ABSTRACT
BACKGROUND: COVID-19, caused by SARS-CoV-2, is a potentially lethal, rapidly-expanding pandemic and many efforts are being carried out worldwide to understand and control the disease. COVID-19 patients may display a cytokine release syndrome, which causes severe lung inflammation, leading, in many instances, to death. OBJECTIVE: This paper is intended to explore the possibilities of controlling the COVID-19-associated hyperinflammation by using licensed drugs with anti-inflammatory effects. HYPOTHESIS: We have previously described that pentoxifylline alone, or in combination with oxypurinol, reduces the systemic inflammation caused by experimentally-induced pancreatitis in rats. Pentoxifylline is an inhibitor of TNF-α production and oxypurinol inhibits xanthine oxidase. TNF-α, in turn, activates other inflammatory genes such as Nos2, Icam or IL-6, which regulate migration and infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the lung parenchyma. In acute pancreatitis, the anti-inflammatory action of pentoxifylline seems to be mediated by the prevention of the rapid and presumably transient loss of PP2A activity. This may also occur in the hyperinflammatory -cytokine releasing phase- of SARS-CoV-2 infection. Therefore, it may be hypothesized that early treatment of COVID-19 patients with pentoxifylline, alone or in combination with oxypurinol, would prevent the potentially lethal acute respiratory distress syndrome. CONCLUSION: Pentoxifylline and oxypurinol are licensed drugs used for diseases other than COVID-19 and, therefore, phase I clinical trials would not be necessary for the administration to SARS-CoV-2- infected people. It would be worth investigating their potential effects against the hyperinflammatory response to SARS-CoV-2 infection.
Subject(s)
Coronavirus Infections/drug therapy , Cytokine Release Syndrome/prevention & control , Oxypurinol/therapeutic use , Pentoxifylline/therapeutic use , Pneumonia, Viral/drug therapy , Acute Disease , Animals , Betacoronavirus , COVID-19 , Cytokine Release Syndrome/virology , Humans , Pancreatitis , Pandemics , Rats , SARS-CoV-2ABSTRACT
Allopurinol, a first line urate-lowering therapy, has been associated with serious cutaneous reactions that have a high mortality. A number of risk factors for these serious adverse reactions have been identified including ethnicity, HLA-B∗5801 genotype, kidney impairment, allopurinol starting dose, and concomitant diuretic use. There is a complex interplay between these risk factors, which may (albeit rarely) lead to allopurinol-related serious adverse events. Although oxypurinol, the active metabolite of allopurinol, has been implicated, there is no defined drug concentration at which the reaction will occur. There is no specific treatment other than the cessation of allopurinol and supportive care. Whether hemodialysis, which rapidly removes oxypurinol, improves outcomes remains to be determined. Strategies to help reduce this risk are therefore important, which includes screening for HLA-B∗5801 in high-risk individuals, commencing allopurinol at low dose, and educating patients about the signs and symptoms of severe cutaneous adverse reactions, and what to do if they occur.
Subject(s)
Allopurinol/adverse effects , Drug Hypersensitivity , Gout , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/etiology , Drug Hypersensitivity/prevention & control , Gout/drug therapy , Gout Suppressants/adverse effects , Humans , Oxypurinol/therapeutic useABSTRACT
Several trials have been completed in patients with heart failure (HF) treated with uric acid (UA)-lowering agents with inconsistent results. We aimed to investigate whether lowering UA would have an effect on mortality and cardiovascular (CV) events in patients with HF in a systematic review and meta-analysis. The primary outcome measures were all-cause mortality, CV mortality, CV events, and CV hospitalization in patients with HF. We included 11 studies in our final analysis. Overall, allopurinol treatment was associated with a significant increase in the risk for all-cause mortality (hazard ratio [HR]: 1.24, 95% confidence interval [CI]: 1.04-1.49, P = .02). The trial heterogeneity is high (heterogeneity χ2 = 37.3, I2 = 73%, P < .001). With regard to CV mortality, allopurinol treatment was associated with a 42% increased risk of CV mortality (HR: 1.42, 95% CI: 1.11-1.81, P = .005). There was a trend toward increased CV hospitalization in the same group (HR: 1.21, 95% CI: 0.95-1.53, P = .12). Uric acid-lowering treatments increase all-cause and CV mortality but did not increase CV hospitalization significantly in this study.
