-
Pharmacology Research & Perspectives Aug 2020We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID-19. Pentoxifylline is an... (Review)
Review
We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID-19. Pentoxifylline is an immunomodulator with anti-inflammatory properties. It is a nonselective phosphodiesterase inhibitor and through Adenosine A2A Receptor-mediated pathways reduces tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferon gamma and may act to reduce tissue damage during the cytokine storm host response to SARS-CoV-2 infection. This agent has been used clinically for many years and has a favorable profile of safety and tolerability. Pre-clinical data support pentoxifylline as effective in cytokine-driven lung damage. Clinical studies of pentoxifylline in radiation and cytokine-induced lung damage in humans are positive and consistent with anti-inflammatory efficacy. Pentoxifylline is a readily available, off-patent and inexpensive drug, suitable for large-scale use including in resource-limited countries. Current trials of therapeutics are largely focused on the inhibition of viral processes. We advocate urgent randomized trials of pentoxifylline for COVID-19 as a complementary approach to target the host responses.
Topics: Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Pandemics; Pentoxifylline; Phosphodiesterase Inhibitors; Pneumonia, Viral; Research Design; SARS-CoV-2; Tumor Necrosis Factor-alpha; COVID-19 Drug Treatment
PubMed: 32715661
DOI: 10.1002/prp2.631 -
Biomedicine & Pharmacotherapy =... Aug 2022Nephrotoxicity (NT) is a renal-specific situation caused by different toxins and drugs like non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs like diclofenac (DCF)...
Nephrotoxicity (NT) is a renal-specific situation caused by different toxins and drugs like non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs like diclofenac (DCF) lead to glomerular dysfunction. Pentoxifylline (PTX) and berberine (BER) have antioxidant and anti-inflammatory properties. Thus, the objective of the present study was to investigate the ameliorative effect of PTX, BER and their combination against DCF-mediated acute NT. Induction of acute NT was done via DCF injection (150 mg/kg I.P, for 6 days) in rats. PTX 200 mg/kg, BER 200 mg/kg and their combination were administrated for 6 days prior to DCF injection and concurrently with DCF for additional 6 days. Acute NT was evaluated biochemically and histopathologically by measuring blood urea (BU), serum creatinine (SCr), kidney injury molecule-1(KIM-1), integrin (ITG), and vitronectin (VTN), interleukin (IL)-18, Neutrophil gelatinase-associated lipocalin (NGAL), glomerular filtration rate (GFR), superoxide dismutase (SOD) and glutathione (GSH) and malondialdehyde (MDA) with the scoring of histopathological alterations. PTX, BER and their combination significantly (P < 0.05) attenuated biochemical and histopathological changes in DCF-mediated acute NT by amelioration of BU, SCr, KIM-1, ITG, VTN, IL-18, NGAL, GFR, SOD, GSH, MDA and scoring of histopathological alterations. The combined effects of PTX and BER produced more significant effects (P < 0.05) than either PTX or BER when used alone against DCF-induced acute NT. In conclusion, BER and BTX were found to have potential renoprotective effects against DCF-induced NT in rats by inhibiting inflammatory reactions and oxidative stress.
Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Berberine; Diclofenac; Drug-Related Side Effects and Adverse Reactions; Glutathione; Inflammation; Kidney; Lipocalin-2; Male; Oxidative Stress; Pentoxifylline; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Superoxide Dismutase
PubMed: 35671584
DOI: 10.1016/j.biopha.2022.113225 -
Veterinary Medicine and Science Nov 2021Pentoxifylline can decrease platelet function in humans, but the anti-platelet effects of pentoxifylline in dogs is unknown. The addition of a luciferin-luciferase...
BACKGROUND
Pentoxifylline can decrease platelet function in humans, but the anti-platelet effects of pentoxifylline in dogs is unknown. The addition of a luciferin-luciferase reagent during platelet aggregometry can induce a dose-dependent potentiation of platelet aggregation.
OBJECTIVE
To determine if exposure to pentoxifylline, without the addition of a luciferin-luciferase reagent during aggregometry, causes canine platelet dysfunction. Our hypotheses were that pentoxifylline would inhibit platelet function, and that the addition of a luciferin-luciferase reagent would obscure detection of pentoxifylline-induced platelet dysfunction as measured via aggregometry.
METHODS
Seven healthy Walker hound dogs. Platelet-rich plasma (PRP) and whole blood were treated for 30 minutes with pentoxifylline: 0 (control), 1 and 2 μg/mL. The platelet aggregation was determined using optical (maximum amplitude) and impedance (ohms) aggregometry using collagen as the agonists, with and without a luciferin-luciferase reagent. Four samples were analysed per concentration and the results were averaged.
