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British Journal of Clinical Pharmacology Dec 1985Antipyrine total clearance and the formation clearance of its major metabolites were studied in normal, healthy male volunteers before and after multiple dosing for...
Antipyrine total clearance and the formation clearance of its major metabolites were studied in normal, healthy male volunteers before and after multiple dosing for approximately three weeks with phenytoin (six subjects) and carbamazepine (six subjects). Total antipyrine clearance increased on average by 91% after phenytoin dosing and by 61% after carbamazepine and individual increases correlated well with mean plasma concentrations of the anti-epileptic drug. The increase in total clearance resulted largely from increased formation clearances of the 4-hydroxy and 3-hydroxymethylantipyrine metabolites with minimal effect on the norantipyrine pathway, following treatment with both enzyme-inducing drugs. It is concluded that both phenytoin and carbamazepine have similar effects on antipyrine metabolism and that these effects are mediated by induction of specific forms of cytochrome P450.
Topics: Adult; Antipyrine; Biotransformation; Carbamazepine; Drug Interactions; Half-Life; Humans; Kinetics; Male; Phenytoin; Saliva
PubMed: 4091993
DOI: 10.1111/j.1365-2125.1985.tb05119.x -
British Journal of Clinical Pharmacology Nov 1984The influence of an 8-day therapy with rifampicin (600 mg daily) was studied on antipyrine plasma clearance and metabolite formation in seven patients with tuberculosis...
The influence of an 8-day therapy with rifampicin (600 mg daily) was studied on antipyrine plasma clearance and metabolite formation in seven patients with tuberculosis (age 18-79 years), who were also treated with isoniazid and pyrazinamide. After rifampicin treatment the elimination half-life of antipyrine had decreased in all patients from 12.9 +/- 5.0 to 8.8 +/- 2.0 h (P less than 0.05). Antipyrine clearance had increased from 2.2 +/- 0.9 to 2.9 +/- 0.7 l/h (P less than 0.05), while no change in apparent volume of distribution was observed. The increase in antipyrine clearance was primarily due to a selective increase in the rate of formation of norantipyrine by 80% from 6.9 +/- 3.4 to 12.4 +/- 3.4 ml/min. Rifampicin seems to induce preferentially the cytochrome P-450 (iso-) enzyme(s) involved in the demethylation of antipyrine to norantipyrine. Other pathways of antipyrine metabolism were hardly affected. This provides further evidence for the involvement of different iso-enzymes of the cytochrome P-450 system in antipyrine metabolism in man.
Topics: Adolescent; Adult; Aged; Antipyrine; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Rifampin; Tuberculosis, Pulmonary
PubMed: 6508979
DOI: 10.1111/j.1365-2125.1984.tb02532.x -
Anesthesiology Dec 1997The cardiovascular effects of halothane are well recognized, but little is known of how this affects drug distribution. The effect of halothane anesthesia on physiologic... (Comparative Study)
Comparative Study
BACKGROUND
The cardiovascular effects of halothane are well recognized, but little is known of how this affects drug distribution. The effect of halothane anesthesia on physiologic factors that affect drug disposition from the moment of injection was investigated.
METHODS
The dispositions of markers of intravascular space and blood flow (indocyanine green), extracellular space and free water diffusion (inulin), and total body water and tissue perfusion (antipyrine) were determined in four purpose-bred coonhounds. The dogs were studied while awake and while anesthetized with 1%, 1.5%, and 2% halothane in a randomized order determined by a repeated measures Latin square experimental design. Marker dispositions were described by recirculatory pharmacokinetic models based on frequent early and less frequent later arterial blood samples. These models characterize the role of cardiac output and its distribution on drug disposition.
RESULTS
Halothane caused a significant and dose-dependent decrease in cardiac output. The disposition of antipyrine was most profoundly affected by halothane anesthesia, which increased both nondistributive intercompartmental clearance and volume while decreasing fast and slow tissue clearances and elimination clearance in a halothane dose-dependent manner.
CONCLUSIONS
Halothane-induced changes in blood flow to the compartments of the antipyrine recirculatory model were not proportional to changes in cardiac output. Halothane anesthesia significantly increased (to more than double) the area under the drug concentration versus time curve due to an increase in the apparent peripheral blood flow not involved in drug distribution, despite a dose-dependent cardiac output decrease. Recirculatory pharmacokinetic models include the best aspects of traditional compartmental and physiologic pharmacokinetic models while offering advantages over both.
Topics: Anesthesia, Inhalation; Anesthetics, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antipyrine; Area Under Curve; Coloring Agents; Dogs; Dose-Response Relationship, Drug; Halothane; Hemodynamics; Indocyanine Green; Inulin; Male; Tissue Distribution
PubMed: 9416724
DOI: 10.1097/00000542-199712000-00018 -
British Journal of Clinical Pharmacology Feb 1984The possible dietary influences on in vivo antipyrine and aminopyrine kinetics with reference to energy (1500, 1800, 3000 kcal) and protein (5, 10, 15, 20% protein...