Subject(s)
Enzyme Inhibitors/therapeutic use , Heart Failure/drug therapy , Xanthine Oxidase/antagonists & inhibitors , Allopurinol/therapeutic use , Febuxostat/therapeutic use , Heart Failure/mortality , Humans , Oxypurinol/therapeutic use , Uric AcidABSTRACT
Xanthine oxidase (XO) is one of the major enzymes to generate superoxide anion (O2(-)), that is frequently associated with various diseases involving reactive oxygen species (ROS). 4-Amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) is a potent XO inhibitor showing therapeutic potential for oxidative inflammatory diseases. However its very poor aqueous solubility makes pharmaceutical application difficult. To overcome this drawback, we have successfully synthesized a water soluble polyethylene glycol (PEG) conjugate of AHPP (PEG-AHPP) that exhibited good water solubility, forming micelles in aqueous solution. In the present study, the in vivo pharmacokinetics of this PEG-AHPP was examined. Further its therapeutic potential was investigated in dextran sulfate sodium (DSS) induced mouse colitis model. Compared to parental AHPP, the plasma t1/2 of PEG-AHPP was increased remarkably from 3h to 14h, indicating macromolecular nature of AHPP in circulation. In the DSS induced colitis model, oral administration of 2% DSS in drinking water resulted in the progression of the colitis with diarrhea and hematochezia as well as shortening of the large bowel. Administration of PEG-AHPP intravenously (10mg/kg) or orally (20mg/kg) suppressed pathogenesis significantly; namely diarrhea was reduced markedly, and the length of large bowel returned to almost normal level. Pathological examination clearly revealed improvement of colonic ulcer or necrosis. Production of inflammatory cytokines, i.e., interleukin-6 and tumor necrosis factor (TNF)-α, was significantly increased in DSS-induced colitis mice. However, it was markedly suppressed by PEG-AHPP administration. Similar results were found when serum 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances (TBARS), that are the index of oxidative injury, were measured. PEG-AHPP thus may be a potential candidate drug for ROS-related diseases including inflammatory bowel disease.
Subject(s)
Colitis/drug therapy , Oxypurinol/analogs & derivatives , Polyethylene Glycols/administration & dosage , Xanthine Oxidase/antagonists & inhibitors , 8-Hydroxy-2'-Deoxyguanosine , Animals , Caco-2 Cells , Colitis/chemically induced , Colitis/immunology , Colitis/metabolism , Colon/drug effects , Colon/immunology , Colon/metabolism , Colon/pathology , Cytokines/immunology , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/blood , Dextran Sulfate , Female , Humans , Mice, Inbred ICR , Micelles , Oxypurinol/administration & dosage , Oxypurinol/pharmacokinetics , Oxypurinol/therapeutic use , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/therapeutic use , Reactive Oxygen Species , Solubility , Thiobarbituric Acid Reactive Substances/analysis , Water/chemistry , Xanthine Oxidase/blood , Xanthine Oxidase/metabolismABSTRACT
BACKGROUND: Ventricular tachycardia or fibrillation (VT/VF) of focal origin due to triggered activity (TA) from delayed afterdepolarizations (DADs) is reproducibly inducible after anterior coronary artery occlusion. Both VT/VF and TA can be blocked by reducing reactive oxygen species (ROS). We tested the hypothesis that inhibition of NADPH oxidase and xanthine oxidase would block VT/VF. METHODS: 69 dogs received apocynin (APO), 4 mg/kg intraveneously (IV), oxypurinol (OXY), 4 mg/kg IV, or both APO and OXY (BOTH) agents, or saline 3 h after coronary occlusion. Endocardium from ischemic sites (3-D mapping) was sampled for Rac1 (GTP-binding protein in membrane NADPH oxidase) activation or standard microelectrode techniques. Results (mean±SE, * p<0.05): VT/VF originating from ischemic zones was blocked by APO in 6/10 *, OXY in 4/9 *, BOTH in 5/8 * or saline in 1/27; 11/16 VT/VFs blocked were focal. In isolated myocardium, TA was blocked by APO (10(-6) M) or OXY (10(-8) M). Rac1 levels in ischemic endocardium were decreased by APO or OXY. CONCLUSION: APO and OXY suppressed focal VT/VF due to DADs, but the combination of the drugs was not more effective than either alone. Both drugs inhibited ischemic Rac1 with inhibition by OXY suggesting ROS-induced ROS. The inability to totally prevent VT/VF suggests that other mechanisms also contribute to ischemic VT.
