Journal articles on the topic 'Xanthines – therapeutic use'
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Cazzola, Mario, Luigino Calzetta, Peter J. Barnes, Gerard J. Criner, Fernando J. Martinez, Alberto Papi, and Maria Gabriella Matera. "Efficacy and safety profile of xanthines in COPD: a network meta-analysis." European Respiratory Review 27, no. 148 (May 2, 2018): 180010. http://dx.doi.org/10.1183/16000617.0010-2018.
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Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.
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Cicero, Arrigo F. G., Federica Fogacci, Masanari Kuwabara, and Claudio Borghi. "Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update." Medicina 57, no. 1 (January 10, 2021): 58. http://dx.doi.org/10.3390/medicina57010058.
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This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.
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Cicero, Arrigo F. G., Federica Fogacci, Masanari Kuwabara, and Claudio Borghi. "Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update." Medicina 57, no. 1 (January 10, 2021): 58. http://dx.doi.org/10.3390/medicina57010058.
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This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.
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Ahmad, Saeed, Ejaz Mohiuddin, Syed Muhammad Ali Shah, Muhammad Akram, Muhammad Amjad, Jaweria Nisar, Muhammad Riaz, Naveed Munir, and Ghulam Rasool. "Therapeutic Efficacy of Urinile Against Gouty Arthritis." Dose-Response 18, no. 4 (October 1, 2020): 155932582094693. http://dx.doi.org/10.1177/1559325820946934.
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Gout is arthritis caused due to Monosodium urate (MSU) crystals deposition occurring particularly in patients with associated comorbidities limiting the use of conventional therapies. This study was planned to evaluate the therapeutic efficacy of urinile (a herbal drug) for the treatment of gouty arthritis. Allopurinol was used as standard drug (positive control). The study population of 250 volunteers (gouty arthritis patients) were divided into 2 groups as test and control group (n = 125 each). Gouty arthritis patients in test and control group were treated with 300 mg each of urinile and allopurinol, respectively. Clinical symptoms of all the study volunteers were recorded and serum uric acid was determined. Significant (p < 0.05) reduction in serum uric acid level toward normal was found in test group individuals. Clinical symptoms of gouty arthritis patients were also improved in test group compared to control group. Results showed that urinile has the potential to decrease serum uric acid level in gouty arthritis patients probably because of its antioxidant potential and xanthine oxidase inhibitory activity. It can be concluded that the tested herbal drug urinile is more potent in treating gouty arthritis patients and can be used as an effective alternative to the most commonly used allopathic drugs.
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Shen, Z., C. Colton, R. Yan, E. Polvent, V. Hingorani, S. Yan, and L. T. Yeh. "POS1128 COMBINATION TREATMENT OF AR882, A NEW URAT1 INHIBITOR, AND XANTHINE OXIDASE INHIBITORS ALLOPURINOL OR FEBUXOSTAT: EFFECT ON URIC ACID, HYPOXANTHINE AND XANTHINE IN PLASMA OR SERUM AND URINE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 843.2–843. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1215.
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Background:Xanthine oxidase inhibitors (XOI) are commonly used as urate lowering therapy (ULT) for the treatment of gout. Allopurinol, the first-line treatment, demonstrates low response rate (< 40%), defined as serum urate (sUA) lowering effect below 6 mg/dL, in multiple large-scale clinical trials. As recommended in EULAR guidelines and other literatures, targeting sUA <5 mg/dL or even <4 mg/dL, provides a better opportunity to lower incidence of gout flare and resolution of tophi in gout patients. Febuxostat, a more potent XOI, has been classified as a second-line ULT agent due to increased cardiovascular risks in certain patient populations. For XOI intolerance and non-responders, replacing the agent with a potent URAT1 inhibitor or adding an URAT1 inhibitor onto a current treatment regimen provides opportunities to improve response rates in patients with refractory gout. AR882 is a uricosuric agent that blocks the reabsorption of uric acid in the apical side of renal tubule, hence increases excretion of uric acid into the urine. A phase 2a study has demonstrated the additive effects of AR882 in combination with allopurinol or febuxostat.Objectives:To evaluate the effect of AR882 alone or in combination with allopurinol or febuxostat on circulating levels and urinary excretion of hypoxanthine, xanthine and uric acid. Furthermore, to elucidate the contribution of each drug towards the combination effect in sUA lowering.Methods:Plasma, serum, and urine samples were collected from 17 patients with gout who received a once-daily dosing of AR882 50 mg, allopurinol 300 mg or febuxostat 40 mg, or in combination for one week in a phase 2a study. Samples were collected to measure hypoxanthine, xanthine and uric acid levels in plasma or serum and the amount of each excreted in the urine. Plasma Cmax and AUC and 24-hour urine excretion amount (mg) of hypoxanthine and xanthine were calculated by non-compartmental analysis method.Results:In monotherapy, AR882 demonstrated better sUA lowering effect (↓53%) compared to allopurinol (↓35%) or febuxostat (↓39%). Combination of AR882 and allopurinol lowered sUA by 66% while combination of AR882 and febuxostat lowered sUA by 71%. Based on the change of xanthine in plasma following combination treatments, it can be calculated that allopurinol contributed 28% of the urate lowering effect, whereas AR882 contributed 38% of the effect. Similarly, febuxostat contributed 33% of the urate lowering effect and AR882 contributed to about 36-38% of the effect when used in combination. The combination treatments significantly increased the response ratio for patients achieving sUA levels < 5 mg/dL, 4 mg/dL, and even 3 mg/dL. In the combination with allopurinol, 100%, 100%, 100%, and 44% patients achieved sUA < 6 mg/dL, < 5 mg/dL, 4 mg/dL, and 3 mg/dL, respectively. Similar results were seen with the combination of AR882 and febuxostat. Treatment with allopurinol or febuxostat alone resulted in 8 to 10-fold and 16-fold increases of xanthine exposure, respectively. The combination of AR882 and allopurinol or febuxostat showed approximately 5-8 fold or 13-fold increases in plasma xanthine, respectively. Treatment with allopurinol or febuxostat alone resulted in 2-3 fold increase in hypoxanthine exposure. Relative changes of hypoxanthine were not significantly different in the presence versus absence of AR882. Increased excretion of xanthine and hypoxanthine was also observed in urine. AR882 was well tolerated in gout patients, showing a similar safety profile to that observed in healthy volunteer studies.Conclusion:AR882 dose alone had no effect on plasma or urine hypoxanthine and xanthine levels. AR882 contributed to a greater portion of the serum urate lowering effects when used in combination with XO inhibitors, and with 100% of patients achieving levels below 4 mg/dL when combined with allopurinol. The use of AR882 in combination with XO inhibitors may provide an option for preventing flares as well as tophi reduction in advanced patients.Disclosure of Interests:Zancong Shen Employee of: arthrosi therapeutics, Chris Colton Employee of: Arthrosi therapeutics Inc, Rongzi Yan Employee of: Arthrosi therapeutics Inc, Elizabeth Polvent Employee of: Arthrosi therapeutics Inc, Vijay Hingorani Consultant of: Arthrosi therapeutics Inc, Shunqi Yan Employee of: Arthrosi therapeutics Inc, Li-Tain Yeh Employee of: Arthrosi therapeutics Inc.
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Aouffen, M'hammed, Joanne Paquin, Eric De Grandpré, Réginald Nadeau, and Mircea-Alexandru Mateescu. "Deglycosylated ceruloplasmin maintains its enzymatic, antioxidant, cardioprotective, and neuronoprotective properties." Biochemistry and Cell Biology 79, no. 4 (August 1, 2001): 489–97. http://dx.doi.org/10.1139/o01-125.