The possible dietary influences on in vivo antipyrine and aminopyrine kinetics with reference to energy (1500, 1800, 3000 kcal) and protein (5, 10, 15, 20% protein energy-PE) intake were studied in a carefully controlled metabolic experiment in young healthy adult male volunteers aged between 25-34 years. Antipyrine and aminopyrine were used to evaluate drug metabolism. On 1500 kcal intake with 10% PE, the metabolism of both aminopyrine and antipyrine were significantly reduced whereas on 1800 kcal with 10% PE intake, only aminopyrine metabolism decreased significantly as compared to 3000 kcal with 10% PE. Antipyrine clearance on 1800 kcal with 10% PE however had not decreased to the same extent as on 1500 kcal with 10% PE. The results indicate that on low calorie intake with 10% PE, the drug metabolism is decreased. When the protein intake on 1500 kcal was doubled (20% PE) there was a significant stimulation of both aminopyrine and antipyrine metabolism. Aminopyrine and antipyrine clearances on 3000 kcal with 5% PE were significantly reduced as compared to 3000 kcal with 10% and 15% PE indicating that unlike proteins, carbohydrate and/or fat calories per se do not significantly stimulate drug metabolism. When the protein energy in the diet was increased from 5% to 10% or 15% at 3000 kcal, there was a stimulation of both antipyrine and aminopyrine metabolism. Significant differences between 10% and 15% of protein energy were not observed when the energy was adequate (3000 kcal). Therefore it is necessary to consider both proteins and energy as important variables affecting drug clearances from plasma in malnourished conditions.
Topics: Adult; Aminopyrine; Antipyrine; Body Weight; Diet; Energy Intake; Humans; Kinetics; Male
PubMed: 6704283
DOI: 10.1111/j.1365-2125.1984.tb02328.x -
Journal of Postgraduate Medicine Jan 1991Pathological conditions are known to affect pharmacokinetics of many drugs. Antipyrine half-life is used as a marker of liver microsomal enzyme function. Antipyrine... (Comparative Study)
Comparative Study
Pathological conditions are known to affect pharmacokinetics of many drugs. Antipyrine half-life is used as a marker of liver microsomal enzyme function. Antipyrine pharmacokinetics, therefore, was investigated in 23 thyrotoxic and 11 euthyroid goitre patients. Of these, 11 thyrotoxic and 9 euthyroid goitre patients also participated in doxycycline bioavailability studies. In thyrotoxic patients, antipyrine half-life and AUCo infinity and doxycycline Cpmax and AUCo infinity were found to be reduced as compared to those of healthy euthyroid normal subjects. Following treatment of thyrotoxicosis, the antipyrine half-life and AUCo infinity returned to normal. Doxycycline AUCo infinity returned to near normal range but Cpmax did not.
Topics: Administration, Oral; Adult; Antipyrine; Biological Availability; Doxycycline; Female; Goiter; Half-Life; Humans; Male; Middle Aged; Thyrotoxicosis
PubMed: 1941694
DOI: No ID Found -
PloS One 2016Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterized by cognitive declines in patients after surgery. Previous studies have suggested that...
Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterized by cognitive declines in patients after surgery. Previous studies have suggested that surgery contributed to such impairment. It has been proven that neuroinflammation may exacerbate surgery-induced cognitive impairment in aged rats. The free radical scavenger edaravone has high blood brain barrier permeability, and was demonstrated to effectively remove free radicals from the brain and alleviate the development of POCD in patients undergoing carotid endarterectomy, suggesting its potential role in preventing POCD. For this reason, this study was designed to determine whether edaravone is protective against POCD through its inhibitory effects on inflammatory cytokines and oxidative stress. First, Sprague Dawley adult male rats were administered 3 mg/kg edaravone intraperitoneally after undergoing a unilateral nephrectomy combined with lipopolysaccharide injection. Second, behavioral parameters related to cognitive function were recorded by fear conditioning and Morris Water Maze tests. Last, superoxide dismutase activities and malondialdehyde levels were measured in the hippocampi and prefrontal cortex on postoperative days 3 and 7, and microglial (Iba1) activation, p-Akt and p-mTOR protein expression, and synaptic function (synapsin 1) were also examined 3 and 7 days after surgery. Rats that underwent surgery plus lipopolysaccharide administration showed significant impairments in spatial and working memory, accompanied by significant reductions in hippocampal-dependent and independent fear responses. All impairments were attenuated by treatment with edaravone. Moreover, an abnormal decrease in superoxide dismutase activation, abnormal increase in malondialdehyde levels, significant increase in microglial reactivity, downregulation of p-Akt and p-mTOR protein expression, and a statistically significant decrease in synapsin-1 were observed in the hippocampi and prefrontal cortices of rats at different time points after surgery. All mentioned abnormal changes were totally or partially reversed by edaravone. To our knowledge, few reports have shown greater protective effects of edaravone on POCD induced by surgery plus lipopolysaccharide administration from its anti-oxidative stress and anti-inflammatory effects, as well as maintenance of Akt/mTOR signal pathway activation; these might be closely related to the therapeutic effects of edaravone. Our research demonstrates the potential use of edaravone in the treatment of POCD.