Subject(s)
Myocardial Ischemia/enzymology , NADPH Oxidases/metabolism , Tachycardia, Ventricular/enzymology , Ventricular Fibrillation/enzymology , Xanthine Oxidase/metabolism , Acetophenones/pharmacology , Acetophenones/therapeutic use , Action Potentials/drug effects , Animals , Blotting, Western , Disease Models, Animal , Dogs , Female , Male , Myocardial Ischemia/diagnostic imaging , Myocardial Ischemia/drug therapy , Myocardial Ischemia/physiopathology , NADPH Oxidases/antagonists & inhibitors , Oxypurinol/pharmacology , Oxypurinol/therapeutic use , Tachycardia, Ventricular/complications , Tachycardia, Ventricular/drug therapy , Tachycardia, Ventricular/physiopathology , Ultrasonography , Ventricular Fibrillation/complications , Ventricular Fibrillation/drug therapy , Ventricular Fibrillation/physiopathology , Xanthine Oxidase/antagonists & inhibitors , rac1 GTP-Binding Protein/metabolismABSTRACT
BACKGROUND: Cachexia is a common complication of cancer and may be responsible for 22% of all cancer-related deaths. The exact cause of death in cancer cachexia patients is unknown. Recently, atrophy of the heart has been described in cancer cachexia animal models, which resulted in impaired cardiac function and is likely to contribute to mortality. In cancer patients hyperuricaemia independent of tumour lysis syndrome is often associated with a worse prognosis. Xanthine oxidase (XO) metabolizes purines to uric acid and its inhibition has been shown to improve clinical outcome in patients with chronic heart failure. METHODS: The rat Yoshida AH-130 hepatoma cancer cachexia model was used in this study. Rats were treated with 4 or 40 mg/kg/d oxypurinol or placebo starting one day after tumour-inoculation for maximal 15 days. Cardiac function was analyzed by echocardiography on day 11. RESULTS: Here we show that inhibition of XO by oxypurinol significantly reduces wasting of the heart and preserves cardiac function. LVEF was higher in tumour-bearing rats treated with 4 mg/kg/d (61±4%) or 40 mg/kg/d (64±5%) oxypurinol vs placebo (51±3%, both p<0.05). Fractional shortening was improved by 4 mg/kg/d (43±3%) oxypurinol vs placebo (30±2, p<0.05), while 40 mg/kg/d oxypurinol (41±5%) did not reach statistical significance. Cardiac output was increased in the 4 mg/kg/d dose only (71±11 mL/min vs placebo 38±4 mL/min, p<0.01). CONCLUSION: Inhibition of XO with oxypurinol has beneficial effects on cardiac mass and function in a rat model of severe cancer cachexia, suggesting that XO might be a viable drug target in cancer cachexia.