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Ceruloplasmin (CP), an important serum antioxidant, is a blue copper glycoprotein with ferroxidase and oxidase activities. Among other physiological actions, plasma CP was shown to protect isolated rat hearts and cultured P19 neurons exposed to oxidative stress conditions, raising the possibility of using this protein in the treatment of cardiac and neuronal diseases related to oxidative damage. However, since therapeutic applications of CP must be compatible with restrictions in the administration of blood derivatives to humans, there is a need to produce the protein by genetic engineering. To help in the choice of adequate expression systems, we undertook this study to determine if the carbohydrate moiety on the protein is essential for its functions. CP was completely deglycosylated using N-glycosidase F under nondenaturing conditions. Deglycosylated CP was found to retain most of the conformational, antioxidant, and enzymatic properties of the native protein in vitro. Moreover, both forms of the protein had similar cardioprotective and neuronoprotective effects against oxidative stress as evaluated with isolated rat hearts undergoing ischemiareperfusion and with cultured P19 neurons exposed to xanthine xanthine oxidase. The data thus indicate that the carbohydrate moiety of CP is not essential for its enzymatic and protective actions. Accordingly, even the use of expression systems that do not glycosylate mammalian proteins could provide a recombinant CP that retains its therapeutic potential.Key words: copperproteins, protein-linked carbohydrates, ischemia-reperfusion, isolated rat hearts, cultured P19 neurons.
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Munteanu, Mircea, Adrian Sturza, Adalbert Schiller, and Romulus Timar. "Endothelial Dysfunction in Diabetes – Clasic Sources of Vascular Oxidative Stress (Nadph Oxidases, Enos Uncoupling and Xanthine Oxidase)." Romanian Journal of Diabetes Nutrition and Metabolic Diseases 20, no. 2 (June 1, 2013): 149–55. http://dx.doi.org/10.2478/rjdnmd-2013-0019.
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Abstract Cardiovascular disease is the leading cause of disease / mortality worldwide. It is generally accepted that increased production of reactive oxygen species (ROS) has an important role in cardiovascular pathology, contributing to endothelial dysfunction and to the aggravation of atherosclerosis. Among all cardiovascular risk factors, diabetes mellitus is one of the most important. The worldwide prevalence of diabetes has increased rapidly even in developing countries, doubling the combined risk of cardiovascular events in patients with hypertension. In diabetes, increased reactive oxygen species (ROS) production leads to endothelial dysfunction, recognized by the presence of impaired vascular relaxation, increased vascular smooth muscle cells growth and hypertrophy, all together contributing to atherosclerotic plaque formation. On this basis, the vascular endothelium has emerged as a therapeutic target, with the aim to improve systemic metabolic state by improving vascular function. In this review we have focused on the most important sources of reactive oxygen species generated by vascular endothelium in diabetic patients (NADPH Oxidases, eNOS uncoupling, Xanthine oxidase). The importance of oxidative stress in mediating the vascular complications of diabetes is supported by studies showing that antioxidant therapy correct the vascular function in humans or in experimental models of diabetes. Therefore, understanding the physiological mechanisms involved in vascular disorders resulting from hyperglycemia is essential for the proper use of available therapeutic resources.
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Mozgovaya, E., S. Bedina, A. Trofimenko, M. Mamus, S. Spitsina, and I. Zborovskaya. "AB0061 ALTERATIONS OF XANTHINE OXIDOREDUCTASE ACTIVITY IN RED BLOOD CELLS AFTER GLUCOCORTICOID TREATMENT IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1062.1–1062. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3168.
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Background:According to modern concepts, rheumatoid arthritis (RA) refers to severe autoimmune rheumatic diseases. The activation of free radical oxidation processes is essential in the development of this disease [1]. Xanthine oxidoreductase is a significant reactive oxygen species source [2]. Despite the great advances in the treatment of rheumatoid arthritis (RA) associated with the introduction of innovative drugs and especially the improvement of the strategy for their use into clinical practice, glucocorticoids still remain an important component of RA pharmacotherapy in actual clinical practice.Objectives:to evaluate the changes in activities of xanthine oxidoreductase interconvertible forms (xanthine oxidase, ЕС 1.17.3.2 and xanthine dehydrogenase, ЕС 1.17.1.4) in lysed red blood cells of RA patients in relation with glucocorticoid treatment.Methods:47 RA patients with verified RA and 30 healthy controls were enrolled in the study. The diagnosis was verified using the 2010 ACR/EULAR criteria 2010. All patients have moderate DAS28 scores. RA patients were randomized into 2 groups comparable in gender, age and the principal clinical manifestations. Methylprednisolone (Metipred, Orion Corp.), average dose 30 mg/day, and betamethasone (Diprospan, Schering-Plough), single dose7 mg, were administered intramuscularly in the respective groups. Хanthine oxidase (XO) and xanthine dehydrogenase (XDG) activities were measured in lysed red blood cells by spectrophotometric method as previously described [3]. The changes of these enzymes activities were studied in RA patients before and after the injection of glucocorticoids. Statistical comparison tests were selected in according to common guidelines, differences were considered significant when p<0.05. Central tendencies were expressed as means±SEM.Results:Mean age of patients in methylprednisolone group was 41.8±1.05 years, and mean RA duration (± SEM) was 7.9±0.21 years. Mean age of patients in diprospan group was 40.9±1.07 years, and mean RA duration was 8.0±0.33 years. Significant decreases of XO activity and increase of XDG activity were observed in lysed red blood cells of RA patients just after the injection of each glucocorticoid drug. Changes of the enzymatic activities in lysed red blood cells were more pronounced in methylprednisolone group. However enzymatic activity did not reach the level of healthy controls. As described previously, decreased XO activity and increased XDG activity were observed in plasma of RA patients just after the injection of the average therapeutic doses of glucocorticoids, as well as in lysed lymphocytes just after the injection of methylprednisolone [4].Conclusion:Treatment with methylprednisolone and betamethasone can affect the balance of XO/XDG activity and increase the antioxidant potential of the blood. This effect can exert beneficial influence on autoimmune inflammation in RA.References:[1]Mateen S., et al. Increased reactive oxygen species formation and oxidative stress in rheumatoid arthritis. PLoS ONE 2016;11(4):e0152925.[2]Çimen M.Y., et al. Oxidant/antioxidant status of the erythrocytes from patients with rheumatoid arthritis. Clin Rheumatol 2000;19(4):275-277.[3]Zborovskaya I.A., et al. Influence of analgetics on plasma and lymphocytic activity of the purine metabolism enzymes in rheumatoid arthritis patients. Russian Journal of Pain 2018;3:47.[4]Mozgovaya E.E., et al. Xanthinoxidase and xanthine dehydrogenase activities in rheumatoid arthritis after glucocorticoid treatment. Osteoporosis International 2019;30(2):S433-434.Disclosure of Interests:None declared
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Mokra, Daniela, and Juraj Mokry. "Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?" International Journal of Molecular Sciences 22, no. 4 (February 16, 2021): 1929. http://dx.doi.org/10.3390/ijms22041929.
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Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial–endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.
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Auberval, Nathalie, Stéphanie Dal, William Bietiger, Elodie Seyfritz, Jean Peluso, Christian Muller, Minjie Zhao, et al. "Oxidative Stress Type Influences the Properties of Antioxidants Containing Polyphenols in RINm5F Beta Cells." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/859048.
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Thein vitromethods currently used to screen bioactive compounds focus on the use of a single model of oxidative stress. However, this simplistic view may lead to conflicting results. The aim of this study was to evaluate the antioxidant properties of two natural extracts (a mix of red wine polyphenols (RWPs) and epigallocatechin gallate (EGCG)) with three models of oxidative stress induced with hydrogen peroxide (H2O2), a mixture of hypoxanthine and xanthine oxidase (HX/XO), or streptozotocin (STZ) in RINm5F beta cells. We employed multiple approaches to validate their potential as therapeutic treatment options, including cell viability, reactive oxygen species production, and antioxidant enzymes expression. All three oxidative stresses induced a decrease in cell viability and an increase in apoptosis, whereas the level of ROS production was variable depending on the type of stress. The highest level of ROS was found for the HX/XO-induced stress, an increase that was reflected by higher expression antioxidant enzymes. Further, both antioxidant compounds presented beneficial effects during oxidative stress, but EGCG appeared to be a more efficient antioxidant. These data indicate that the efficiency of natural antioxidants is dependent on both the nature of the compound and the type of oxidative stress generated.
