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Endotoxemia in Primate Models
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Heinz Redl, Günther Schlag, Soheyl Bahrami
Various drugs that block TNF production by LPS-activated macrophages in vitro have been used to mitigate LPS toxicity in vivo. Drugs that act at the transcriptional level, such as pentoxifylline (80) or derivatives thereof such as lisofylline (81) and HWA138, are found to protect against endotoxin shock (82) but are not fully protective in baboon sepsis (G. Schlag et al., unpublished data). Chimpanzees were infused with pentoxyfylline shortly before low-dose endotoxin administration (83). Pentoxifylline markedly inhibited increases in the levels of TNF and IL-6, as well as the effects on coagulation and fibrinolysis. The discrepancy between the effect seen in the baboon E. coli model and the LPS chimpanzee model is probably due to the large differences in the level of endotoxemia. Thus, high endotoxin levels (ng/ml) in the baboon E. coli model LPS appears to induce responses additional to cytokine induction (which is attenuated by pentoxyfylline). Such differences in response to LPS are similar to previous results in the rat, where HWA 138 prevented cytokine formation only in (sensitized) rats receiving low doses (μg) of LPS, but not in (normal) rats receiving high endotoxin doses (84).
Transplantation Tolerance, Microchimerism, and the Two-Way Paradigm
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Thomas E. Starzl, Anthony J. Demetris, Noriko Murase, Massimo Trucco, Angus W. Thomson, Abdul S. Rao, John J. Fung
The contention that stem cells are present in the adult liver and in other organs (but in smaller numbers) has been upheld by direct experimentation. Irradiated rats can be reconstituted with the expedient of orthotopic liver transplantation just as reliably as with bone marrow [108], Importantly, heterotopic heart transplantation had a therapeutic effect similar to that of 0.5 × 106 infused donor bone marrow cells or a large blood transfusion, allowing permanent hematopoietic reconstitution of occasional cardiac recipients and prolongation of survival of almost all other [108], This occasional rescue is increased to nearly 100% by the post-cardiac transplantation administration of lisofylline (Murase et al., manuscript in preparation). This phosphatidic acid inhibitor facilitates bone marrow engraftment by suppressing hematopoiesis-inhibiting cytokines (tumor necrosis factor α [TNF-α], TGF-/β, macrophage inhibitory protein 1-α, platelet factor 4, etc.) released in response to activation stimuli (interleukin 1 [IL-1], IL-8, lipopolysaccharide [LPS], platelet activating factor [PAF], cellular transformation) that are typical in the posttransplant period while not altering levels or activities of the myeloid progenitor cell promoting cytokines granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) [109].
Electrical, Cold, and Chemical Injuries
Published in Stephen M. Cohn, Matthew O. Dolich, Kenji Inaba, Acute Care Surgery and Trauma, 2016
Finally, caustic injury secondary to aspiration pneumonitis is an intensive care unit (ICU) challenge that continues to plague clinicians. Following aspiration, one-third of patients will develop severe pulmonary symptoms and up to 22% are at risk of acute respiratory distress syndrome (ARDS) with the associated morbidity and mortality. Aspiration may result in a profound inflammatory response, with activation of cytokines including TNFa, IL-1, and IL-8. Attempts to modulate the development of ARDS increasingly focus on anti-inflammatory agents and immunomodulators. Pawlik et al. examined the role of pentoxifylline, which inhibits the release of TNFa, in limiting the development of ARDS following aspiration. In this animal model (n = 24), animals receiving pentoxifylline had significantly improved oxygenation, less atelectasis, and less evidence of inflammation on CT than animals in the untreated group. Mortality was also significantly less in the treated group. These results are directly opposite to findings in the ARDSNet trial using lisofylline, a pentoxifylline derivative. However, method of drug administration and ventilatory methods were quite different between the studies, making direct comparison between the two studies difficult [46].
Tissue engineering approaches and generation of insulin-producing cells to treat type 1 diabetes
Published in Journal of Drug Targeting, 2023
Mozafar Khazaei, Fatemeh Khazaei, Elham Niromand, Elham Ghanbari
Exendin-4 is a 39 amino acid peptide isolated from the saliva or venom of the lizard Heloderma suspectum. Several studies have been conducted to determine its in vivo effect. It demonstrated that exendin-4 increased β-cell function and mass by stimulating their proliferation and neogenesis in diabetic rats [90], whereas Yang et al. reported that combined therapy with lisofylline and exendin-4 reversed pancreatic β-cell dysfunction and enhanced their proliferation in diabetic non-obese diabetic (NOD) mice [91]. It has been revealed to differentiate stem cells from various origins into IPCs. The exendin-4 increased the expression levels of β cell-related genes Nkx2.2, Isl-1, PDX-1 and MafA. Furthermore, it exhibited a synergistic effect in the induction of these markers with nicotinamide and β-mercaptoethanol [92].
Topical drug therapeutics for neuropathic pain
Published in Expert Opinion on Pharmacotherapy, 2018
While the above approach in section 7.2 involves a multimodal targeting of various excitatory and inhibitory targets, recent studies have also shown that synergistic analgesic effects can be produced in animal models of CRPS and NP using combinations of agents that target more specific pathophysiological mechanisms associated with these conditions. Deep tissue and/or endoneurial microvascular dysfunction contributes to the pathophysiology of CRPS and NP [90]. It has recently been shown that alleviating microvascular dysfunction by using topical combinations of nitric oxide donors or α2-adrenergic agonists (which increase thermoregulatory blood flow) with type IV phosphodiesterase (PDE) inhibitors (which increase nutritive blood flow) produces synergistic analgesic effects in animal models of CRPS and NP [91,92]. Thus, topical combinations of α2-adrenergic agonists (clonidine and apraclonidine) or NO donors (linsidomine, S-nitroso-N-acetylpenicillamine) with PDE inhibitors (pentoxifylline and lisofylline) produce analgesic effects that are much greater than the analgesic effects of the individual agents given on their own. Given that the anti-allodynic effects of these treatments are paralleled by their anti-ischemic effects, it suggests their synergistic analgesic effects may depend partly on disease-modifying actions. It has also been recently shown that one such combination clonidine + pentoxifylline produces significantly greater analgesic effects than either of the single agents in a surrogate of NP (postcapsaicin ischemia-induced pain) in healthy human volunteers [93].
Redox signaling and antioxidant therapies in acute respiratory distress syndrome: a systematic review and meta-analysis
Published in Expert Review of Respiratory Medicine, 2021
Liyan Bo, Faguang Jin, Zhuang Ma, Congcong Li
The antioxidant strategy and the mechanism of action are shown in Table 1. The characteristics of the included trials are summarized in Table 2. Stratified by the type of antioxidant strategy, in two studies [34,35], albumin was used for treatment, six studies [28–31,33,37] used enteral feeding with antioxidants, six studies [18–23] used NAC for treatment, one study [27] employed selenium treatment, one study [17] was conducted with vitamin C, two studies [18,32] used oxothiazolidine-4-carboxylic acid for treatment, and another study [36] used lisofylline for therapy. The mean age of the patients ranged from 42.40 to 72.50 years. The mortality rate of the control group ranged from 12.50% to 76.92%.