Subject(s)
Cachexia/drug therapy , Cardiomyopathies/drug therapy , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms/drug therapy , Oxypurinol/therapeutic use , Xanthine Oxidase/antagonists & inhibitors , Animals , Cachexia/complications , Cachexia/enzymology , Cardiomyopathies/enzymology , Cardiomyopathies/etiology , Liver Neoplasms/complications , Liver Neoplasms/enzymology , Liver Neoplasms, Experimental/complications , Liver Neoplasms, Experimental/enzymology , Male , Oxypurinol/pharmacology , Rats , Rats, WistarABSTRACT
Cancer cachexia is a wasting condition, driven by systemic inflammation and oxidative stress. This study investigated eicosapentaenoic acid (EPA) in combination with oxypurinol as a treatment in a mouse model of cancer cachexia. Mice with cancer cachexia were randomized into 4 treatment groups (EPA (0.4 g/kg/day), oxypurinol (1 mmol/L ad-lib), combination, or control), and euthanized after 29 days. Analysis of oxidative damage to DNA, mRNA analysis of pro-oxidant, antioxidant and proteolytic pathway components, along with enzyme activity of pro- and antioxidants were completed on gastrocnemius muscle. The control group displayed earlier onset of tumor compared to EPA and oxypurinol groups (P<0.001). The EPA group maintained body weight for an extended duration (20 days) compared to the oxypurinol (5 days) and combination (8 days) groups (P<0.05). EPA (18.2±3.2 pg/ml) and combination (18.4±3.7 pg/ml) groups had significantly higher 8-OH-dG levels than the control group (12.9±1.4 pg/ml, P≤0.05) indicating increased oxidative damage to DNA. mRNA levels of GPx1, MURF1 and MAFbx were higher following EPA treatment compared to control (P≤0.05). Whereas oxypurinol was associated with higher GPx1, MnSOD, CAT, XDH, MURF1, MAFbx and UbB mRNA compared to control (P≤0.05). Activity of total SOD was higher in the oxypurinol group (32.2±1.5 U/ml) compared to control (27.0±1.3 U/ml, P<0.01), GPx activity was lower in the EPA group (8.76±2.0 U/ml) compared to control (14.0±1.9 U/ml, P<0.05), and catalase activity was lower in the combination group (14.4±2.8 U/ml) compared to control (20.9±2.0 U/ml, P<0.01). There was no change in XO activity. The increased rate of weight decline in mice treated with oxypurinol indicates that XO may play a protective role during the progression of cancer cachexia, and its inhibition is detrimental to outcomes. In combination with EPA, there was little significant improvement from control, indicating oxypurinol is unlikely to be a viable treatment compound in cancer cachexia.
Subject(s)
Adenocarcinoma/complications , Cachexia/drug therapy , Eicosapentaenoic Acid/therapeutic use , Enzyme Inhibitors/therapeutic use , Muscular Atrophy/drug therapy , Neoplasms, Experimental/complications , Oxypurinol/therapeutic use , Adenocarcinoma/drug therapy , Animals , Cachexia/etiology , Catalase/metabolism , Cell Line, Tumor , Drug Evaluation, Preclinical , Drug Therapy, Combination , Eicosapentaenoic Acid/pharmacology , Enzyme Inhibitors/pharmacology , Female , Gene Expression/drug effects , Mice , Mice, Inbred BALB C , Mice, Nude , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/etiology , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Organ Size/drug effects , Oxidative Stress , Oxypurinol/pharmacology , Superoxide Dismutase/metabolism , Tumor Burden , Weight Loss/drug effects , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/metabolismABSTRACT
Uric acid is the end product of purine metabolism. Its immediate precursor, xanthine, is converted to uric acid by an enzymatic reaction involving xanthine oxidoreductase. Uric acid has been formerly considered a major antioxidant in human plasma with possible beneficial anti-atherosclerotic effects. In contrast, studies in the past two decades have reported associations between elevated serum uric acid levels and cardiovascular events, suggesting a potential role for uric acid as a risk factor for atherosclerosis and related diseases. In this paper, the molecular pattern of uric acid formation, its possible deleterious effects, as well as the involvement of xanthine oxidoreductase in reactive oxygen species generation are critically discussed. Reactive oxygen species contribute to vascular oxidative stress and endothelial dysfunction, which are associated with the risk of atherosclerosis. Recent studies have renewed attention to the xanthine oxidoreductase system, since xanthine oxidoreductase inhibitors, such as allopurinol and oxypurinol, would be capable of preventing atherosclerosis progression by reducing endothelial dysfunction. Also, beneficial effects could be obtained in patients with congestive heart failure. The simultaneous reduction in uric acid levels might contribute to these effects, or be a mere epiphenomenon of the drug action. The molecular mechanisms involved are discussed.