RESULTS
Based on optical aggregometry, there was no difference (p = 0.964) in the mean maximum amplitude at any pentoxifylline concentration, with and without the luciferin-luciferase reagent. During impedance aggregometry, the addition of a luciferin-luciferase reagent was associated with significantly (p < 0.001) greater platelet aggregation in response to a collagen agonist, regardless of the presence or absence of pentoxifylline.
CONCLUSIONS
Pentoxifylline does not exert an in vitro anti-platelet effect on canine platelet aggregation when collagen is used as an agonist, but it is unknown if long-term oral drug administration will inhibit platelet aggregation. The addition of a luciferin-luciferase reagent during platelet aggregometry can artificially enhance canine platelet aggregation.
Topics: Animals; Blood Platelets; Dogs; Electric Impedance; Pentoxifylline; Platelet Aggregation; Platelet Function Tests
PubMed: 34358418
DOI: 10.1002/vms3.595 -
Inflammopharmacology Jun 2022The existing pandemic viral infection caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) leads to coronavirus disease 2019 (Covid-19).... (Review)
Review
The existing pandemic viral infection caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) leads to coronavirus disease 2019 (Covid-19). SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as an entry-point into affected cells and down-regulation of ACE2 by this virus triggers the release of pro-inflammatory cytokines and up-regulation of angiotensin II. These changes may lead to hypercytokinemia and the development of cytokine storm with the development of acute lung injury and acute respiratory distress syndrome. Different repurposed had been in use in the management of Covid-19, one of these agents is pentoxifylline (PTX) which has anti-inflammatory and antioxidant properties. Therefore, the objective of the present mini-review is to highlight the potential role of PTX in Covid-19 regarding its anti-inflammatory and antioxidant effects. PTX is a non-selective phosphodiesterase inhibitor that increases intracellular cyclic adenosine monophosphate which stimulates protein kinase A and inhibits leukotriene and tumor necrosis factor. PTX has antiviral, anti-inflammatory and immunomodulatory effects, thus it may attenuate SARS-CoV-2-induced hyperinflammation and related complications. As well, PTX can reduce hyper-viscosity and coagulopathy in Covid-19 through increasing red blood cell deformability and inhibition of platelet aggregations. In conclusion, PTX is a non-selective phosphodiesterase drug, that has anti-inflammatory and antioxidant effects thereby can reduce SARS-CoV-2 infection-hyperinflammation and oxidative stress. Besides, PTX improves red blood cells (RBCs) deformability and reduces blood viscosity so can mitigate Covid-19-induced hyper-viscosity and RBCs hyper-aggregation which is linked with the development of coagulopathy. Taken together, PTX seems to be an effective agent against Covid-19 severity.
Topics: Angiotensin-Converting Enzyme 2; Anti-Inflammatory Agents; Antioxidants; Cytokine Release Syndrome; Humans; Pentoxifylline; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35486310
DOI: 10.1007/s10787-022-00993-1 -
Molecules (Basel, Switzerland) Jun 2021Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given...
Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given their well-established safety and pharmacological profiles. This study aimed to analyze potential interactions between xanthines and aromatic antibiotics (i.e., tetracycline and ciprofloxacin), and their impact on antibiotic antibacterial activity. UV-vis spectroscopy, statistical-thermodynamical modeling, and isothermal titration calorimetry were used to quantitatively evaluate xanthine-antibiotic interactions. The antibacterial profiles of xanthines, and xanthine-antibiotic mixtures, towards important human pathogens , , , , , and were examined. Caffeine and pentoxifylline directly interact with ciprofloxacin and tetracycline, with neighborhood association constant values of 15.8-45.6 M and enthalpy change values up to -4 kJ·M. Caffeine, used in mixtures with tested antibiotics, enhanced their antibacterial activity in most pathogens tested. However, antagonistic effects of caffeine were also observed, but only with ciprofloxacin toward Gram-positive pathogens. Xanthines interact with aromatic antibiotics at the molecular and in vitro antibacterial activity level. Given considerable exposure to caffeine and pentoxifylline, these interactions might be relevant for the effectiveness of antibacterial pharmacotherapy, and may help to identify optimal treatment regimens in the era of multidrug resistance.
