allopurinol and Acidosis

Tumor lysis syndrome is an oncologic emergency that is characterized by severe electrolyte abnormalities. The syndrome occurs in patients with lymphoproliferative malignancies, most often after chemotherapy, but also spontaneously. The pathophysiology involves tumor cell lysis resulting in the release of potassium, phosphate and uric acid. The deposition of uric acid and calcium phosphate crystals in the renal tubules may lead to acute renal failure. The treatment consists in hydration, correction of the acidosis and hyperkalemia, use of allopurinol and recombinant urate oxidase (rasburicase) for preventing urate nephropathy and haemodialysis. The authors report a case of a patient with acute myeloid leukemia, who developed severe tumor lysis syndrome after chemotherapy.

Topics: Acidosis; Acute Kidney Injury; Allopurinol; Fluid Therapy; Humans; Hyperkalemia; Kidney Tubules; Recombinant Proteins; Renal Dialysis; Tumor Lysis Syndrome; Urate Oxidase; Uric Acid

Advances have recently been made in understanding the pharmacokinetics of theophylline. To correlate the new knowledge of theophylline pharmacokinetics with the drug's current status in therapy, we have critically reviewed the relevant investigations of the last 5 years. We consider data on its presumed mechanisms of action, factors affecting its clearance, its use in pregnancy, treatment of overdoses, and important drug interactions. Theophylline clearance is decreased by concomitant use of erythromycin, cimetidine, high-dose allopurinol, oral contraceptives, and caffeine. Clearance is increased by concomitant use of phenobarbital and phenytoin. Newly discovered actions of theophylline include dose-dependent improvement of diaphragmatic contractility, augmentation of ventilatory response to hypoxia, and sleep disturbances (especially with high-dose treatments). Points clinically relevant to the daily use of theophylline derivatives and the importance of sustained-release preparations are discussed. Theophylline continues to play a major role in therapy for reactive airways disease.

Topics: Acidosis; Aging; Allopurinol; Animals; Anti-Bacterial Agents; Breast Feeding; Bronchodilator Agents; Caffeine; Contraceptives, Oral; Cooking; Cystic Fibrosis; Drug Interactions; Erythromycin; Female; Heart Diseases; Histamine H2 Antagonists; Humans; Hypoxia; Infections; Kinetics; Liver Diseases; Lung Diseases, Obstructive; Maternal-Fetal Exchange; Phenobarbital; Phenytoin; Pregnancy; Respiration Disorders; Sleep; Smoking; Theophylline

Topics: Acidosis; Acute Kidney Injury; Allopurinol; Aluminum Hydroxide; Burkitt Lymphoma; Child; Humans; Hypercalcemia; Hyperlipidemias; Hypertension, Renal; Hypoglycemia; Lymphoma; Male; Mannitol; Metabolic Diseases; Phosphorus Metabolism Disorders; Uric Acid; Xanthines

Hyperuricemia and metabolic acidosis have emerged as important risk factors for progression of kidney disease. In this study, we aimed to investigate the effects of allopurinol on metabolic acidosis and endothelial functions in hyperuricemic stage 2-4 chronic kidney disease (CKD) patients.. Thirty patients with stage 2-4 CKD and serum uric acid levels over 5.5 mg/dl were included in the study group. They were prescribed 300 mg/day per oral allopurinol treatment for three months. Age- and gender-matched CKD patients (n = 30) with similar clinical characteristics were taken as the control group and were not given allopurinol treatment. Endothelial functions were measured via flow-mediated dilatation (∆FMD %) over the forearm. pH and HCO3 levels in venous blood, Cr clearance and proteinuria levels were calculated in all patients at baseline and in the third month.. Serum uric acid levels significantly decreased in the study group from 7.9 ± 1.6 to 6.4 ± 1.7 (p < 0.001). Cr clearance (from 43.4 ± 20.1 to 51.4 ± 24.9, p = 0.011), serum bicarbonate levels (from 21.4 ± 3.4 to 23.0 ± 3.4, p = 0.007) and ΔFMD % values (from 5.8 ± 2.5 to 6.2 ± 2.7, p = 0.006) increased significantly in the allopurinol group. There were no significant changes except for ∆FMD % values (decreased from 6.27 ± 1.62 to 5.71 ± 1.90, p = 0.005) in the control group. ∆FMD % variations within the two groups were clearly significant in the repeated ANOVA general linear model.. We assume that decreasing uric acid levels with allopurinol treatment seems to be helpful in restoring endothelial functions, preventing metabolic acidosis and slowing down the progression of CKD.