Subject(s)
Cardiovascular Diseases/etiology , Endothelium, Vascular/physiopathology , Hyperuricemia/complications , Uric Acid/adverse effects , Xanthine Dehydrogenase/antagonists & inhibitors , Xanthine Dehydrogenase/physiology , Allopurinol/pharmacology , Allopurinol/therapeutic use , Antioxidants , Atherosclerosis/drug therapy , Atherosclerosis/etiology , Atherosclerosis/prevention & control , Cardiovascular Diseases/drug therapy , Humans , Molecular Targeted Therapy , Oxidative Stress , Oxypurinol/pharmacology , Oxypurinol/therapeutic use , Reactive Oxygen Species/metabolism , Risk Factors , Uric Acid/metabolismABSTRACT
Previously, we showed that oral allopurinol increased survival in mice with post-ischemic cardiomyopathy and attributed this outcome to an improvement of excitation-contraction coupling that boosted contractility. In this study, we tested the sustainability of this enhanced contraction associated with decreased oxidative damage over an extended time. Mice were divided into three groups: sham-operated control, myocardial infarction-heart failure (MI-HF), and oxypurinol-treated heart failure (Oxy-HF). After 9-11 months, echocardiography showed that mice treated with oxypurinol (1mM in drinking water) had significantly higher left ventricle fractional contraction and fractional wall thickening during systole than did mice in the MI-HF group (left ventricle fractional contraction: 28.4+/-2.2% vs. 19.9+/-2.3%, P<0.05; left ventricle fractional wall thickening: 45.0+/-4.0% vs. 23.5+/-2.0%, P<0.05). Left ventricular diastolic dimension, however, remained enlarged (0.50+/-0.04 vs. 0.54+/-0.05 cm, not significant). Twitch force was significantly higher at any given external Ca(2+) concentration in the Oxy-HF group than in the MI-HF group (P<0.01); amplitudes of intracellular Ca(2+) transients were also higher in the Oxy-HF group but were not statistically different from those of the MI-HF group. Force-frequency relation was improved in the Oxy-HF group. Muscle in the Oxy-HF group exhibited increases in myofilament Ca(2+) responsiveness, as evidenced by significantly higher maximal Ca(2+)-activated force (77.8+/-12.7 vs. 36.4+/-4.4 mN/mm(2), P<0.01). Finally, lipid peroxidation and myofilament oxidation were suppressed in the Oxy-HF group. These results indicate that the beneficial effects of antioxidation can be sustained by long-term treatment with oxypurinol after ischemic heart failure, with significantly improved cardiac contractility.
Subject(s)
Enzyme Inhibitors/pharmacology , Heart Failure/drug therapy , Heart Failure/physiopathology , Myocardial Contraction/drug effects , Myocardial Ischemia/complications , Oxypurinol/pharmacology , Oxypurinol/therapeutic use , Animals , Calcium/metabolism , Enzyme Inhibitors/therapeutic use , Excitation Contraction Coupling/drug effects , Heart/drug effects , Heart/physiopathology , Heart Failure/etiology , Heart Failure/pathology , Male , Mice , Myocardium/metabolism , Myocardium/pathology , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , Time Factors , Xanthine Oxidase/antagonists & inhibitorsABSTRACT
At present no standard pharmacological intervention strategy is available to reduce these adverse effects of birth asphyxia. In the present study we aimed to evaluate placental transfer of allopurinol, an inhibitor of XOR. For this purpose, fetal catheterization of the jugular vein was conducted in five late pregnant sows (one fetus per sow). At 24-48 h after surgery, sows received allopurinol (15 mg/kg body weight; i.v.) and pharmacokinetics of allopurinol and its active metabolite oxypurinol were measured in both late pregnant sows and fetuses. Maternal and fetal blood samples were collected during and after allopurinol administration. Maternal C(max) values averaged 41.90 microg/mL (allopurinol) and 3.68 microg/mL (oxypurinol). Allopurinol crossed the placental barrier as shown by the average fetal C(max) values of 5.05 microg/mL at 1.47 h after allopurinol administration to the sow. In only one fetus low plasma oxypurinol concentrations were found. Incubations of subcellular hepatic fractions of sows and 24-h-old piglets confirmed that allopurinol could be metabolized into oxypurinol. In conclusion, we demonstrated that allopurinol can cross the placental barrier, a prerequisite for further studies evaluating the use of allopurinol as a neuroprotective agent to reduce the adverse effects following birth asphyxia in neonatal piglets.
