline (LSF), a synthetic modified methylxanthine, was originally designed and tested as an agent to reduce mortality during serious infections associated with cancer chemotherapy. Experimental studies and several clinical trials showed that LSF inhibited the generation of phosphatidic acid and free fatty acids. LSF also blocked the release of pro-inflammatory cytokines in oxidative tissue injury, in response to cancer chemotherapy and in experimental sepsis. Recent research has revealed a new potential to extend the therapeutic application of LSF especially for diabetes mellitus. These new studies demonstrate multiple actions of LSF in the regulation of immune cell function and autoimmune response by inhibition of IL-12 signalling and cytokine production. Supporting the new potential for LSF is the discovery of beneficial effects in protecting pancreatic β cells and in preventing autoimmunity. In this article, these new observations about LSF are reviewed and a strategy proposed for using this compound in new clinical applications. LSF may, thus, have therapeutic value in the prevention of autoimmune disorders, including Type 1 diabetes, and autoimmune recurrence following islet transplantation, and in preservation of β cell functional mass during islet isolation.
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the novel anti inflammatory agent Lisofylline prevents autoimmune diabetic recurrence after islet transplantation
Transplantation, 2004Co-Authors: Zandong Yang, Meng Chen, Lawrence B Fialkow, Justin D Ellett, Jeffrey D Carter, Jerry L NadlerAbstract:BACKGROUND Pancreatic islet transplantation has become a promising treatment for type 1 diabetes. However, autoimmune reactivity destroys engrafted islets in type 1 diabetic recipients. The authors' previous studies demonstrated that a novel anti-inflammatory agent, Lisofylline (LSF), suppressed autoimmune reactivity and protected nonobese diabetic (NOD) mice from diabetes. In this study, the authors investigated the potential of LSF in preventing autoimmune diabetes recurrence after islet transplantation. METHODS Spontaneously diabetic NOD mice received NOD severe combined immunodeficiency islet transplants and were treated with daily LSF injections at 50 mg/kg for 3 weeks. Blood glucose levels were monitored. Serum cytokine levels were measured at 1 and 3 weeks after engraftment. Nephrectomy of the islet-implanted kidney was performed in LSF-treated recipients. Histology of islet grafts was assessed at the end of the study. The effect of LSF on beta-cell function was studied in vitro. RESULTS Without immunosuppressants and insulin, the LSF-treated recipient mice maintained euglycemia significantly longer than the saline-treated recipients (mean, >65 days in the LSF-treated group vs. 6 days in saline controls; P=0.0004). Serum levels of interferon-gamma were markedly reduced in LSF-treated recipients at 1 and 3 weeks posttransplant. Diabetes recurred in the LSF-treated recipients after removing the islet-implanted kidneys. Immunohistochemistry showed retention of insulin-positive cells in the grafts of the LSF-treated recipients. LSF preserved beta-cell insulin secretory function in the presence of inflammatory cytokines in vitro. CONCLUSIONS This study demonstrates that autoimmune diabetes recurrence after islet transplantation could be prevented by treatment with LSF. LSF and its analogues may have the potential to prevent islet autoimmune destruction in clinical transplantation.
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the novel anti inflammatory compound Lisofylline prevents diabetes in multiple low dose streptozotocin treated mice
Pancreas, 2003Co-Authors: Zandong Yang, Meng Chen, Lawrence B Fialkow, Justin D Ellett, Jerry L NadlerAbstract:IntroductionProinflammatory cytokines play an important role in the development of type 1 diabetes. Lisofylline (LSF) is a novel anti-inflammatory compound that specifically inhibits proinflammatory cytokine production and action.AimTo investigate the effect of LSF on diabetes prevention.Methodology
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Inhibition of STAT4 activation by Lisofylline is associated with the protection of autoimmune diabetes.
Annals of the New York Academy of Sciences, 2003Co-Authors: Zandong Yang, Meng Chen, Lawrence B Fialkow, Justin D Ellett, Jerry L NadlerAbstract:: We investigated the signal transduction pathway of IL-12 and showed that Lisofylline (LSF) inhibited the signal transducer and activator of transcription factor-4 (STAT4) activation. Interruption of IL-12-mediated STAT4 activation prevented autoimmune diabetes in NOD mice.
Stuart L Bursten - One of the best experts on this subject based on the ideXlab platform.
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effects of Lisofylline on hyperoxia induced lung injury
American Journal of Physiology-lung Cellular and Molecular Physiology, 1999Co-Authors: Caroline L S George, Giamila Fantuzzi, Stuart L Bursten, Laura Leer, Edward AbrahamAbstract:Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] decreases lipid peroxidation in vitro and in vivo suppresses proinflammatory cytokine expression in models of lung injury due to sepsis, blood...