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Hu, Weilei, Guosheng Wang, Lonny B. Yarmus, and Yuan Wan. "Combined Methylome and Transcriptome Analyses Reveals Potential Therapeutic Targets for EGFR Wild Type Lung Cancers with Low PD-L1 Expression." Cancers 12, no. 9 (September 3, 2020): 2496. http://dx.doi.org/10.3390/cancers12092496.
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Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated remarkable treatment efficacy in advanced non-small cell lung cancer (NSCLC). However, low expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type NSCLCs are refractory, and only few therapeutic options exist. Currently, combination therapy with ICIs is frequently used in order to enhance the treatment response rates. Yet, this regimen is still associated with poor treatment outcome. Therefore, identification of potential therapeutic targets for this subgroup of NSCLC is strongly desired. Here, we report the distinct methylation signatures of this special subgroup. Moreover, several druggable targets and relevant drugs for targeted therapy were incidentally identified. We found hypermethylated differentially methylated regions (DMRs) in three regions (TSS200, TSS1500, and gene body) are significantly higher than hypomethylated ones. Downregulated methylated genes were found to be involved in negative regulation of immune response and T cell-mediated immunity. Moreover, expression of four methylated genes (PLCXD3 (Phosphatidylinositol-Specific Phospholipase C, X Domain Containing 3), BAIAP2L2 (BAR/IMD Domain Containing Adaptor Protein 2 Like 2), NPR3 (Natriuretic Peptide Receptor 3), SNX10 (Sorting Nexin 10)) can influence patients’ prognosis. Subsequently, based on DrugBank data, NetworkAnalyst 3.0 was used for protein–drug interaction analysis of up-regulated differentially methylated genes. Protein products of nine genes were identified as potential druggable targets, of which the tumorigenic potential of XDH (Xanthine Dehydrogenase), ATIC (5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase), CA9 (Carbonic Anhydrase 9), SLC7A11 (Solute Carrier Family 7 Member 11), and GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase) have been demonstrated in previous studies. Next, molecular docking and molecular dynamics simulation were performed to verify the structural basis of the therapeutic targets. It is noteworthy that the identified pemetrexed targeting ATIC has been recently approved for first-line use in combination with anti-PD1 inhibitors against lung cancer, irrespective of PD-L1 expression. In future work, a pivotal clinical study will be initiated to further validate our findings.
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Mukhopadhyay, Partha, Mohanraj Rajesh, Sándor Bátkai, Yoshihiro Kashiwaya, György Haskó, Lucas Liaudet, Csaba Szabó, and Pál Pacher. "Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 5 (May 2009): H1466—H1483. http://dx.doi.org/10.1152/ajpheart.00795.2008.
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Doxorubicin (DOX) is a potent available antitumor agent; however, its clinical use is limited because of its cardiotoxicity. Cell death is a key component in DOX-induced cardiotoxicity, but its mechanisms are elusive. Here, we explore the role of superoxide, nitric oxide (NO), and peroxynitrite in DOX-induced cell death using both in vivo and in vitro models of cardiotoxicity. Western blot analysis, real-time PCR, immunohistochemistry, flow cytometry, fluorescent microscopy, and biochemical assays were used to determine the markers of apoptosis/necrosis and sources of NO and superoxide and their production. Left ventricular function was measured by a pressure-volume system. We demonstrated increases in myocardial apoptosis (caspase-3 cleavage/activity, cytochrome c release, and TUNEL), inducible NO synthase (iNOS) expression, mitochondrial superoxide generation, 3-nitrotyrosine (NT) formation, matrix metalloproteinase (MMP)-2/MMP-9 gene expression, poly(ADP-ribose) polymerase activation [without major changes in NAD(P)H oxidase isoform 1, NAD(P)H oxidase isoform 2, p22 phox, p40 phox, p47 phox, p67 phox, xanthine oxidase, endothelial NOS, and neuronal NOS expression] and decreases in myocardial contractility, catalase, and glutathione peroxidase activities 5 days after DOX treatment to mice. All these effects of DOX were markedly attenuated by peroxynitrite scavengers. Doxorubicin dose dependently increased mitochondrial superoxide and NT generation and apoptosis/necrosis in cardiac-derived H9c2 cells. DOX- or peroxynitrite-induced apoptosis/necrosis positively correlated with intracellular NT formation and could be abolished by peroxynitrite scavengers. DOX-induced cell death and NT formation were also attenuated by selective iNOS inhibitors or in iNOS knockout mice. Various NO donors when coadministered with DOX but not alone dramatically enhanced DOX-induced cell death with concomitant increased NT formation. DOX-induced cell death was also attenuated by cell-permeable SOD but not by cell-permeable catalase, the xanthine oxidase inhibitor allopurinol, or the NADPH oxidase inhibitors apocynine or diphenylene iodonium. Thus, peroxynitrite is a major trigger of DOX-induced cell death both in vivo and in vivo, and the modulation of the pathways leading to its generation or its effective neutralization can be of significant therapeutic benefit.
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Nowacka-Jechalke, Natalia, Renata Nowak, Marta Kinga Lemieszek, Wojciech Rzeski, Urszula Gawlik-Dziki, Nikola Szpakowska, and Zbigniew Kaczyński. "Promising Potential of Crude Polysaccharides from Sparassis crispa against Colon Cancer: An In Vitro Study." Nutrients 13, no. 1 (January 6, 2021): 161. http://dx.doi.org/10.3390/nu13010161.
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The aim of the present study was to evaluate in vitro the beneficial potential of crude polysaccharides from S. crispa (CPS) in one of the most common cancer types—colon cancer. The determination of the chemical composition of CPS has revealed that it contains mostly carbohydrates, while proteins or phenolics are present only in trace amounts. 1H NMR and GC–MS methods were used for the structural analysis of CPS. Biological activity including anticancer, anti-inflammatory and antioxidant properties of CPS was investigated. CPS was found to be non-toxic to normal human colon epithelial CCD841 CoN cells. Simultaneously, they destroyed membrane integrity as well as inhibited the proliferation of human colon cancer cell lines: Caco-2, LS180 and HT-29. Antioxidant activity was determined by various methods and revealed the moderate potential of CPS. The enzymatic assays revealed no influence of CPS on xanthine oxidase and the inhibition of catalase activity. Moreover, pro-inflammatory enzymes such as cyclooxygenase-2 or lipooxygenase were inhibited by CPS. Therefore, it may be suggested that S. crispa is a valuable part of the regular human diet, which may contribute to a reduction in the risk of colon cancer, and possess promising activities encouraging further studies regarding its potential use as chemopreventive and therapeutic agent in more invasive stages of this type of cancer.
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Pasina, Luca, Barbara Brignolo Ottolini, Laura Cortesi, Mauro Tettamanti, Carlotta Franchi, Alessandra Marengoni, Pier Mannuccio Mannucci, and Alessandro Nobili. "Need for Deprescribing in Hospital Elderly Patients Discharged with a Limited Life Expectancy: The REPOSI Study." Medical Principles and Practice 28, no. 6 (2019): 501–8. http://dx.doi.org/10.1159/000499692.
