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Clinical Pharmacokinetics Nov 2022Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with...
BACKGROUND AND OBJECTIVE
Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy.
METHODS
Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM, version 7.5).
RESULTS
In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33-0.77) and 0.2 1/h (95% confidence interval 0.09-0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48-0.92), suggesting full xanthine oxidoreductase inhibition during the period studied.
CONCLUSIONS
This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.
Topics: Humans; Infant, Newborn; Allopurinol; Hypoxanthine; Hypoxia; Hypoxia-Ischemia, Brain; Mannitol; Oxypurinol; Uric Acid; Xanthine; Xanthine Dehydrogenase; Clinical Studies as Topic
PubMed: 36040612
DOI: 10.1007/s40262-022-01164-9 -
Experimental Biology and Medicine... Jun 2015Cardiac ischemia associated with acute coronary syndrome and myocardial infarction is a leading cause of mortality and morbidity in the world. A rapid detection of the... (Review)
Review
Cardiac ischemia associated with acute coronary syndrome and myocardial infarction is a leading cause of mortality and morbidity in the world. A rapid detection of the ischemic events is critically important for achieving timely diagnosis, treatment and improving the patient's survival and functional recovery. This minireview provides an overview on the current biomarker research for detection of acute cardiac ischemia. We primarily focus on inosine and hypoxanthine, two by-products of ATP catabolism. Based on our published findings of elevated plasma concentrations of inosine/hypoxanthine in animal laboratory and clinical settings, since 2006 we have originally proposed that these two purine molecules can be used as rapid and sensitive biomarkers for acute cardiac ischemia at its very early onset (within 15 min), hours prior to the release of heart tissue necrosis biomarkers such as cardiac troponins. We further developed a chemiluminescence technology, one of the most affordable and sensitive analytical techniques, and we were able to reproducibly quantify and differentiate total hypoxanthine concentrations in the plasma samples from healthy individuals versus patients suffering from ischemic heart disease. Additional rigorous clinical studies are needed to validate the plasma inosine/hypoxanthine concentrations, in conjunction with other current cardiac biomarkers, for a better revelation of their diagnostic potentials for early detection of acute cardiac ischemia.
Topics: Adenosine Triphosphate; Animals; Biomarkers; Humans; Hypoxanthine; Inosine; Myocardial Ischemia; Point-of-Care Systems
PubMed: 25956679
DOI: 10.1177/1535370215584931 -
Journal of Diabetes Investigation Jul 2020Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen...
AIMS/INTRODUCTION
Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue.
MATERIALS AND METHODS
The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study.
RESULTS
Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity.
CONCLUSIONS
The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.
Topics: Adipose Tissue; Aged; Alanine Transaminase; Biomarkers; Body Mass Index; Enzyme Inhibitors; Female; Humans; Hyperuricemia; Hypoxanthine; Japan; Liver; Male; Middle Aged; Obesity; Regression Analysis; Signal Transduction; Triglycerides; Xanthine; Xanthine Dehydrogenase
PubMed: 31916414
DOI: 10.1111/jdi.13207 -
Journal of Clinical Laboratory Analysis Jun 2019Hyperuricemia is the only biochemical index in the classification of acute gouty arthritis in American Rheumatism Association 1977 and the main basis of clinical...
BACKGROUND
Hyperuricemia is the only biochemical index in the classification of acute gouty arthritis in American Rheumatism Association 1977 and the main basis of clinical diagnosis for most doctors. However, nearly half of the time gout occurs without hyperuricemia, especially in an acute attack,which leads to an urgent need to find a new substitute diadynamic criteria of gout. Xanthine and hypoxanthine, as precursors of uric acid, have been reported to be high in gout patients with hyperuricemia and presumed to be gout biomarkers.
OBJECTIVES
To further explore the possibility of xanthine and hypoxanthine to be gout biomarkers as substitutes for uric acid.
METHODS
A reversed-phase HPLC-UV method was employed for simultaneous quantitative detection of uric acid (UA), xanthine (X), and hypoxanthine (HX) in gout patients' (with and without hyperuricemia) and healthy persons' serum.
RESULTS
The xanthine and hypoxanthine concentrations in gout patients with hyperuricemia and without hyperuricemia are higher than in healthy persons with a P < 0.001.
CONCLUSIONS
This study supplements previous researches by confirming that xanthine and hypoxanthine are significantly elevated in gout patients' serum especially in patients' with normouricemia, which supported xanthine and hypoxanthine may have clinical application for the diagnosis of gout.