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Lisofylline causes rapid and prolonged suppression of serum levels of free fatty acids
Journal of Pharmacology and Experimental Therapeutics, 1998Co-Authors: Stuart L Bursten, David Federighi, Jeffrey Wald, Brent Meengs, William Spickler, Edward NudelmanAbstract: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. The present investigation, a component of a pharmacokinetics study, was performed to assess the effect of LSF on serum-free fatty acids (FFA). LSF was administered at doses of either 1, 2 or 3 mg/kg every 24 hr for 3 days by 10 min intravenous infusion to 12 healthy volunteers, followed 24 hr later by a single oral dose of 6 mg/kg, which was determined not to be bioavailable. Total serum FFA were quantitated after separation from other lipids by thin-layer chromatography in samples from 10 of 12 subjects, and serum levels of individual fatty acids were measured by high-performance liquid chromatography in samples from 11 of 12 subjects. Six hours after the first LSF dose of 1, 2 or 3 mg/kg, FFA levels decreased from the time zero levels by a mean (±S.D.) of 64.7 ± 7.4% (range, 37–80%; P < .001 vs . time zero levels). Six hours after the third i.v. LSF dose, the FFA reached a nadir of 71.5 ± 5.5% below the time zero levels (range, 55–88%; P < .001 vs . time zero). Equivalent effects were observed after the first LSF dose regardless of whether patients received LSF at 1, 2 or 3 mg/kg. The decrease in serum FFA was still present 48 hr after the final i.v. dose and 24 hr after the oral dose, with a mean decrease of 34 ± 9.8% (P < .01 vs . time zero). Serum triglycerides began to increase after the first i.v. LSF dose and were at the highest measured level 6 hr after the third dose, increasing by 74.5 ± 19.7% from the time zero levels (range, 36–146%; P = .02 vs . time zero). The increase in serum triglycerides also persisted for 36 hr after the final i.v. LSF dose. LSF and its two principal metabolites had plasma clearance t 1/2 values of 0.75 hr, 0.78 hr and 1.17 hr, respectively. Therefore the effects of LSF on lipid metabolism were present for a prolonged period compared with measurable persistence in plasma; this points to unique functions or unknown metabolites of LSF. These alterations in serum lipids may be relevant to the anti-inflammatory activity of LSF and may serve as surrogate markers for the pharmacodynamics of LSF.
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Lisofylline prevents leak but not neutrophil accumulation in lungs of rats given il 1 intratracheally
Journal of Applied Physiology, 1997Co-Authors: Brooks M Hybertson, Stuart L Bursten, Jonathan A Leff, Young Mook Lee, Eric K Jepson, Chris R Dewitt, John Zagorski, Hyun Gug Cho, John E RepineAbstract:Hybertson, Brooks M., Stuart L. Bursten, Jonathan A. Leff, Young M. Lee, Eric K. Jepson, Chris R. Dewitt, John Zagorski, Hyun G. Cho, and John E. Repine. Lisofylline prevents leak, but not neutroph...
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the effects of post treatment with Lisofylline a phosphatidic acid generation inhibitor on sepsis induced acute lung injury in pigs
American Journal of Respiratory and Critical Care Medicine, 1997Co-Authors: Naoki Hasegawa, Stuart L Bursten, Yoshio Oka, Mitsuo Nakayama, Gerald J Berry, Glenn C Rice, Thomas A RaffinAbstract: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. Sepsis was induced by an intravenous infusion of Pseudomonas aeruginosa (1 x 10(6)/colony-forming units/kg/min over 2 h). Saline was used as the control vehicle. Six groups were studied: saline control group (SALINE: n = 5); sepsis control group (SEPSIS: n = 5); LSF control group (LSF: n = 5), which received a 25-mg/kgbolus of LSF 30 min before time zero followed by continuous infusion of 10 mg/kg/h throughout the study; LSF-treated septic groups, which were treated with LSF 30 min prior to sepsis (Pre: n = 5), 1 h postonset (Post-1 h: n = 8) or h postonset (Post-2 h: n = 8) of the bacterial infusion. Hemodynamics PaO2, neutrophil counts, and plasma porcine tumor necrosis factor-alpha concentrations were monitored for 6 h. After the minipigs were killed, lung tissue was sampled...
Anupama Mittal - One of the best experts on this subject based on the ideXlab platform.
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nanoparticulate tablet dosage form of Lisofylline linoleic acid conjugate for type 1 diabetes in situ single pass intestinal perfusion spip studies and pharmacokinetics in rat
Aaps Pharmscitech, 2021Co-Authors: Kishan S Italiya, Deepak Chitkara, Arihant Kumar Singh, Anupama MittalAbstract:Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (Lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.