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Objective: Older people approaching the end of life are at a high risk for adverse drug reactions. Approaching the end of life should change the therapeutic aims, triggering a reduction in the number of drugs.The main aim of this study is to describe the preventive and symptomatic drug treatments prescribed to patients discharged with a limited life expectancy from internal medicine and geriatric wards. The secondary aim was to describe the potentially severe drug-drug interactions (DDI). Materials and Methods: We analyzed Registry of Polytherapies Societa Italiana di Medicina Interna (REPOSI), a network of internal medicine and geriatric wards, to describe the drug therapy of patients discharged with a limited life expectancy. Results: The study sample comprised 55 patients discharged with a limited life expectancy. Patients with at least 1 preventive medication that could be considered for deprescription at the end of life were significantly fewer from admission to discharge (n = 30; 54.5% vs. n = 21; 38.2%; p = 0.02). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, lipid-lowering drugs, and clonidine were the most frequent potentially avoidable medications prescribed at discharge, followed by xanthine oxidase inhibitors and drugs to prevent fractures. Thirty-seven (67.3%) patients were also exposed to at least 1 potentially severe DDI at discharge. Conclusion: Hospital discharge is associated with a small reduction in the use of commonly prescribed preventive medications in patients discharged with a limited life expectancy. Cardiovascular drugs are the most frequent potentially avoidable preventive medications. A consensus framework or shared criteria for potentially inappropriate medication in elderly patients with limited life expectancy could be useful to further improve drug prescription.
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Cerchietti, Leandro, Chen Qiuying, ShaoNing Yang, Wang Chunjie, and Steven Gross. "Serum Metabolomics Uncovers a New Therapeutic Target in Diffuse Large B Cell Lymphoma (DLBCL)." Blood 120, no. 21 (November 16, 2012): 1648. http://dx.doi.org/10.1182/blood.v120.21.1648.1648.
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Abstract Abstract 1648 DLBCL is a molecularly heterogeneous disease usually treated with chemoimmunotherapy ultimately curing ∼65% of pts. In order to improve therapy for these pts, the identification of broadly relevant therapeutic targets is critical. One such target is HSP90. Tumor cells are enriched for a fraction of HSP90 found in higher-order multi-chaperone complexes. Tumor-enriched HSP90 (teHSP90) displays higher affinity for HSP90 inhibitors than normal tissues, which contain latent, uncomplexed HSP90. Many client proteins are depleted upon exposure to teHSP90 inhibitors. PU-H71 is a highly teHSP90 selective inhibitor with an excellent toxicity profile currently being tested for DLBCL in clinical trials. Combination therapies involving teHSP90 inhibitors may synergize with drugs targeting client proteins of teHSP90 by more powerfully inhibit survival pathways. Cell replication involves substantial metabolic demands and PU-H71-induced degradation of enzymatic client proteins may affect critical metabolic pathways. We hypothesized that by identifying PU-H71-induced metabolic changes, metabolomics could point to potential new targets for combinatorial therapeutic intervention. We therefore analyzed the global metabolic consequence of teHSP90 inhibition in DLBCL by PU-H71. The metabolome was analyzed in the serum of LY7 DLBCL xenografted mice treated with 75 mg/m2 of PU-H71 for 24 h (n=5) or vehicle (n=5) by HPLC/MS. Bioinformatic analysis revealed significant changes in 122 metabolites in PUH-71- vs. vehicle-treated mice; including significantly lower levels of xanthine, hypoxanthine, adenosine, xanthosine monophosphate (XMP), depletion of the guanine nucleoside pool, together with higher levels of inosine and inosine monophosphate (IMP). These metabolic changes pointed towards possible PU-H71 mediated inhibition of inosine monophosphate dehydrogenase (IMPDH). IMPDH catalyzes the NAD-dependent oxidation of IMP to XMP, which is the committed step in de novo guanosine nucleotide biosynthesis. This reaction is particularly important to lymphocytes, which depend on IMPDH activity to generate the guanosine nucleotide levels needed to initiate a proliferative response to antigen. Increased IMPDH activity has also been observed in leukemia and lymphoma, mostly as consequence of up-regulation of the IMPDH2 isoform. In order to determine whether IMPDH1/2 stability depends on teHSP90, we treated a panel of 6 DLBCL cell lines (including LY7) with the mean GI50 of PU-H71 (1 μM) for up to 24 h and checked for IMPDH1/2 abundance. We found a time-dependent decrease in IMPDH2 protein levels. Similar results were obtained with the chemically unrelated HSP90 inhibitor 17-DMAG. To confirm that IMPDH2 binds to teHSP90, we took advantage of an affinity-based PUH-71 pull-down method we recently developed. In this assay PU-H71-beads preferentially bind to teHSP90 complexes pecipitating cancer-related client proteins. By using this assay, we determined that IMPDH2 was indeed a teHSP90 client in DLBCL cells. We also found that PU-H71 (and 17-DMAG) inhibited the activity of IMPDH in DLBCL cells by shortening its half-live (IMPDH t1/2from 2 h to 45 min). To determine whether the combination of teHSP90 inhibitors will synergize with IMPDH inhibitors in killing DLBCL, we treated a panel of 10 DLBCL cell lines with the combination of PU-H71 and two IMPDH inhibitors in clinical use, mycophenolic acid (MPA, an uncompetitive inhibitor) and ribavirin (RIB, a competitive inhibitor). We found that most cell lines showed synergistic killing effect when treated with the combination of drugs compared to each drug alone (determined by isobologram method). This prompted us to test the combination in vivo. SCID mice were xenografted with LY7 and SUDHL6 and once tumor developed, they were treated with vehicle, PU-H71, mycophenolate mofetil (MMF, the pro-drug of MPA), RIB and the combination of PU-H71 and MMF or RIB. We found that mice treated with the combination of drugs exhibited greater effect that each drug alone (p=0.002 for SU-DHL6 and p>0.001 for LY7 for PU-H71+MMF, and p=0.01 for SU-DHL6 and p=0.02 for LY7 for PU-H71+RIB, all T-test day 10). There were no toxic effects. In sum, our work uses serum metabolomics to provide new insights into the pharmacological targets of a particular HSP90 inhibitor, and unveiled a critical survival pathway in DLBCL that was harnessed to develop a rationally combined targeted therapy. Disclosures: No relevant conflicts of interest to declare.
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Yao, Jianbiao, Houhong He, Jin Xue, Jianfang Wang, Huihui Jin, Jian Wu, Jiangning Hu, Ruwei Wang, and Kenny Kuchta. "Mori Ramulus (Chin.Ph.)—the Dried Twigs of Morus alba L./Part 1: Discovery of Two Novel Coumarin Glycosides from the Anti-Hyperuricemic Ethanol Extract." Molecules 24, no. 3 (February 11, 2019): 629. http://dx.doi.org/10.3390/molecules24030629.
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In Traditional Chinese Medicine (TCM), Mori ramulus (Chin.Ph.)—the dried twigs of Morus alba L.—is extensively used as an antirheumatic agent and also finds additional use in asthma therapy. As a pathological high xanthine oxidase (XO, EC 1.1.3.22) activity is strongly correlated to hyperuricemy and gout, standard anti-hyperuremic therapy typically involves XO inhibitors like allopurinol, which often cause adverse effects by inhibiting other enzymes involved in purine metabolism. Mori ramulus may therefore be a promissing source for the development of new antirheumatic therapeutics with less side effects. Coumarins, one of the dominant groups of bioactive constituents of M. alba, have been demonstrated to possess anti-inflammatory, antiplatelet aggregation, antitumor, and acetylcholinesterase (AChE) inhibitory activities. The combination of HPLC (DAD) and Q-TOF technique could give excellent separating and good structural characterization abilities which make it suitable to analyze complex multi-herbal extracts in TCM. The aim of this study was to develop a HPLC (DAD)/ESI-Q-TOF-MS/MS method for the identification and profiling of pharmacologically active coumarin glycosides in Mori ramulus refined extracts for used in TCM. This HPLC (DAD)/ESI-Q-TOF-MS/MS method provided a rapid and accurate method for identification of coumarin glycosides—including new natural products described here for the first time—in the crude extract of M. alba L. In the course of this project, two novel natural products moriramulosid A (umbelliferone-6-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside) and moriramulosid B (6-[[6-O-(6-deoxy-α-l-mannopyranosyl)-β-d-glucopyranosyl]oxy]-2H-1-benzopyran-1-one) were newly discovered and the known natural product Scopolin was identified in M. alba L. for the first time.