Topics: Acidosis; Adult; Aged; Allopurinol; Bicarbonates; Creatinine; Endothelium; Female; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Uric Acid; Vasodilation

The prevalence of chronic kidney disease (CKD) is increasing worldwide; black patients have an increased risk of developing CKD and end stage kidney disease (ESKD) at significantly higher rates than other races.. A cross sectional study was carried out on black patients with CKD attending the kidney outpatient clinic at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) in South Africa, between September 2019 to March 2020. Demographic and clinical data were extracted from the ongoing kidney outpatient clinic records and interviews, and were filled in a questionnaire. Patients provided blood and urine for laboratory investigations as standard of care, and data were descriptively and inferentially entered into REDcap and analysed using STATA version 17. Multivariable logistic regression analysis was used to identify demographic and clinical variables associated with advanced CKD.. A total of 312 black patients with CKD were enrolled in the study with a median age of 58 (IQR 46-67) years; 58% patients had advanced CKD, 31.5% of whom had grossly increased proteinuria, 96.7% had hypertension, 38.7% had diabetes mellitus and 38.1% had both hypertension and diabetes mellitus. In patients with advanced CKD, the median age was 61 (IQR 51-69) years, eGFR 33 (30-39) mL/min/1.73 m2, serum bicarbonate 22 (IQR 20-24), haemoglobin 12.9 (IQR 11.5-14.0) g/dl and serum uric acid 0.43 (IQR 0.37-0.53). The prevalence of metabolic acidosis was 62.4%, anemia 46.4% and gout 30.9% among those with advanced CKD, while the prevalence of metabolic acidosis and anaemia was 46.6% and 25.9% respectively in those with early CKD. Variables with higher odds for advanced CKD after multivariable logistic regression analysis were hypertension (OR 3.3, 95% CI 1.2-9.2, P = 0.020), diabetes mellitus (OR 1.8, 95% CI 1.1-3.3, P = 0.024), severe proteinuria (OR 3.5, 95% CI 1.9-6.5, P = 0.001), angina (OR 2.5, 95% CI 1.2-5.1, P = 0.008), anaemia (OR 2.9, 95% CI 1.7-4.9, P = 0.001), hyperuricemia (OR 2.4, 95% CI 1.4-4.1, P = 0.001), and metabolic acidosis (OR 2.0, 95% CI 1.2-3.1, P = 0.005). Other associations with advanced CKD were loss of spouse (widow/widower) (OR 3.2, 95% CI 1.4-7.4, P = 0.006), low transferrin (OR 2.4, 95% CI 1.1-5.1, P = 0.028), hyperkalemia (OR 5.4, 95% CI 1.2-24.1, P = 0.029), use of allopurinol (OR 2.4, 95% CI 1.4-4.3, P = 0.005) and doxazosin (OR 1.9, 95% CI 1.2-3.1, P = 0.006).. Hypertension and diabetes mellitus were strongly associated with advanced CKD, suggesting a need for primary and secondary population-based prevention measures. Metabolic acidosis, anemia with low transferrin levels, hyperuricemia and hyperkalemia were highly prevalent in our patients, including those with early CKD, and they were strongly associated with advanced CKD, requiring clinicians and dietitians to be proactive in supporting the needs of CKD patients in meeting their daily dietary requirements towards preventing and slowing the progression of CKD.