Topics: Anti-Bacterial Agents; Bacteria; Caffeine; Central Nervous System Stimulants; Drug Interactions; Heterocyclic Compounds; Microbial Sensitivity Tests; Pentoxifylline; Phosphodiesterase Inhibitors
PubMed: 34198510
DOI: 10.3390/molecules26123628 -
Molecules (Basel, Switzerland) Apr 2021Millions of people around the world suffer from psychiatric illnesses, causing unbearable burden and immense distress to patients and their families. Accumulating... (Review)
Review
Millions of people around the world suffer from psychiatric illnesses, causing unbearable burden and immense distress to patients and their families. Accumulating evidence suggests that inflammation may contribute to the pathophysiology of psychiatric disorders such as major depression and bipolar disorder. Copious studies have consistently shown that patients with mood disorders have increased levels of plasma tumor necrosis factor (TNF)-α. Given these findings, selective anti-TNF-α compounds were tested as a potential therapeutic strategy for mood disorders. This mini-review summarizes the results of studies that examined the mood-modulating effects of anti-TNF-α drugs.
Topics: Bipolar Disorder; Depression; Female; Humans; Inflammation; Male; Pentoxifylline; Tumor Necrosis Factor-alpha
PubMed: 33921721
DOI: 10.3390/molecules26082368 -
Turkish Neurosurgery 2021To investigate the preventive effects of systemic honokiol and pentoxifylline treatments on epidural fibrosis (EF) in the experimental laminectomy model.
AIM
To investigate the preventive effects of systemic honokiol and pentoxifylline treatments on epidural fibrosis (EF) in the experimental laminectomy model.
MATERIAL AND METHODS
Thirty-two rats were divided into four equal groups. Laminectomy was performed in all rats except for the control group. One group was kept as the negative control group. Moreover, 10 mg/kg pentoxifylline and 10 mg/kg honokiol were administered intraperitoneally for 5 days, respectively, to the other two groups. The rats were sacrificed after 4 weeks. The samples were examined biochemically in terms of oxidative stress and inflammation induced by tissue damage. Histopathological and immunohistochemical investigations were also performed to detect EF severity.
RESULTS
In honokiol and pentoxifylline groups compared with the negative control group, tumor necrosis factor-beta and interleukin-10 levels (indicating inflammation); myeloperoxidase, malondialdehyde, and hydroxyproline levels (indicating oxidative stress); and intercellular adhesion molecule levels (indicating fibrosis) were decreased. Histopathologically and immunohistochemically, EF was significantly reduced in the pentoxifylline and honokiol groups. Biochemical findings were consistent with the histopathological and immunohistochemical findings.
CONCLUSION
Both pentoxifylline and honokiol prevent EF formation. However, this effect is more pronounced in honokiol.
Topics: Animals; Biphenyl Compounds; Epidural Space; Fibrosis; Laminectomy; Lignans; Pentoxifylline; Rats
PubMed: 34664691
DOI: 10.5137/1019-5149.JTN.33382-20.2 -
European Review For Medical and... Dec 2022Non-alcoholic fatty liver disorders (NAFLD), particularly non-alcoholic steatohepatitis (NASH), have emerged as a leading cause of liver transplantation and mortality....
Pentoxifylline and its association with kaempferol improve NASH-associated manifestation in mice through anti-apoptotic, anti-necroptotic, antioxidant, and anti-inflammatory mechanisms.
OBJECTIVE
Non-alcoholic fatty liver disorders (NAFLD), particularly non-alcoholic steatohepatitis (NASH), have emerged as a leading cause of liver transplantation and mortality. However, the pathophysiology of NASH remains unknown. Oxidative stress, apoptosis, and necroptosis pathways are heavily linked to NASH. Therefore, the current study aimed to investigate the underlying mechanism for Pentoxifylline's (PTX) activity in NASH management, either alone or in combination with Kaempferol (KP).
MATERIALS AND METHODS
A total of 32 male C57BL/6J mice were divided into four groups: the mice in the control group were fed a standard chow diet and given a vehicle; the mice in NASH group were maintained on NASH protocol for 25 days; the mice in the PTX group were kept on NASH protocol for 25 days and given PTX (100 mg/kg), and PTX+KP mice group were given NASH protocol along with KP (50 mg/kg) and PTX (100 mg/kg) simultaneously.