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Szebeni, János, Lajos Baranyi, Sándor Sávay, Michael Bodó, János Milosevits, Carl R. Alving, and Rolf Bünger. "Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function." American Journal of Physiology-Heart and Circulatory Physiology 290, no. 3 (March 2006): H1050—H1058. http://dx.doi.org/10.1152/ajpheart.00622.2005.
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Cardiac anaphylaxis is a severe, life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs. Earlier studies highlighted an amplifying effect of locally applied C5a on the process; however, the role of systemic complement (C) activation with C5a liberation in blood has not been explored to date. In the present study, we used the porcine liposome-induced cardiopulmonary distress model for 1) characterizing and quantifying peripheral C activation-related cardiac dysfunction; 2) exploring the role of C5a in cardiac abnormalities and therapeutic potential of C blockage by soluble C receptor type 1 (sCR1) and an anti-C5a antibody (GS1); and 3) elucidating the role of adenosine and adenosine receptors in paradoxical bradycardia, one of the symptoms observed in this model. Pigs were injected intravenously with different liposomes [Doxil and multilamellar vesicles (MLV)], zymosan, recombinant human (rhu) C5a, and adenosine, and the ensuing hemodynamic and cardiac changes (hypotension, tachy- or bradycardia, arrhythmias, ST-T changes, ventricular fibrillation, and arrest) were quantified by ranking on an arbitrary scale [cardiac abnormality score (CAS)]. There was significant correlation between CAS and C5a production by liposomes in vitro, and the liposome-induced cardiac abnormalities were partially or fully reproduced with zymosan, rhuC5a, adenosine, and the selective adenosine A1 receptor agonist cyclopentyl-adenosine. The use of C nonactivator liposomes or pretreatment of pigs with sCR1 or GS1 attenuated the abnormalities. The selective A1 blocker cyclopentyl-xanthine inhibited bradycardia without influencing hypotension, whereas the A2 blocker 4-(2-{7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino}ethyl)phenol (ZM-24135) had no such effect. These data suggest that 1) systemic C activation can underlie cardiac anaphylaxis, 2) C5a plays a causal role in the reaction, 3) adenosine action via A1 receptors may explain paradoxical bradycardia, and 4) inhibition of C5a formation or action or of A1-receptor function may alleviate the acute cardiotoxicity of liposomal drugs and other intravenous agents that activate C.
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BASIVIREDDY, Jayasree, Molly JACOB, and Kunissery A. BALASUBRAMANIAN. "Oral glutamine attenuates indomethacin-induced small intestinal damage." Clinical Science 107, no. 3 (August 24, 2004): 281–89. http://dx.doi.org/10.1042/cs20030390.
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The use of NSAIDs (non-steroidal anti-inflammatory drugs), although of great therapeutic value clinically, is limited by their tendency to cause mucosal damage in the gastrointestinal tract. In the small intestine, the effects these drugs have been shown to produce include inhibition of cyclo-oxygenase, mitochondrial dysfunction and free radical-induced oxidative changes, all of which contribute to the mucosal damage seen. Glutamine is a fuel preferentially used by enterocytes and is known to contribute to maintaining the integrity of these cells. In the present study, we investigated the effect of glutamine on indomethacin-induced changes in the small intestinal mucosa. Rats were given 2% glutamine or glutamic acid or isonitrogenous amino acids, glycine or alanine, in the diet for 7 days. Indomethacin was then administered orally at a dose of 40 mg/kg of body weight. After 1 h, the small intestine was removed and used for the measurement of parameters of oxidative stress and mitochondrial and BBM (brush border membrane) function. Evidence of oxidative stress was found in the mucosa of the small intestine of drug-treated rats, as indicated by significantly increased activity of xanthine oxidase (P<0.001) and myeloperoxidase (P<0.001), with corresponding decreases in the levels of several free radical scavenging enzymes and α-tocopherol (P<0.001 in all cases). Levels of products of peroxidation were also significantly elevated (P<0.001 for all the parameters measured). In addition, oxidative stress was evident in isolated intestinal mitochondria and BBMs (P<0.001 for all the parameters measured), with associated alterations in function of these organelles (P<0.001 for all the parameters measured). Supplementation of the diet with glutamine or glutamic acid prior to treatment with indomethacin produced significant amelioration in all the effects produced by the drug in the small intestine (P<0.001 for all the parameters measured). Glycine and alanine were found to be much less effective in these respects.
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Koomen, David C., Joy D. Guingab, Paula S. Oliveira, Bin Fang, Min Liu, Eric A. Welsh, Mark B. Meads, et al. "Proteometabolomics of Melphalan Resistance in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 5619. http://dx.doi.org/10.1182/blood-2018-99-117747.
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Abstract Although advancements in therapeutic regimens for treating multiple myeloma (MM) have prolonged patient survival, the disease remains incurable. Several classes of drugs have contributed to these improvements, such as proteasome inhibitors, immunomodulators, deacetylase inhibitors, monoclonal antibodies, and alkylating agents including melphalan. An expanded arsenal of diverse chemotherapy targets has improved patient care significantly, yet we still lack sufficient knowledge of how cellular metabolism and drug processing can contribute to drug resistance. To address this issue, we utilize cell line models to simulate naïve and drug resistant states, which identify drug modifications, endogenous metabolites, proteins, and acute metabolic profile alterations associated with therapeutic escape. Here, we specifically focus on melphalan; an alkylating agent that forms DNA interstrand crosslinks, inhibits cell division, and leads to cell death through apoptosis (Povirk & Shuker. Mutat. Res. 1994, 318, 205). Melphalan remains a critical component of high dose therapy in the context of stem cell transplant and induction therapy in transplant ineligible patients outside the US. Ineffectiveness of alkylating agents remains a critical problem and serves as an excellent model for investigation of cellular metabolism and its contribution to drug resistance. Two parental MM cell lines (8226 & U266) were obtained from ATCC and resistant derivatives of each cell line (8226-LR5 & U266-LR6) were selected after chronic drug exposure. To assess mechanisms of melphalan resistance, we use liquid chromatography-mass spectrometry-based metabolomics and proteomics approaches, including studies of drug metabolism, untargeted metabolomics, and activity based protein profiling (ABPP). Drug metabolism monitors the intracellular and extracellular drug modifications over a 24-hour period after acute treatment. Untargeted metabolomics is used to compare the steady state endogenous intracellular metabolites of naïve and drug resistant cells. Differences in endogenous metabolites between naïve and drug resistant cell lines are also examined in the acute treatment dataset. ABPP utilizes desthiobiotinylating probes to enrich for ATP-utilizing enzymes, which are identified and quantified to enable comparison. We initially compared acute melphalan treatment in drug naive and resistant isogenic cell line pairs. Predictably, melphalan was converted into monohydroxylated and dihydroxylated metabolites more quickly in cells than in media controls. Differences in the formation of these metabolites between the naïve and resistant cell lines were not observed. The untargeted metabolomics data indicated in the 8226-LR5 model, glutathione and xanthine levels are elevated, while guanine is suppressed relative to naive cells. ABPP demonstrated changes in several enzymes related to purine and glutathione metabolism (Figure 1). Interestingly, the U266/U266-LR6 cell line models exhibit higher baseline levels of glutathione when compared with 8226/8226-LR5, indicating heterogeneous means of drug resistance. Alterations in arginine biosynthesis and nicotinate/nicotinamide metabolism are observed in the untargeted metabolomics and ABPP of U266/U266-LR6. Common pathways (e.g. purine biosynthesis) are altered in both models, although the changes involve different molecules. In examining two models of acquired melphalan resistance, we demonstrate frank differences in metabolic pathways associated with steady state and acute drug response. These data demonstrate the potential heterogeneity in drug resistance mechanisms and the need for more biomarkers to personalize treatment. Ongoing studies involve introduction of enzyme inhibitors in targeted pathways and supplementation of metabolites to validate their role in resistance. Furthermore, we will examine expression of these metabolic pathways associated with ex vivo melphalan resistance in a cohort of over 100 patient samples with paired RNA sequencing. The long term goals are to elucidate mechanisms of therapeutic response, identify biomarkers of metabolism in melphalan resistance, enhance drug efficacy, predict personalized patient treatment, and improve overall MM patient care. Disclosures No relevant conflicts of interest to declare.