Topics: Acidosis; Aged; Allopurinol; Anemia; Bicarbonates; Cross-Sectional Studies; Diabetes Mellitus; Doxazosin; Hemoglobins; Humans; Hyperkalemia; Hypertension; Hyperuricemia; Middle Aged; Prevalence; Proteinuria; Renal Insufficiency, Chronic; South Africa; Tertiary Care Centers; Transferrins; Uric Acid

Nitrite reduction to nitric oxide (NO) may be potentiated by a nitrite reductase activity of deoxyHb and contribute to systemic hypoxic vasodilation. The effect of nitrite on the pulmonary circulation has not been well characterized. We explored the effect of nitrite on hypoxic pulmonary vasoconstriction (HPV) and the role of the red blood cell (RBC) in nitrite reduction and nitrite-mediated vasodilation. As to method, isolated rat lungs were perfused with buffer, or buffer with RBCs, and subjected to repeated hypoxic challenges, with or without nitrite. As a result, in buffer-perfused lungs, HPV was reduced at nitrite concentrations of 7 muM and above. Nitrite inhibition of HPV was prevented by excess free Hb and RBCs, suggesting that vasodilation was mediated by free NO. Nitrite-inhibition of HPV was not potentiated by mild acidosis (pH = 7.2) or xanthine oxidase activity. RBCs at 15% but not 1% hematocrit prevented inhibition of HPV by nitrite (maximum nitrite concentration of approximately 35 muM) independent of perfusate Po(2). Degradation of nitrite was accelerated by hypoxia in the presence of RBCs but not during buffer perfusion. In conclusion, low micromolar concentrations of nitrite inhibit HPV in buffer-perfused lungs and when RBC concentration is subphysiological. This effect is lost when RBC concentration approaches physiological levels, despite enhanced nitrite degradation in the presence of RBCs. These data suggest that, although deoxyHb may generate NO from nitrite, insufficient NO escapes the RBC to cause vasodilation in the pulmonary circulation under the dynamic conditions of blood flow through the lungs and that RBCs are net scavengers of NO.

Topics: Acidosis; Animals; Breath Tests; Dose-Response Relationship, Drug; Erythrocytes; Hemoglobins; Hypoxia; Lung; Nitric Oxide; Perfusion; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Sodium Nitrite; Time Factors; Vasoconstriction; Xanthine Oxidase

Several investigators have reported patients with acute pure red cell aplasia (PRCA) caused by anticonvulsants, antibiotics, or antithyroid agents. Allopurinol is known to be a causative agent of aplastic anemia, but there have been few reports of acute PRCA induced by allopurinol. We describe here a 15-year-old boy who suffered from anemia 6 weeks after initiation of allopurinol therapy; his anemia immediately improved after cessation of the drug. His bone marrow showed severe erythroid hypoplasia with a myeloid/erythroid ratio of 18.6 and low expression of glycophorin A detected on cell-surface antigen analysis. No morphological abnormalities were observed in myeloid series and megakaryocytes. The prolonged plasma iron disappearance rate and the decreased plasma iron turnover rate also indicated erythroid hypoplasia. He had been free from any infections, including parvovirus B19, before manifestation of PRCA. Taken together, these results suggest a diagnosis of acute PRCA. This side effect of allopurinol should be taken into consideration.

Topics: Acidosis; Adolescent; Allopurinol; Antimetabolites; Bone Marrow Cells; Erythrocyte Count; Hematopoietic Stem Cells; Humans; Leukocyte Count; Male; Megakaryocytes; Platelet Count; Red-Cell Aplasia, Pure; Williams Syndrome

Primary non-function of liver allografts is related to preservation time, during which hypoxia leads to intracellular accumulation of acid. Preservation-induced failure of hepatocellular pH regulation may play a role in the pathogenesis of primary graft non-function.. Using cultured/suspended rat hepatocytes and fluorimetric determination of intracellular pH, we determined whether preservation in University of Wisconsin solution (4 degrees C) impairs hepatocellular defence mechanisms against acidosis.. In non-preserved, 24-h-preserved and 48-h-preserved hepatocytes acidified to pH 6.7-6.8, initial Na+/H+ antiport-mediated H+ fluxes averaged 12 +/- 5, 9 +/- 5 and 12 +/- 5 nmol microL-1 min-1 and initial Na+/HCO3- symport-mediated HCO3- fluxes 7 +/- 2, 7 +/- 3 and 6 +/- 2 nmol microL-1 min respectively (P = NS). Preservation did not affect the inverse relationship between Na+/H+ antiport activity and intracellular pH. Thus, hepatocellular defence against intracellular acidosis is maintained during up to 48 h in University of Wisconsin solution.. Altered pHi homeostasis is unlikely to play a role in the pathogenesis of primary non-function of liver allografts.