RESULTS
The LDL-C, total cholesterol, triglycerides, glutathione peroxidase (GPx), superoxide dismutase (SOD), malondialdehyde (MDA), glucose, insulin, and HOMA-IR levels were considerably decreased in the PTX and PTX+KP treated groups. AMP-activated protein kinase (AMPK) Gene expression of the liver was significantly increased in the other treated groups, but peroxisome proliferator-activated receptor (PPAR), phosphorylated mixed lineage kinase-like protein (pMLKL), and sterol regulatory element binding protein 1 (SREBP1) were reduced significantly. Caspase-8 and receptor-interacting serine/threonine protein kinase (RIPK3) protein expression were significantly decreased in the PTX and PTX+KP groups compared to NASH group and nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) immunohistochemistry expression.
CONCLUSIONS
Our current study suggests that PTX and its combination with KP have a significant ameliorative effect against NASH via novel mechanisms involving the regulation of apoptosis and necroptosis, as well as decreased oxidative stress, lipogenesis, proinflammatory cytokines, and modulation of histopathological manifestation.
Topics: Mice; Animals; Male; Non-alcoholic Fatty Liver Disease; Pentoxifylline; Antioxidants; Kaempferols; Mice, Inbred C57BL; Liver; Anti-Inflammatory Agents
PubMed: 36524484
DOI: 10.26355/eurrev_202212_30535 -
World Journal of Gastroenterology Apr 2016The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most... (Review)
Review
The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using "Omics" platforms, newer options for patients with alcoholic hepatitis are expected soon.
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Drug Resistance; Gastrointestinal Microbiome; Gastrointestinal Tract; Genetic Therapy; Hepatitis, Alcoholic; Humans; Liver Transplantation; Nutritional Support; Pentoxifylline; Prebiotics; Probiotics; Steroids; Treatment Outcome
PubMed: 27099434
DOI: 10.3748/wjg.v22.i15.3892 -
The Cochrane Database of Systematic... Nov 2014Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants. BPD is associated with poor long-term respiratory and neurodevelopmental outcome and... (Review)
Review
BACKGROUND
Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants. BPD is associated with poor long-term respiratory and neurodevelopmental outcome and increased mortality. The prophylactic use of agents that modulate inflammation such as pentoxifylline, a synthetic methylxanthine and phosphodiesterase inhibitor, may reduce the incidence of BPD.
OBJECTIVES
The primary objective of this review was to determine the effect of pentoxifylline on the incidence of BPD, death prior to 36 weeks postmenstrual age (PMA), and BPD or death prior to 36 weeks PMA in preterm neonates.
SEARCH METHODS
We searched the Cochrane Neonatal Review Group Specialized Register, CENTRAL (The Cochrane Library Issue 9, 2012), EMBASE (January 1974 to September 2012), PubMed (January 1966 to September 2012), and CINAHL (January 1982 to September 2012) in September 2012. We checked references and cross-references from identified studies. We handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings (from January 1990 to September 2012). We placed no restrictions on language.
SELECTION CRITERIA
Randomised or quasi-randomised clinical trials of systemic or nebulised pentoxifylline in preterm neonates less than 32 weeks gestational age or less than 1500 g birth weight, reporting on at least one outcome of interest, were eligible for inclusion in the review.
DATA COLLECTION AND ANALYSIS
We used the standard methods of the Cochrane Neonatal Review Group and The Cochrane Collaboration. Two review authors (SMS and SK) independently searched the literature as described above and selected studies. Any disagreements were resolved by discussion involving all review authors.
MAIN RESULTS
We identified one randomised clinical trial eligible for inclusion in this review. This study compared the use of nebulised pentoxifylline versus placebo for prevention of BPD in 100 preterm infants and was at high risk of bias due to lack of blinding of intervention and outcome assessors, and incomplete outcome data. There was no statistically significant effect of nebulised pentoxifylline versus placebo on individual outcomes of BPD at 36 weeks PMA or on death prior to 36 weeks PMA. There was no significant effect of nebulised pentoxifylline on intraventricular haemorrhage, periventricular leukomalacia, sepsis, or patent ductus arteriosus (PDA) requiring ligation. The study did not report any of the other secondary outcomes considered for this review. Reporting of adverse events was very limited and did not allow for reliable judgement on the incidence of such events. No long-term outcomes were reported.
AUTHORS' CONCLUSIONS
There is insufficient evidence to determine the safety and efficacy of pentoxifylline for prevention of BPD in preterm neonates. We encourage researchers to conduct clinical trials to confirm or refute the role of pentoxifylline for prevention of BPD in preterm neonates. These trials should report on clinically important outcomes and, ideally, on long-term neurodevelopmental outcome.
Topics: Bronchopulmonary Dysplasia; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Pentoxifylline; Phosphodiesterase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 25418278
DOI: 10.1002/14651858.CD010018.pub2