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scalable self assembling micellar system for enhanced oral bioavailability and efficacy of Lisofylline for treatment of type i diabetes
Molecular Pharmaceutics, 2019Co-Authors: Kishan S Italiya, Samrat Mazumdar, Deepak Chitkara, Moumita Basak, Deepak Kumar Sahel, Richa Shrivastava, Anupama MittalAbstract:The study summarizes the development of an orally active nanoformulation of a potent but one of the least explored molecules, Lisofylline (LSF), in type 1 diabetes (T1D). LSF undergoes rapid metabolism, resulting in poor oral bioavailability and short half-life. In this work, to improve its pharmacokinetic (PK) properties, LSF was encapsulated in the form of its ester prodrug [LSF-linoleic acid (LA) prodrug] into biodegradable self-assembling polymeric micelles [LSF-LA PLM, size: 149.3 nm; polydispersity index: 0.209; critical micelle concentration (cmc); 5.95 μg/mL and Nagg: 14.82 at 10 cmc] of methoxypoly(ethylene glycol)-b-poly(carbonate-co-l-lactide) (mPEG-b-P(CB-co-LA)) block copolymer. LSF-LA PLM was found to be equally effective as the LSF-LA prodrug in cell culture studies in insulin-secreting MIN6 cells and showed excellent stability in simulating biological fluids and plasma. PK of LSF-LA PLM (10 mg/kg dose) revealed a significant improvement in oral bioavailability of LSF (74.86%; 3.3-fold increase in comparison to free LSF) and drastic reduction in the drug metabolism. Further, LSF-LA PLM showed a significant reduction in fasting glucose levels and increase in insulin levels by intraperitoneal as well oral routes in a streptozotocin (STZ)-induced T1D rat model. Production of inflammatory cytokines (TNF-α and IFN-γ) and different biochemical markers for liver and kidney functions were much reduced in diabetic animals after treatment with LSF-LA PLM. LSF-LA PLM-treated pancreatic sections showed minimal infiltration of CD4+ and CD8+ T-cells as indicated by hematoxylin/eosin staining and immunohistochemical analysis.
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self assembling Lisofylline fatty acid conjugate for effective treatment of diabetes mellitus
Nanomedicine: Nanotechnology Biology and Medicine, 2019Co-Authors: Kishan S Italiya, Samrat Mazumdar, Saurabh Sharma, Deepak Chitkara, Ram I Mahato, Anupama MittalAbstract:Abstract Lisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 μg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.
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simultaneous estimation of Lisofylline and pentoxifylline in rat plasma by high performance liquid chromatography photodiode array detector and its application to pharmacokinetics in rat
Journal of Chromatography B, 2017Co-Authors: Kishan S Italiya, Saurabh Sharma, Deepak Chitkara, Ishit R Kothari, Anupama MittalAbstract:Abstract Lisofylline (LSF) is an anti-inflammatory and immunomodulatory agent with proven activity in serious infections associated with cancer chemotherapy, hyperoxia-induced acute lung injury, autoimmune disorders including type-1 diabetes (T1DM) and islet rejection after islet transplantation. It is also an active metabolite of another anti-inflammatory agent, Pentoxifylline (PTX). LSF bears immense therapeutic potential in multiple pharmacological activities and hence appropriate and accurate quantification of LSF is very important. Although a number of analytical methods for quantification of LSF and PTX have been reported for pharmacokinetics and metabolic studies, each of these have certain limitations in terms of large sample volume required, complex extraction procedure and/or use of highly sophisticated instruments like LC–MS/MS. The aim of current study is to develop a simple reversed-phase HPLC method in rat plasma for simultaneous determination of LSF and PTX with the major objective of ensuring minimum sample volume, ease of extraction, economy of analysis, selectivity and avoiding use of instruments like LC–MS/MS to ensure a widespread application of the method. A simple liquid-liquid extraction method using methylene chloride as extracting solvent was used for extracting LSF and PTX from rat plasma (200 μL). Samples were then evaporated, reconstituted with mobile phase and injected into HPLC coupled with photo-diode detector (PDA). LSF, PTX and 3-isobutyl 1-methyl xanthine (IBMX, internal standard) were separated on Inertsil® ODS (C18) column (250 × 4.6 mm, 5 μm) with mobile phase consisting of A-methanol B-water (50:50 v/v) run in isocratic mode at flow rate of 1 mL/min for 15 min and detection at 273 nm. The method showed linearity in the concentration range of 50–5000 ng/mL with LOD of 10 ng/mL and LLOQ of 50 ng/mL for both LSF and PTX. Weighted linear regression analysis was also performed on the calibration data. The mean absolute recoveries were found to be 80.47 ± 3.44 and 80.89 ± 3.73% for LSF and PTX respectively. The method was successfully applied for studying the pharmacokinetics of LSF and PTX after IV bolus administration at dose of 25 mg/kg in Wistar rat. In conclusion, a simple, sensitive, accurate and precise reversed-phase HPLC-UV method was established for simultaneous determination of LSF and PTX in rat plasma.