Topics: Acidosis; Adenosine; Allopurinol; Animals; Cells, Cultured; Cold Temperature; Glutathione; Hydrogen-Ion Concentration; Insulin; Ion Transport; Linear Models; Liver; Liver Transplantation; Male; Organ Preservation; Organ Preservation Solutions; Raffinose; Rats; Rats, Sprague-Dawley

Relative hypoventilation, involving passively-or "permissively"-generated hypercapnic acidosis (HCA), may improve outcome by reducing ventilator-induced lung injury. However, the effects of HCA per se on pulmonary microvascular permeability (Kf,c) in noninjured or injured lungs are unknown. We investigated the effects of HCA in the isolated buffer-perfused rabbit lung, under conditions of: (1) no injury; (2) injury induced by warm ischemia-reperfusion; and (3) injury induced by addition of purine and xanthine oxidase. HCA (fraction of inspired carbon dioxide [FICO2] 12%, 25% versus 5%) had no adverse microvascular effects in uninjured lungs, and prevented (FICO2 25% versus 5%) the increase in Kf,c following warm ischemia-reperfusion. HCA (FICO2 25% versus 5%) reduced the elevation in Kf,c, capillary (Pcap), and pulmonary artery (Ppa) pressures in lung injury induced by exogenous purine/xanthine oxidase; inhibition of endogenous NO synthase in the presence of 25% FICO2 had no effect on Kf,c, but attenuated the reduction of Pcap and Ppa. HCA inhibited the in vitro generation of uric acid from addition of xanthine oxidase to purine. We conclude that in the current models, HCA is not harmful in uninjured lungs, and attenuates injury in free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine oxidase.

Topics: Acidosis; Analysis of Variance; Animals; Blood Pressure; Capillaries; Capillary Permeability; Carbon Dioxide; Free Radicals; Hydrostatic Pressure; Hypercapnia; Lung; Male; Microcirculation; Nitric Oxide Synthase; Pulmonary Artery; Purines; Rabbits; Reperfusion Injury; Respiration, Artificial; Respiratory Distress Syndrome; Uric Acid; Vascular Resistance; Xanthine Oxidase

1. Following ischaemic reperfusion, large amounts of superoxide anion (.O2-), hydroxyl radical (.OH) and H2O2 are produced, resulting in brain oedema and changes in cerebral vascular permeability. We have found that H2O2 (100 microM) induces a significant intracellular acidosis in both cultured rat cerebellar astrocytes (0.37 +/- 0.04 pH units) and C6 glioma cells (0.33 +/- 0.07 pH units). 2. Two membrane-crossing ferrous iron chelators, phenanthroline and deferoxamine, almost completely inhibited H2O2-induced intracellular acidosis, while the non-membrane-crossing iron chelator apo-transferrin had no effect. Furthermore, the acidosis was completely inhibited by two potent membrane-crossing .OH scavengers, N-(2-mercaptopropionyl)-glycine (N-MPG) and dimethyl thiourea (DMTU). Since .OH can be produced during iron-catalysed H2O2 breakdown (Fenton reaction), we have shown that a large reduction in pH1 in glial cells can result from the production of intracellular .OH via H2O2 oxidation. 3. We have ruled out the possible involvement of: (i) an increase in intracellular Ca2+ levels; and (ii) inhibition of oxidative phosphorylation. 4. Our results suggest that .OH inhibits glycolysis, leading to ATP hydrolysis and intracellular acidosis. This conclusion is based on the following observations: (i) in glucose-free medium, or in the presence of iodoacetate or 2-deoxy-D-glucose, H2O2-induced acidosis is completely suppressed; (ii) H2O2 and iodoacetate both produce an increase in levels of intracellular free Mg2+, an indicator of ATP breakdown; and (iii) direct measurement of intracellular ATP levels and lactate production show 50 and 55% reductions in ATP content and lactate production, respectively, following treatment with 100 microM H2O2. 5. Inhibition of the pH1 regulators (i.e. the Na(+)-H+ exchange and possibly the Na(+)-HCO3(-)-dependent pH1 transporters) resulting from H2O2-induced intracellular ATP reduction may also be involved in the H2O2-evoked intracellular acidosis in glial cells.

