Lisofylline / Islet Sci - LARVOL DELTA

Osteopontin promoted cardiac inflammation through increased interleukin-12 in acute myocarditis. (PubMed, Mol Biomed) - "Correspondingly, pharmacological inhibition of STAT4 using lisofylline significantly suppressed OPN expression in vivo. In summary, OPN functions as a crucial pro-inflammatory regulator in acute viral myocarditis and represents a promising therapeutic target for mitigating virus-induced cardiac damage."

Journal • Cardiovascular • Inflammation • IL12A • SPP1 • STAT4

Iron-lead mixed exposure causes bone damage in mice: A multi-omics analysis. (PubMed, Ecotoxicol Environ Saf) - "Combined analysis showed that Fpr2, Lifr, Lisofylline, 7-Ketocholesterol, LacCer (d18: 1/14:0) and other substances may be involved in the process of bone injury mediated by mixed metal exposure. In summary, we hypothesise that mixed exposure to Fe and Pb leads to osteoclast activation via the JAK-STAT signalling pathway in situ and indirectly via the gut-bone axis, resulting in bone damage. In general, our study potentially suggests that bone injury induced by mixed exposure of Fe and Pb may be related to osteoclast proliferation mediated by changes in inflammatory levels in vivo."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Osteoporosis • Rheumatology • FPR2 • LIFR

Restoring physiological parameters of the pancreas and kidney through treatment with a polymeric nano-formulation of C-peptide and lisofylline combination in diabetic nephropathy. (PubMed, Nanoscale) - "In vivo pharmacokinetics depicted an increase in t½ and mean residence time in rats, which further improved the BGL and renal conditions and reduced plasma IL-6 and TNF-α levels in the STZ-induced DN animal model when treated with mPLM-LSF-OA-CPep compared to free LSF and CPep. Moreover, an increase in the plasma insulin level and detection of proliferative marker cells in pancreatic islets suggested the regeneration of β-cells in diabetic animals."

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Solid Tumor • IL6 • TNFA

High Levels of Triggering Receptor Expressed in Myeloid Cells-Like Transcript-1 Positive, but Not Glycoprotein 1b+, Microparticles Are Associated With Poor Outcomes in Acute Respiratory Distress Syndrome. (PubMed, Crit Care Explor) - "Although both αIIbβIIIa+ and TLT+ microparticles (αIIbβIIIa, TLT-1) were associated with mortality, TLT-1+ MPs demonstrated stronger correlations with Acute Physiology and Chronic Health Evaluation III scores, unassisted breathing, and multiple system organ failure. These findings warrant further exploration of the mechanistic role of TLT-1+ PMP in ARDS or acute lung injury progression."

Journal • Retrospective data • Acute Lung Injury • Acute Respiratory Distress Syndrome • Hematological Disorders • Pulmonary Disease • Respiratory Diseases • Thrombocytopenia

Factor H preserves alternative complement function during ARDS, linked to improved survival. (PubMed, ERJ Open Res) - "Total alternative pathway function was measured by serum haemolytic assay (AH50) using available samples from the ARDSnet Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial (n=218)...Higher factor H levels associated with lower inflammatory markers. Relative factor H deficiency, higher Ba:B and C3a:C3 ratios and lower factor B and C3 levels suggest a subset of ARDS with complement factor exhaustion, impaired alternative pathway function, and increased mortality, that may be amenable to therapeutic targeting."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Septic Shock

Interleukin-23 Mediates Osteoclastogenesis in Collagen-Induced Arthritis by Modulating MicroRNA-223. (PubMed, Int J Mol Sci) - "Lentiviral vectors expressing short hairpin RNA (shRNA) targeting IL-23p19 and lisofylline (LSF) were injected intraperitoneally into arthritic mice...This study is the first to demonstrate that IL-23 promotes osteoclastogenesis by transcriptional regulation of miR-223 in murine macrophages and mice with CIA. Furthermore, our data indicate that LSF, a selective inhibitor of STAT4, should be an ideal therapeutic agent for treating RA through down-regulating miR-223-associated osteoclastogenesis."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • IL23A • MIR223 • STAT4

Acute Respiratory Distress Syndrome and COVID-19: A Literature Review. (PubMed, J Inflamm Res) - "Several pharmacological agents, including corticosteroids, nitric oxide, neuromuscular blocker, anti-TNF, statins, and exogenous surfactant, have been studied and some are under investigation, like ketoconazole, lisofylline, N-acetylcysteine, prostaglandins, prostacyclin, and fish oil. The purpose of this review is to appraise the understanding of the pathophysiology of ARDS, biomarkers, and clinical trials of pharmacological therapies of ARDS and COVID-19-related ARDS."