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Vasta, Lauren Marie, Richard C. Zanetti, Dina S. Parekh, Anne B. Warwick, and Kenneth Lieuw. "A Retrospective Review of Mercaptopurine Metabolism Reveals High Rate of Patients with Suboptimal Metabolites Successfully Corrected with Allopurinol." Blood 134, Supplement_1 (November 13, 2019): 3878. http://dx.doi.org/10.1182/blood-2019-126184.
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Introduction: 6-Mercaptopurine (6-MP) is the most frequently used chemotherapy agent in the management of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Skewed drug metabolism can decrease the effectiveness of 6-MP while also resulting in unnecessary toxicities. Each individual's ability to metabolize 6-MP into the desired therapeutic product, 6-thioguanine nucleotide (6-TGN), is directly opposed by the development of the hepatotoxic byproduct, 6-methyl-mercaptopurine (6-MMPN). Certain individuals, referred to as 'shunters,' preferentially generate high levels of 6-MMPN resulting in decreased production of 6-TGN. Current guidelines suggest holding or lowering 6-MP doses in the setting of toxicity. However this approach results in decreased intensity of 6-MP treatment, potentially risking an increase in disease relapse. Allopurinol, a drug used to manage hyperuricemia, can alter 6-MP metabolism to maximize 6-TGN production while reducing the hepatotoxic metabolite, 6-MMPN. Methods: We performed a single institution, IRB approved, retrospective cohort study to quantify and characterize the rate of shunters treated in our center. Chart review was conducted of ALL and LL patients treated for at least one year of maintenance therapy at our center over a 10 year period from January 1, 2009 to June 1, 2019. Incidents of hypoglycemia (glucose <74), hepatic inflammation (ALT >123), and hypogammaglobulinemia (IgG <400) were recorded. If available, metabolite levels were collected, noting levels of 6-MMPN from 6,000 -10,000 and greater than 10,000 pmol/8 x 108 RBC. If the patient was started on allopurinol, we noted the effects of the intervention on the aforementioned lab values and their clinical course. Stata was utilized for all statistical analysis. Results: We performed a chart review on 42 eligible patients and included demographic information (Table 1). Using lab data, we documented potential markers of toxicity (Table 2). Seventy four percent of patients had a least one episode of documented hypoglycemia, and 88% had at least one episode of elevated ALT > 3 times the upper limit of normal. Metabolites were checked in 66% (28/42) of our patients. 6-MMPN levels were > 10,000 in 82.1% (23/28). Shunting was observed in 54% of the patients; meaning one half of the patients were eligible for allopurinol combination therapy. Allopurinol was initiated by the primary team for metabolite and laboratory derangements in 12 of 23 patients. All patients who received allopurinol had normalization of laboratory values with combined treatment. Discussion: In our population of pediatric and young adults treated for leukemia and lymphoblastic lymphoma, over half of the patients were shunters with metabolite derangements and associated signs of toxicity. Current guidelines in the Children's Oncology Group (COG) leukemia protocols recommend checking metabolites in the context of increased sensitivity to 6-MP, as in the case of TPMT and NUDT15 deficient patients, but do not specifically address the more common problem of skewed metabolism. Previous gastroenterology publications suggest there may be as many as 15% of shunters in their population of patients being prescribed 6MP. We found a much higher incidence of shunters among our leukemia population, many of whom had concurrent toxicities. The patients who received allopurinol during their treatment period showed adequate count suppression with reversal of undesired toxicities, suggesting that combination therapy may be beneficial for many more patients in the future. All of these patients remain in remission through 1 Jun 2019, the longest being 6 years post-treatment. Based on our institutional experience, we propose an algorithm for the use of allopurinol in conjunction with chemotherapy for patients with ALL or LL who have inappropriate 6-MP metabolism (Figure 1) to optimize their treatment while decreasing 6-MP associated toxicities. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Allopurinol inhibits the enzyme, xanthine oxidase, and is commonly used for prevention of tumor lysis syndrome and gout. However, it is understood that allopurinol also affects the metabolism of 6-Mercaptopurine. Allopurinol directs 6MP metabolism towards 6-TGN, the desired product, and away from 6-MMPN. 6-MMPN is associated with increased toxicity in patients. We describe in our abstract the incorporation of allopurinol therapy in many of our patients with abnormal 6-MP metabolism
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Martorell, Miquel, Xavier Lucas, Pedro Alarcón-Zapata, Xavier Capó, Maria Magdalena Quetglas-Llabrés, Silvia Tejada, and Antoni Sureda. "Targeting xanthine oxidase by natural products as a therapeutic approach for mental disorders." Current Pharmaceutical Design 26 (June 21, 2020). http://dx.doi.org/10.2174/1381612826666200621165839.
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: Mental disorders comprise diverse human pathologies including depression, bipolar affective disorder, schizophrenia, and dementia that affect millions of people around the world. The causes of mental disorders are unclear but growing evidence suggests that oxidative stress and the purine/adenosine system play a key role in their development and progression. Xanthine oxidase (XO) is a flavoprotein enzyme essential for the catalysis of the oxidative hydroxylation of purines -hypoxanthine and xanthine- to generate uric acid. As a consequence of the oxidative reaction of XO, reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are produced and, further, contribute to the pathogenesis of mental disorders. Altered XO activity has been associated with free radical-mediated neurotoxicity inducing cell damage and inflammation. Diverse studies reported a direct association between an increased activity of XO and diverse mental diseases including depression or schizophrenia. Small-molecule inhibitors, such as the well-known allopurinol, and dietary flavonoids, can modulate the XO activity and subsequent ROS production. In the present work, we review the available literature on XO inhibition by small molecules and their potential therapeutic application in mental disorders. In addition, we discuss the chemistry and molecular mechanism of XO inhibitors, as well as the use of structure-based and computational methods to design specific inhibitors with the capability of modulating XO activity.
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Kaur, Jaspreet, Shahaf Tuler, and Constantin A. Dasanu. "Acute gout flare of bilateral first metatarsophalangeal joints due to ibrutinib use in chronic lymphocytic leukemia." Journal of Oncology Pharmacy Practice, July 5, 2021, 107815522110297. http://dx.doi.org/10.1177/10781552211029703.
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Introduction Bruton tyrosine kinase inhibitors represent important tools in the therapeutic armamentarium against chronic lymphocytic leukemia (CLL) and other B-lymphoproliferative disorders. Case Report We describe herein a unique 65-year-old patient who presented with bilateral foot pain four months after starting treatment with ibrutinib for CLL. Of note, the patient had previously been diagnosed with gout, and was taking allopurinol prophylactically at the time of the event. Compliance with allopurinol was in excess of 99%. Yet, he was diagnosed with acute gout flare of bilateral first metatarsophalangeal (MTP) joints. Management & Outcome: Ibrutinib dose was reduced by one third, and the patient’s gout flare up was treated with ibuprofen as needed. After symptoms abated, ibrutinib was continued at 2/3rds of the dose, with an excellent CLL control. The patient tolerated this dose without any further adverse effects. Discussion/Conclusions: We have reported a unique side effect of acute bilateral first MTP joint gout flare likely triggered by ibrutinib use for CLL while the patient was taking a xanthine oxidase inhibitor. The mechanism by which ibrutinib caused this phenomenon remains to be elucidated.