Topics: Acidosis; Adenosine Triphosphate; Animals; Astrocytes; Catalase; Cells, Cultured; Cerebellum; Citric Acid Cycle; Deferoxamine; Electron Transport; Female; Glioma; Glycolysis; Hydrogen Peroxide; Hypoxanthine; Lactates; Male; Oxidative Stress; Phenanthrolines; Rats; Rats, Wistar; Siderophores; Sodium-Hydrogen Exchangers; Superoxide Dismutase; Transferrin; Tumor Cells, Cultured; Xanthine Oxidase

Acidosis during exercise has long been associated with skeletal muscle fatigue. Recent evidence also has linked reactive oxygen species (ROS) with fatigue in skeletal muscle, including the diaphragm. We hypothesized that acidosis (designed to mimic blood pH during maximal exercise) would worsen ROS-induced depression of diaphragm contractility. The xanthine oxidase (XO) reaction in solution (0.01 U/ml) allows direct assessment of the effects of oxidant stress by ROS. Costal diaphragm fiber bundles from 24 Sprague-Dawley rats (200-250 g) were divided into four treatment groups: 1) pH 7.4, no XO (H); 2) pH 7.4 + XO (HXO); 3) pH 7.0, no XO (L); and 4) pH 7.0 + XO (LXO). Baseline twitch mechanics and force-frequency relationships (Pre) were determined in control Krebs solution (pH 7.4, no XO) before treatment. Treatment solutions were introduced, and the diaphragm underwent 2 min of contractions at 25 Hz (250 ms) at a rate of 1/s. After 10 min of recovery, the control solution was reintroduced into the bath and postcontractile function (Post) was measured. Significant reductions in twitch tension and low-frequency tetanic tension were greater in HXO and LXO compared with H, without an effect on maximal tetanic tension. One-half relaxation time was prolonged only by the combination of acidosis and oxidative stress. Addition of superoxide dismutase (50 U/ml) worsened and catalase (1,800 U/ml) attenuated XO-induced depression of diaphragm contractility. We concluded that XO induced a reduction of low-frequency tension in the fatigued diaphragm, which was mediated directly or indirectly through hydrogen peroxide and was exacerbated to a modest extent with acidosis.

Topics: Acidosis; Animals; Antioxidants; Diaphragm; Muscle Contraction; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxides; Xanthine Oxidase

After a transient ischemic attack of the cardiac vascular system, reactive oxygen-derived free radicals, including the superoxide (O2-.) and hydroxyl (.OH) radicals can be easily produced during reperfusion. These free radicals have been suggested to be responsible for reperfusion-induced cardiac stunning and reperfusion-induced arrhythmia. Hydrogen peroxide (H2O2) is often used as an experimental source of oxygen-derived free radicals. Using freshly dissociated single rat cardiac myocytes and the rat cardiac myoblast cell line, H9c2, we have shown, for the first time, that an intriguing pHiota acidification (approximately 0.24 pH unit) is induced by the addition of 100 micromol/L H2O2 and that this dose is without effect on the intracellular free Ca2+ levels or viability of the cells. Using H9c2 as a model cardiac cell, we have shown that it is the intracellular production of .OH, and not O2-. or H2O2, that results in this acidification. We have excluded any involvement of (1) the three known cardiac pHi regulators (the Na+-H+ exchanger, the Cl--HCO3 exchanger, and the Na+-HCO3 co-transporter), (2) a rise in intracellular Ca2+ levels, and (3) inhibition of oxidative phosphorylation. However, we have found that H2O2-induced acidosis is due to inhibition of the glycolytic pathway, with hydrolysis of intracellular ATP and the resultant intracellular acidification. In cardiac muscle and in skinned cardiac muscle fiber, it has been shown that a small intracellular acidification may severely inhibit contractility. Therefore, the sustained pHi decrease caused by hydroxyl radicals may contribute, in some part, to the well-documented impairment of cardiac mechanical function (ie, reperfusion cardiac stunning) seen during reperfusion ischemia.