Journal • Review • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases

Role of Chain Length and Degree of Unsaturation of Fatty Acids in the Physicochemical and Pharmacological Behavior of Drug-Fatty Acid Conjugates in Diabetes. (PubMed, J Med Chem) - "In the present study, four different FAs (linoleic acid, oleic acid, palmitic acid, and α-lipoic acid) were selected based on their chain length and degree of unsaturation and conjugated to Lisofylline (LSF), an antidiabetic molecule to obtain different drug-FA prodrugs and characterized for molecular weight, hydrophobicity, purity, self-assembly, and efficacy in vitro and in vivo in type 1 diabetes model...Diabetic animals treated with prodrugs, once daily for 5 weeks, maintained a steady fasting blood glucose level with a significant increase in insulin level, considerable restoration of biochemical parameters, and preserved β-cells integrity. Among the different LSF-FA prodrugs, LSF-OA and LSF-PA demonstrated the most favorable physicochemical, systemic pharmacokinetic, and pharmacodynamic profiles."

Journal • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

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. (PubMed, AAPS PharmSciTech) - "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. Pharmacokinetic studies of LSF-LA PLM tablet showed greater C 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."

Journal • PK/PD data • Preclinical • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Lisofylline mitigates cardiac inflammation in a mouse model of obesity through improving insulin secretion and activating cardiac AMPK signaling pathway. (PubMed, Cytokine) - "We observed that LSF alleviated obesity-induced cardiac injury indirectly by improving both pancreatic β-cell function and insulin sensitivity, as well as, directly via upregulation of cardiac AMPK expression and downregulation of cardiac inflammation and apoptosis. LSF may represent an effective therapy targeting obesity-induced metabolic and cardiovascular complications."

Journal • Preclinical • Cardiovascular • Diabetes • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Obesity • Type 1 Diabetes Mellitus • AMPK • TNFA

A scalable self-assembling micellar system for enhanced oral bioavailability and efficacy of lisofylline for treatment of type-I diabetes. (PubMed, Mol Pharm) - "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 H&E staining and immunohistochemical analysis."

Clinical • Journal • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Comparative Assessment of the New PDE7 Inhibitor - GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach. (PubMed, Pharm Res) - "PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders."

Journal • PK/PD data • Preclinical

Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late-onset sepsis or necrotising enterocolitis: a pilot study incorporating clinical outcomes. (PubMed, Br J Clin Pharmacol) - "The developed model can be used to explore dosing strategies based on size and maturation for pre-term infants."

Clinical • Clinical data • Journal • PK/PD data

Influence of inflammatory disorders on pharmacokinetics of lisofylline in rats: implications for studies in humans. (PubMed, Xenobiotica) - "Too low LSF serum levels might have been one of the reasons for clinical trial failures. A long-term i.v. infusion of LSF seems to be more effective compared to short-term multiple infusions that were used in clinical trials, as it may provide concentrations above IC for inhibition of both TNF-alpha release and cAMP degradation in serum for a longer period of time."

Journal • PK/PD data • Preclinical

Pharmacological agents for adults with acute respiratory distress syndrome. (PubMed, Cochrane Database Syst Rev) - "We found insufficient evidence to determine with certainty whether corticosteroids, surfactants, N-acetylcysteine, statins, or beta-agonists were effective at reducing mortality in people with ARDS, or duration of mechanical ventilation, or increasing ventilator-free days. Three studies awaiting classification may alter the conclusions of this review. As the potential long-term consequences of ARDS are important to survivors, future research should incorporate a longer follow-up to measure the impacts on quality of life."

Clinical • Journal • Review