Topics: Blood Chemical Analysis; Chromatography, High Pressure Liquid; Gout; Humans; Hyperuricemia; Hypoxanthine; Limit of Detection; Male; Reproducibility of Results; Uric Acid; Xanthine
PubMed: 30803031
DOI: 10.1002/jcla.22868 -
Archives of Medical Research Oct 2021An elevated level of plasma uric acid has been widely recognized as a risk factor for non-alcoholic fatty liver disease (NAFLD), where oxidative stress and inflammation...
BACKGROUND
An elevated level of plasma uric acid has been widely recognized as a risk factor for non-alcoholic fatty liver disease (NAFLD), where oxidative stress and inflammation play an important role in the pathophysiology of the disease. Although the complete molecular mechanisms involved remain unknown, while under physiological conditions uric acid presents antioxidant properties, hyperuricemia has been linked to oxidative stress, chronic low-grade inflammation, and insulin resistance, basic signs of NAFLD.
AIM OF STUDY
Employing in vivo experimentation, we aim to investigate whether a high-fat diet rich in cholesterol (HFD), modifies the metabolism of purines in close relationship to molecular events associated with the development of NAFLD. In vitro experiments employing HepG2 cells are also carried out to study the phenomenon of oxidative stress.
METHODS
Adult male rabbits were fed for 8 weeks an HFD to induce NAFLD. At the beginning of the experiment and every 15 d until the completion of the study, plasma levels of lipids, lipoproteins, and uric acid were measured. Liver tissue was isolated, and histology performed followed by the biochemical determination of hypoxanthine, protein expression of xanthine oxidoreductase (XOR) by western blot analysis, and xanthine oxidase (XO) activity using an enzymatic kinetic assay. Furthermore, we employed in vitro experimentation studying HepG2 cells to measure the effect of hypoxanthine and HO upon the production of radical oxygen species (ROS), XO activity, and cell viability.
RESULTS AND CONCLUSION
Hepatic tissue from rabbits fed the HFD diet showed signs of NAFLD associated with an increased ROS concentration and an altered purine metabolism characterized by the increase in hypoxanthine, together with an apparent equilibrium displacement of XOR towards the xanthine dehydrogenase (XDH) isoform of the enzyme. This protein shift visualized by a western blot analysis, associated with an increase in plasma uric acid and hepatocyte hypoxanthine could be understood as a compensatory series of events secondary to the establishment of oxidative stress associated with the chronic establishment of fatty liver disease.
Topics: Animals; Hydrogen Peroxide; Hyperuricemia; Hypoxanthine; Liver; Male; Non-alcoholic Fatty Liver Disease; Rabbits
PubMed: 33966916
DOI: 10.1016/j.arcmed.2021.04.005 -
Clinical Pharmacokinetics Feb 2022Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE).... (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates.
BACKGROUND
Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates.
OBJECTIVE
The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated.
METHODS
Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling.
RESULTS
Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (V) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and V relative to a formation fraction (f) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42).
CONCLUSION
The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.
Topics: Allopurinol; Biomarkers; Enzyme Inhibitors; Humans; Hypoxanthine; Hypoxia-Ischemia, Brain; Infant, Newborn; Oxypurinol; Uric Acid; Xanthine; Xanthine Oxidase
PubMed: 34617261
DOI: 10.1007/s40262-021-01068-0 -
Nature Communications Sep 2019The synthesis of nucleobases in natural environments, especially in interstellar molecular clouds, is the focus of a long-standing debate regarding prebiotic chemical...
The synthesis of nucleobases in natural environments, especially in interstellar molecular clouds, is the focus of a long-standing debate regarding prebiotic chemical evolution. Here we report the simultaneous detection of all three pyrimidine (cytosine, uracil and thymine) and three purine nucleobases (adenine, xanthine and hypoxanthine) in interstellar ice analogues composed of simple molecules including HO, CO, NH and CHOH after exposure to ultraviolet photons followed by thermal processes, that is, in conditions that simulate the chemical processes accompanying star formation from molecular clouds. Photolysis of primitive gas molecules at 10 K might be one of the key steps in the production of nucleobases. The present results strongly suggest that the evolution from molecular clouds to stars and planets provides a suitable environment for nucleobase synthesis in space.