Subject(s)
Allopurinol/pharmacology , Asphyxia Neonatorum/prevention & control , Enzyme Inhibitors/pharmacology , Maternal-Fetal Exchange , Oxypurinol/therapeutic use , Xanthine Dehydrogenase/antagonists & inhibitors , Allopurinol/metabolism , Allopurinol/pharmacokinetics , Animals , Area Under Curve , Blood Gas Analysis , Disease Models, Animal , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Female , Half-Life , Humans , Infant, Newborn , Male , Metabolic Clearance Rate , Oxypurinol/blood , Pregnancy , SwineABSTRACT
OBJECTIVES: This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy. BACKGROUND: Increased XO activity may contribute to heart failure pathophysiology. METHODS: Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life. RESULTS: The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by approximately 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (-2.3 +/- 2.1 mg/dl vs. -1.0 +/- 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome. CONCLUSIONS: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687).
Subject(s)
Enzyme Inhibitors/therapeutic use , Heart Failure/drug therapy , Oxypurinol/therapeutic use , Xanthine Oxidase/antagonists & inhibitors , Adolescent , Adult , Aged , Aged, 80 and over , Double-Blind Method , Enzyme Inhibitors/pharmacology , Female , Health Status Indicators , Heart Failure/mortality , Heart Failure/psychology , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/drug effects , Oxypurinol/pharmacology , Quality of Life , Surveys and Questionnaires , Systole/drug effects , Uric Acid/bloodSubject(s)
Enzyme Inhibitors/therapeutic use , Heart Failure/drug therapy , Oxypurinol/therapeutic use , Xanthine Oxidase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Heart Failure/blood , Heart Failure/mortality , Humans , Natriuretic Peptide, Brain/drug effects , Oxypurinol/pharmacology , Risk Factors , Systole/drug effects , Uric Acid/bloodABSTRACT
This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure, presented at the Heart Failure Society of America meeting held in Seattle in September 2006. All reports should be considered as preliminary data, as analyses may change in the final publication. Devices designed to improve cardiac contractility may have improved exercise tolerance and quality of life in the FIX-CHF-4 study; however, uncertainties in trial interpretation exist. The results of a study reporting the first administration of the selective myosin activator CK-1827452 to human volunteers, support the initiation of clinical trials in heart failure patients. In OPT-CHF, oxypurinol failed to show benefit compared to placebo for the treatment of heart failure, although a retrospective subgroup analysis suggests that it may be beneficial in patients with elevated serum uric acid levels.
Subject(s)
Heart Failure/therapy , Cardiotonic Agents/therapeutic use , Clinical Trials as Topic , Enzyme Inhibitors/therapeutic use , Heart Failure/physiopathology , Heart-Assist Devices , Humans , Oxypurinol/therapeutic useABSTRACT
Reactive oxygen species, in particular superoxide, have been closely linked to the underlying pathophysiology of ischemic cardiomyopathy: superoxide not only mediates mechanoenergetic uncoupling of the myocyte but also adversely impacts on myocardial perfusion by depleting endothelial-derived nitric oxide bioavailability. Xanthine oxidase generates superoxide upon oxidation of hypoxanthine and xanthine and has been detected in cardiac myocytes and coronary endothelial cells of patients with ischemic heart disease. Here we investigated the effects of oxypurinol, a xanthine oxidase inhibitor, on myocardial contractility in patients with ischemic cardiomyopathy. Twenty patients (19 males, 66+/-8 years) with stable coronary disease, severely suppressed systolic function (left ventricular ejection fraction 22+/-2%), and nonelevated uric acid plasma levels received a single intravenous dose of oxypurinol (400 mg). Cardiac MRI studies, performed before and 5.2+/-0.9 h after oxypurinol administration, revealed a reduction in end-systolic volumes (-9.7+/-4.2%; p=0.03) and an increase in left ventricular ejection fraction (+17.5+/-5.2%; p=0.003), whereas 6 patients (6 males, 63+/-3.8 years, ejection fraction 26+/-5%) who received vehicle only did not show significant changes in any of the parameters studied. Oxypurinol improves left ventricular function in patients with ischemic cardiomyopathy. These results underscore the significance of reactive oxygen species as important pathophysiological mediators in ischemic heart failure and point toward xanthine oxidase as an important source of reactive species that serve to modulate the myocardial redox state in this disease.