Topics: Acidosis; Acids; Adenosine Triphosphate; Animals; Calcium; Carrier Proteins; Cells, Cultured; Hydrogen Peroxide; Hydrolysis; Hydroxyl Radical; Hypoxanthine; Hypoxanthines; Intracellular Membranes; Male; Myocardium; Rats; Rats, Wistar; Reactive Oxygen Species; Xanthine Oxidase

The present paper shows that cultured bovine endothelial cells can be labeled with 3H-carnitine by incubation. This process is slow and is uphill, requiring Na+/K+ ATPase activity. After 3 days incubation isotopic equilibrium is reached, when the cells contain about 0.5 mM (total) carnitine at a medium concentration of about 3 microM. The plasmamembrane barrier is rather resistant to acidosis and oxygen free radicals (OFR). The rate of carnitine release increases significantly only at pH below 5.8. At pH 6.0 the release of stored carnitine can be initiated by the addition of D- or L-lactate. OFR, generated by the addition of xanthine and xanthine oxidase, did not affect carnitine release. Both mild acidosis and OFR left plasmamembranes of endothelial cells intact as judged by the absence of lactate dehydrogenase loss from the cells. Therefore, the known increase of capillary permeability during ischemia and reperfusion may not be due to plasmalemmal disruption of individual endothelial cells, but to increase of inter-endothelial spaces.

Topics: Acidosis; Animals; Carnitine; Cattle; Cell Membrane; Cells, Cultured; Endothelium, Vascular; Female; Free Radicals; Hydrogen-Ion Concentration; Ischemia; Kinetics; L-Lactate Dehydrogenase; Lactates; Mitochondria; Ouabain; Reactive Oxygen Species; Xanthine; Xanthine Oxidase; Xanthines

Topics: Acidosis; Adrenergic beta-Antagonists; Allopurinol; Antihypertensive Agents; Benzothiadiazines; Diuretics; Humans; Probenecid; Sodium Chloride Symporter Inhibitors; Sulfinpyrazone; Uric Acid

Topics: Acidosis; Animals; Calcium; Calcium-Transporting ATPases; Coronary Disease; Dogs; Free Radicals; Hydrogen-Ion Concentration; Mannitol; Sarcoplasmic Reticulum; Superoxide Dismutase; Xanthine Oxidase

Topics: Acidosis; Alkalosis; Allopurinol; Animals; Cholesterol; Disease Models, Animal; Diuresis; Fructose; Glycine; Gout; Hydrogen-Ion Concentration; Natriuresis; Oxonic Acid; Probenecid; Purines; Rats; Research Design; Species Specificity; Triazines; Triglycerides; Uric Acid

Topics: Acidosis; Allopurinol; Animals; Bicarbonates; Blood Pressure; Carbon Dioxide; Diuresis; Dogs; Female; Hydrogen-Ion Concentration; Male; Partial Pressure; Shock; Time Factors; Tourniquets; Uric Acid; Xanthine Oxidase

Topics: Acidosis; Adolescent; Adult; Alkalies; Allopurinol; Child; Colectomy; Colitis, Ulcerative; Dehydration; Female; Humans; Ileostomy; Male; Postoperative Complications; Uric Acid; Urinary Calculi

Topics: Acidosis; Aged; Allopurinol; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Phenformin; Uric Acid