Topics: Adenine; Ammonia; Carbon Monoxide; Cytosine; Evolution, Chemical; Extraterrestrial Environment; Hypoxanthine; Ice; Methanol; Molecular Structure; Photochemical Processes; Thymine; Ultraviolet Rays; Uracil; Water; Xanthine
PubMed: 31562325
DOI: 10.1038/s41467-019-12404-1 -
Nutrients Jul 2023(1) Background: Many studies have attempted to explore potential biomarkers for the early detection of gout, but consistent and high levels of evidence are lacking. In... (Meta-Analysis)
Meta-Analysis Review
(1) Background: Many studies have attempted to explore potential biomarkers for the early detection of gout, but consistent and high levels of evidence are lacking. In this study, metabolomics was used to summarize the changes of metabolites in the literature and explore the potential value of metabolites in predicting the occurrence and development of gout. (2) Methods: We searched the databases including the EMBASE, the Cochrane Library, PubMed, Web of Science, VIP Date, Wanfang Data, and CNKI, and the screening was fulfilled on 30 July 2022. The records were screened according to the inclusion criteria and the risk of bias was assessed. Qualitative analysis was performed for all metabolites, and meta-analysis was performed for metabolite concentrations using random effects to calculate the Std mean difference and 95% confidence interval. (3) Results: A total of 2738 records were identified, 33 studies with 3422 participants were included, and 701 metabolites were identified. The qualitative analysis results showed that compared with the healthy control group, the concentration of 56 metabolites increased, and 22 metabolites decreased. The results of the meta-analysis indicated that 17 metabolites were statistically significant. (4) Conclusions: Metabolites are associated with gout. Some specific metabolites such as uric acid, hypoxanthine, xanthine, KYNA, guanosine, adenosine, creatinine, LB4, and DL-2-Aminoadipic acid have been highlighted in the development of gout.
Topics: Humans; Gout; Uric Acid; Xanthine; Hypoxanthine; Creatinine
PubMed: 37513561
DOI: 10.3390/nu15143143 -
Biosensors Jan 2021Hypoxanthine (hpx) is an important molecule for both biochemistry research and biomedical applications. It is involved in several biological processes associated to...
Hypoxanthine (hpx) is an important molecule for both biochemistry research and biomedical applications. It is involved in several biological processes associated to energy and purine metabolism and has been proposed as a biomarker for a variety of disease states. Consequently, the discovery and development of systems suitable for the detection of hypoxanthine is pretty appealing in this research field. Thus, we have obtained a stable diruthenium (III) compound in its dehydrated and hydrated forms with formula [{Ru(µ-Cl)(µ-hpx)}Cl] () and [{Ru(µ-Cl)(µ-hpx)}Cl]·2HO (), respectively. This purine-based diruthenium(III) system was prepared from two very different starting materials, namely, inosine and azathioprine, the latter being an immunosuppressive drug. Remarkably, it was observed that an unusual azathioprine hydrolysis occurs in the presence of ruthenium, thus generating hypoxanthine instead of the expected 6-mercaptopurine antimetabolite, so that the hpx molecule is linked to two ruthenium(III) ions. and were characterized through IR, SEM, powder and single-crystal X-ray Diffraction and Cyclic Voltammetry (CV). The electrochemical studies allowed us to detect the hpx molecule when coordinated to ruthenium in the reported compound. The grade of sensitivity, repeatability and stability reached by this diruthenium system make it potentially useful and could provide a first step to develop new sensor devices suitable to detect hypoxanthine.
Topics: Azathioprine; Hydrolysis; Hypoxanthine; Immunosuppressive Agents; Inosine; Limit of Detection; Microscopy, Electron, Scanning; Models, Molecular; Molecular Conformation; Purines; Ruthenium; X-Ray Diffraction
PubMed: 33440852
DOI: 10.3390/bios11010019 -
Journal of Perinatal Medicine Jan 2023Hypoxanthine is a purine metabolite which increases during hypoxia and therefore is an indicator of this condition. Further, when hypoxanthine is oxidized to uric acid... (Review)
Review
Hypoxanthine is a purine metabolite which increases during hypoxia and therefore is an indicator of this condition. Further, when hypoxanthine is oxidized to uric acid in the presence of xanthine oxidase, oxygen radicals are generated. This was the theoretical basis for suggesting and studying, beginning in the 1990s, resuscitation of newborn infants with air instead of the traditional 100% O. These studies demonstrated a 30% reduction in mortality when resuscitation of term and near term infants was carried out with air compared to pure oxygen. The mechanism for this is not fully understood, however the hypoxanthine -xanthine oxidase system increases oxidative stress and plays a role in regulation of the perinatal circulation. Further, hyperoxic resuscitation inhibits mitochondrial function, and one reason may be that genes involved in ATP production are down-regulated. Thus, the study of one single molecule, hypoxanthine, has contributed to the global prevention of an estimated 2-500,000 annual infant deaths.
Topics: Female; Humans; Infant; Infant, Newborn; Pregnancy; Hypoxanthine; Hypoxanthines; Hypoxia; Oxygen; Uric Acid; Xanthine Oxidase
PubMed: 35848535
DOI: 10.1515/jpm-2022-0259