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Basnet, Rajesh, Sandhya Khadka, Buddha Bahadur Basnet, Til Bahadur Basnet, Buddhi Bal Chidi, Sanjeev Nirala, Radheshyam Gupta, and Bidur Sharma. "Xanthine Oxidase and Transforming Growth Factor Beta-activated Kinase 1: potential Targets for Gout Intervention." Current Rheumatology Reviews 16 (November 26, 2020). http://dx.doi.org/10.2174/1573397116666201126162202.
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Background: Gout, an inflammatory arthritis, caused by the deposition of monosodium urate crystals into affected joints and other tissues has become one of the major health problems of today's world. The main risk factor for gout is hyperuricemia, which may be caused by excessive or insufficient excretion of uric acid. The incidence is usually in the age group of 30- 50 years, commonly in males. In developed countries, the incidence of gout ranges from 1 to 4%. Despite effective treatments, there has been an increase in the number of cases over the past few decades. Objective: In recent years, the development of targeted drugs in gout has made significant achievements. The global impact of gout continues to increase, and as a result, the focus of disease-modifying therapies remains elusive. In addition, the characterization of available instrumental compounds is urgently needed to explore the use of novel selective and key protein-ligand interactions for the effective treatment of gout. Xanthine oxidase (XO) is a key target in gout to consider the use of XO inhibitors in patients with mild to moderate condition, however, the costs are high and no other direct progress has been made. Despite many XO inhibitors, a selective potent inhibitor for XO is limited. Likewise, in recent years, attention has been focused on different strategies for the discovery and development of new selectivity ligands against transforming growth factor beta-activated kinase 1 (TAK1), a potential therapeutic target for gout. Therefore the insight on human XO structure and TAK1 provides a clue into protein-ligand interactions and provides the basis for molecular modeling and structure-based drug design. Conclusion: In this review, we briefly introduce the clinical characteristics, the development of crystal, inhibitors, and crystal structure of XO and TAK1 protein.
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AHMANE, Nadjia, Dina ATMANI-KILANI, Nassima CHAHER, Karima AYOUNI, Meriem RAHMANI-BERBOUCHA, Grégory DA COSTA, Nadjet DEBBACHE-BENAIDA, Tristan RICHARD, and Djebbar ATMANI. "Identification of bioactive compounds from Fraxinus angustifolia extracts with anti-NADH oxidase activity of bovine milk xanthine oxidoreductase." TURKISH JOURNAL OF BIOLOGY, April 5, 2019, 133–47. http://dx.doi.org/10.3906/biy-1810-26.
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Fraxinus angustifolia leaves and bark are used in traditional medicine against various inflammatory-related pathologies incumbent to reactive oxygen species (ROS) generation by the NADH oxidase activity of enzymes such as xanthine oxidoreductase (XOR). This study was designed to investigate the in vitro and in vivo inhibitory activities of this enzyme by Fraxinus angustifolia extracts. The leaf organic phase of ethyl acetate (LFA) and its bark aqueous counterpart (BFA) showed the strongest anti-NADH oxidase activity in vitro (IC50 = 38.51 and 42.04 μg mL-1, respectively). They consequently suppressed superoxide generation both enzymatically (53% and 19%, respectively) and nonenzymatically (34% and 19%, respectively). These results were corroborated in vivo, with high anti- NADH oxidase potential of the leaves and bark extracts (75.32% and 51.32%, respectively) concomitant with moderate hypouricemic activities (36.84% and 38.59%, respectively). Bio-guided fractionation led to the identification, by LC-DAD-MS/MS, of esculin and calcelarioside in bark and kaempferol glucoside in leaves as the main compounds responsible for the anti-NADH oxidase activity of XOR. These results plead in favor of the use of F. angustifolia as a source of potentially interesting therapeutic substances.
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Kalu, E. C., C. C. Ikwwuchi, E. O. Ayalogu, and K. T. Nwauche. "Proximate and Phytochemical Profile of Melanthera biflora Leaves." International Journal of Biochemistry Research & Review, May 10, 2019, 1–12. http://dx.doi.org/10.9734/ijbcrr/2019/v25i430082.
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The proximate and phytochemical composition of Melanthera biflora was investigated, using standard methods. From the obtained results the leaves had high moisture contents (71.1± 0.2%) and crude fiber (3.91 ± 0.5) while containing moderate protein (7.0 ± 0.03%), while containing lipid (1.10 ± 4%), ash (2.8 ± 0.2%), total carbohydrate (6.09 ± 0.2%) and caloric value (62.26±0.14 kcal/100g). Eleven Phytochemical families were detected with tannin as the most abundant (27.82%) consisting 100% tannic acid. Thirteen alkaloids (13.65%) were detected consisting mainly of morphine (28.05%), methylmorphine (16.22%), dephnoline (12.02%) biflorin, (20.63%), aromoline (12.61%) homoaromaline (7.79%). Twenty-three flavonoid (5.71%) chief among which were quercetin (44.21%), kaemferol (28.94%), dandzein (7.20%), letuolin (10.17%), salvagenin (6.76%), sinensetin 8.20% were detected. The most prominent of the ten carotenoids (2.48%), is lutein (40.76%), followed by carotene (17.90%), malvidin 5.63%, zeaxanthin (16.5%), viola-xanthin (9.5%). Sixty one terpenoid including linalool (40.98%), germacrene (12.74%), Alpha-terpineal 6.40%, terpinen – 4-01 (5.62%), and Gamma terpine were found in the leaves Of the six phenolic acids (16.26%) the highest was ferulic acid (53.94%), followed closely by vanilic acid (45.8%). Seven phytosterol (2.25%), consisting of sitosterol (65.3%), savenasterol (14.19%) stigmasterol (12.70%), and others were detected. The leaves had very a low hydroxycinnamic acid content (8.93x10-4%) content, consisting of eight known compounds of which caffeic acid (71.93%) and p-coumaric acid (27.91%) were the most abundant. They also had very a low allicins (1.94x10-4%) content, consisting of daillylthiosulphunate (97.05%), and methyl thiosulphinate (2.6%) and allylthiosulphin and allylthiosulphinate (0.3%). The leaves had a very low content of glycosides consisting of eight known compounds of which quabain (78.54%) were detected and they include gitogenin (22.04%), diosgenin (20.02), neohegen (20.79%). Their rich contents of nutrients and many bioactive molecules suggest strong nutraceutical potential of these leaves, further suggesting their likely use as functional a food and therapeutic uses in the management and prevention of diseases.
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Grammatis, A., E. X. Georgiou, and C. M. Becker. "O-134 Cochrane review on the effect of pentoxifylline for endometriosis." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab126.059.