Subject(s)
Cardiomyopathies/drug therapy , Myocardial Contraction/drug effects , Myocardial Ischemia/drug therapy , Oxypurinol/therapeutic use , Xanthine Oxidase/antagonists & inhibitors , Aged , Cardiomyopathies/physiopathology , Cardiotonic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Female , Humans , Hypoxanthine/blood , Magnetic Resonance Imaging, Cine , Male , Middle Aged , Myocardial Contraction/physiology , Myocardial Ischemia/physiopathology , Oxypurinol/blood , Reactive Oxygen Species/metabolism , Uric Acid/blood , Xanthine/blood , Xanthine Oxidase/bloodABSTRACT
BACKGROUND: Reactive oxygen species (ROS) have been linked to hypertrophy, remodeling and abnormal excitation-contraction coupling. Previous data demonstrated that an increase in oxidative stress is associated to the pathogenesis of congestive heart failure (CHF). We examined whether inhibition of the superoxide anion (*O2(-))-generating enzyme xanthine oxidase (XO) with oxypurinol may improve cardiac function in patients with CHF. METHODS AND RESULTS: A randomized, placebo-controlled, double-blind study on 60 patients (30/group) with New York Heart Association class II-III CHF, comparing 600-mg/day oxypurinol during 1 month with placebo, added to standard therapy. Effects on left ventricular ejection fraction (LVEF), serum uric acid (SUA) level, and 6-minute walking test were analyzed. SUA decreased by 16.0 +/- 2.8 mg/L from baseline to Week 4 in the oxypurinol group relative to placebo (P < .01, n = 30 per group). LVEF showed an increase of 4.7 +/- 2.6% from baseline to Week 4 in the oxypurinol group relative to placebo that did not reach statistical significance (P < .08). When patients with LVEF > 40% at baseline were excluded, a statistically significant increase of 6.8 +/- 2.8% from baseline to Week 4 was seen in the oxypurinol group relative to placebo (P < .02, n = 26 placebo, n = 21 oxypurinol). No treatment-related adverse effects or increase in walking capacity were detected. CONCLUSION: Inhibition of XO by oxypurinol in patients with CHF decreases SUA and improves LVEF in patients with LVEF < or = 40% after 1 month of treatment.
Subject(s)
Enzyme Inhibitors/therapeutic use , Heart Failure/drug therapy , Heart Failure/physiopathology , Oxypurinol/therapeutic use , Stroke Volume/drug effects , Xanthine Oxidase/antagonists & inhibitors , Aged , Double-Blind Method , Female , Humans , Male , Physical Endurance , Uric Acid/blood , WalkingABSTRACT
The plasma level of the uric acid is frequently elevated in heart failure, due to increased production and/or to reduced renal excretion of this antioxidant metabolite. The transformation of hypoxanthine to xanthine and the conversion of the latter into uric acid, which occur in purine catabolism, are catalysed by xanthine oxidoreductase. The constitutive xanthine dehydrogenase form of this enzyme generally uses NAD(+) as an electron acceptor, whereas the post-translational xanthine oxidase form uses molecular oxygen and yields four units of reactive oxygen species per unit of transformed substrate. Allopurinol and oxypurinol inhibit xanthine oxidoreductase and thus diminish the generation of reactive species and decrease plasma uric acid. In a recent study in patients with NHYA class II-III heart failure, add-on treatment with allopurinol 300 mg/day for 3 months lowered plasma uric acid but failed to improve laboratory exercise performance or the distance walked in 6 minutes. In another recent trial, which was carried out in patients with NHYA class III-IV heart failure, add-on treatment with oxypurinol 600 mg/day for 24 weeks decreased plasma uric acid concentration but did not change a composite of patient outcome and state. These results indicate that the reduction in plasma uric acid caused by allopurinol or oxypurinol does not benefit patients with heart failure. Moreover, the hypothesis that the diminution in the renal excretion of the antioxidant uric acid caused by diuretics may be salutary in cardiac failure is strengthened by the study results considered.
Subject(s)
Allopurinol/therapeutic use , Antioxidants/therapeutic use , Heart Failure/drug therapy , Oxypurinol/therapeutic use , Allopurinol/pharmacology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Heart Failure/blood , Heart Failure/enzymology , Humans , Oxypurinol/pharmacology , Randomized Controlled Trials as Topic , Uric Acid/blood , Xanthine Oxidase/antagonists & inhibitorsABSTRACT
Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.