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Abstract Study question To assess the effect of pentoxifylline, a methyl-xanthine with anti-inflammatory effects, for the management of premenopausal women with endometriosis. Summary answer There is not enough evidence to support the use of pentoxifylline in the management of premenopausal women with endometriosis to improve fertility and pain outcomes. What is known already Endometriosis is a chronic, inflammatory condition that occurs mainly during the reproductive years. It is characterized by endometrium-like tissue developing outside the uterine cavity. This endometriotic tissue development is dependent on estrogen produced primarily by the ovaries and partially by the endometriotic tissue itself and, therefore, hormonal management is traditionally used. In light of the body of evidence suggesting an immunological component to the pathophysiology of endometriosis, the anti-inflammatory agent pentoxifylline has been proposed as an alternative therapeutic agent. Study design, size, duration A Cochrane systematic review and meta analysis was performed. Electronic searches of the Cochrane Gynaecology and Fertility Specialised Register of Controlled Searches, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL and AMED OVID were conducted to December 2020 to identify relevant randomised controlled trials (RCTs). In addition, electronic searches were conducted on the Epistemonikos database, Human Reproduction, Web of Knowedlge, OpenGrey, LILACS, Pubmed and Google. Participants/materials, setting, methods Participants: premenopausal women with endometriosis via laparoscopy/laparotomy. For extent of endometriosis, grades according to the AFS/rASRM scoring system were used. Intervention: pentoxifylline treatment for any period of time Comparisons: placebo, no treatment, medical treatment, surgical treatment. Two independent authors screened studies and extracted data. Risk ratios were calculated for dichotomous data (Peto odds ratio for low event rates) and mean differences (MD) for continuous data, with 95% confidence intervals (CI). Main results and the role of chance Five RCTs were included, involving 415 participants. Pentoxifylline vs placebo No trials reported on live birth or reduction of pain. We are uncertain whether pentoxifylline affects the clinical pregnancy rate (Peto OR 1.53, 95% CI 0.89 to 2.63; 3 RCTs, n = 285; I2 = 0%; very low-quality evidence), recurrence rate (Peto OR 0.83, 95% CI 0.26 to 2.60; 1 RCT, n = 121; very low-quality evidence), or miscarriage rate (Peto OR 1.99, 95% CI 0.20 to 19.37; 2 RCTs, n = 164; I2= 0%; very low-quality evidence). Pentoxifylline vs no treatment We are uncertain whether pentoxifylline impacts on pain reduction when compared to no treatment at one month (MD -0.36, 95% CI -2.08 to 1.36; 1 RCT; n = 34; very low-quality evidence), two months (MD -1.25, 95% CI -2.67 to 0.17; 1 RCT; n = 34; very low-quality evidence) or three months (MD -1.60; 95% CI -3.32 to 0.12; n = 34; very low-quality evidence). No studies reported on live birth. Pentoxifylline vs medical treatment One study compared pentoxifylline with the combined contraceptive pill, but could not be included in the meta-analysis, as it was unclear if the data were presented as +/- standard deviation. Pentoxifylline vs surgical treatment No study reported on this comparison Limitations, reasons for caution Based on the GRADE criteria, the quality of evidence was classified as very low with issues arising due to risk of bias and imprecision. Four studies did not apply the intention-to-treat principle. None of the studies reported on live birth rate, one of the primary outcomes of the review. Wider implications of the findings Future research should prioritise live birth and overall pain as the primary outcome and include patients with all endometriosis severity types. All included studies compared pentoxifylline with placebo or no treatment after surgery, which highlights the need for more types of comparisons, such as to hormonal contraception. Trial registration number Not applicable
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Bosaeed, Mohammad, Ebrahim Mahmoud, Mohammad Hussein, Ahmad Alharbi, Abdulrahman Alsaedy, Adel Alothman, Majed Aljeraisy, et al. "A Trial of Favipiravir and Hydroxychloroquine combination in Adults Hospitalized with moderate and severe Covid-19: A structured summary of a study protocol for a randomised controlled trial." Trials 21, no. 1 (October 31, 2020). http://dx.doi.org/10.1186/s13063-020-04825-x.
Full textAbstract:
Abstract Objectives The selected combination was based on limited evidence clinically and in vitro on the efficacy of the Favipiravir and Hydroxychloroquine in SARS-CoV-2. The two medications were listed in many guidelines as treatment options and ongoing trials assessing their efficacy and safety. Thus, we want to prove the clinical effectiveness of the combination as therapy. Trial design This is an Open label, multicenter, randomized controlled clinical trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. It is a multicenter trial that will compare Favipiravir plus Hydroxychloroquine combination (experimental arm) to a control arm. Participants All study procedures will be conducted in eight centres in Saudia Arabia: King Abdulaziz Medical City National Guard Health Affairs in Riyadh. King Abdulaziz Hospital - Al Ahsa, Saudi Arabia AlMadina General Hospital, Madnia, Saudi Arabia Al-Qatif Central Hospital, Saudi Arabia Imam Abdulrahman Al Faisal Hospital, Dammam, Saudi Arabia King Abdulaziz Medical City, Jeddah, Saudi Arabia King Abdulaziz Hospital, Makkah, Saudi Arabia Imam Abdulrahman Alfaisal Hospital, Riyadh, Saudi Arabia Inclusion Criteria • Should be at least 18 years of age, • Male or nonpregnant female, • Diagnosed with COVID-19 by PCR confirmed SARS-coV-2 viral infection. • Able to sign the consent form and agree to clinical samples collection (or their legal surrogates if subjects are or become unable to make informed decisions).. • Moderate or Severe COVID-19, defined as oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or significant clinical symptoms that require hospital admission. • patients had to be enrolled within 10 days of disease onset. Exclusion Criteria • Patients who are pregnant or breastfeeding. • Will be transferred to a non-study site hospital or discharged from hospital within 72 hours. • Known sensitivity/allergy to hydroxychloroquine or Favipiravir • Current use of hydroxychloroquine for another indication • Prior diagnosis of retinopathy • Prior diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency • Major comorbidities increasing the risk of study drug including: i. Hematologic malignancy, ii. Advanced (stage 4-5) chronic kidney disease or dialysis therapy, iii. Known history of ventricular arrhythmias, iv. Current use of drugs that prolong the QT interval, Severe liver damage (Child-Pugh score ≥ C, AST> 5 times the upper limit), HIV. • The investigator believes that participating in the trial is not in the best interests of the patient, or the investigator considers unsuitable for enrollment (such as unpredictable risks or subject compliance issues). • Clinical prognostic non-survival, palliative care, or in deep coma and no have response to supportive treatment within three hours of admission • Patient with irregular rhythm • Patient with a history of heart attack (myocardial infarction) • Patient with a family history of sudden death from heart attack before the age of 50 • Take other drugs that can cause prolonged QT interval • Patient who is receiving immunosuppressive therapy (cyclosporin) which cannot be switched to another agent or adjusted while using the investigational drug • Gout/history of Gout or hyperuricemia (above the ULN), hereditary xanthinuria or xanthine calculi of the urinary tract. Intervention and comparator The treatment intervention would be for a maximum of 10 days from randomization and it would be as follows: Favipiravir for 10 days: Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10 days) Hydroxychloroquine for 5 days: (400mg) twice daily on day 1; for days 2-5 (200mg) twice daily. Reference Comparator Therapy: Standard of care is defined as: Treatment that is accepted by medical experts as a proper treatment for Covid-19 disease. Standard care comprised of, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, extracorporeal membrane oxygenation (ECMO), and antiviral therapy except Favipiravir. Also, it may include intravenous fluids and medications for symptoms relief . Main outcomes The primary endpoint is the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first (14 days from Randomization). Randomisation Eligible participants will be randomized in a 1:1 ratio to either the combination group (Favipiravir and Hydroxychloroquine) or a control group. The patients will be randomized utilizing Web based data entry System with a stratification based on the centre and the ICU admission. Blinding (masking) This is an Open label study and only the analyst will be blinded during the study conduct. Numbers to be randomised (sample size) Under the classical two arm parallel design the total effective sample sizes needed is 472 subjects (236 subjects per group). Trial status Protocol version 3.1 (dated 11 Aug 2020), and currently recruitment is ongoing. The date recruitment started was May 21, 2020 and the investigators anticipate the trial will finish recruiting by the end of December 2020. Trial registration ClinicalTrials.gov Identifier: NCT04392973, 19 May 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.