Topics: Animals; Antipyrine; Brain; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Edaravone; Free Radical Scavengers; Humans; Inflammation Mediators; Lipopolysaccharides; Male; Malondialdehyde; Nephrectomy; Neuroprotective Agents; Oxidative Stress; Postoperative Complications; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; TOR Serine-Threonine Kinases
PubMed: 27116382
DOI: 10.1371/journal.pone.0153708 -
British Journal of Clinical Pharmacology Mar 1984Antipyrine clearance was determined in 41 psoriatics and age-sex matched controls, using sequential measurements of salivary concentration. Antipyrine clearance and...
Antipyrine clearance was determined in 41 psoriatics and age-sex matched controls, using sequential measurements of salivary concentration. Antipyrine clearance and elimination rate constant were less in psoriatics (P less than 0.05) and apparent volumes of distribution were similar. These differences were greater between female psoriatics and controls (P less than 0.025; P less than 0.05) and the differences between male psoriatics and controls were not significant. Correlation of simultaneous measurements of saliva and plasma antipyrine concentration in six psoriatics and age-sex matched controls showed no differences between the two groups. We conclude that antipyrine clearance is reduced in psoriasis but the underlying mechanism is unclear.
Topics: Adolescent; Adult; Aged; Antipyrine; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Psoriasis; Sex Factors
PubMed: 6712866
DOI: 10.1111/j.1365-2125.1984.tb02349.x -
British Journal of Clinical Pharmacology Oct 1976Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten...
Liver volume and the clearances of antipyrine and indocyanine green have been measured before and after administration of phenobarbitone (180 mg/day) for 3 weeks to ten healthy subjects. The measurement of liver volume by an ultrasound scanning technique yielded reproducible results which were consistent with predictions of liver size by allometric methods. Before phenobarbitone, antipyrine clearance correlated with liver volume, but there was no correlation between indocyanine green clearance and liver volume. Phenobarbitone administration increased the clearance of antipyrine significantly by 90 +/- 14% but there was no significant change in indocyanine green clearance or liver volume. After phenobarbitone the correlation between antipyrine clearance and liver volume persisted. There was no correlation between indocyanine green clearance and liver volume. These results suggest that in non-medicated subjects some of the difference in antipyrine clearance is due to difference in functional hepatic parenchymal mass and that phenobarbitone increases the drug metabolising capacity per unit of hepatic mass but not total liver size.
Topics: Adult; Antipyrine; Biotransformation; Female; Humans; Indocyanine Green; Liver; Liver Function Tests; Male; Phenobarbital; Ultrasonics
PubMed: 973986
DOI: 10.1111/j.1365-2125.1976.tb00646.x -
Oxidative Medicine and Cellular... 2018Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which...
Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1 antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1 by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.
Topics: 2-Methoxyestradiol; Animals; Antipyrine; Blood Pressure; Catalase; DNA Fragmentation; Disease Models, Animal; Edaravone; Estradiol; Free Radical Scavengers; Heme Oxygenase-1; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-1beta; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sepsis; Survival Rate
PubMed: 29765498
DOI: 10.1155/2018/5216383 -
Brain Research Jun 2011Detection and protection of apoptosis, autophagy and neurovascular unit (NVU) are essentially important in understanding and treatment for ischemic stroke patients. In...
Detection and protection of apoptosis, autophagy and neurovascular unit (NVU) are essentially important in understanding and treatment for ischemic stroke patients. In this study, we have conducted an in vivo optical imaging for detecting apoptosis and activation of matrix metalloproteinases (MMPs), then evaluated the protective effect of 2 package types of free radical scavenger edaravone (A and B) on apoptosis, autophagy and NVU in mice after transient middle cerebral artery occlusion (tMCAO). As compared to vehicle treatment, edaravones A and B showed a significant improvement of clinical scores and infarct size at 48 h after 90 min of tMCAO with great reductions of in vivo fluorescent signal for MMPs and early apoptotic annexin V activations. Ex vivo imaging of MMPSense 680 or annexin V-Cy5.5 showed a fluorescent signal, while which was remarkably different between vehicle and edaravone groups, and colocalized with antibody for MMP-9 or annexin V. Edaravone A and B ameliorated the apoptotic neuronal cell death in immunohistochemistry, and activations of MMP-9 and aquaporin 4 with reducing autophagic activations of microtubule-associated protein 1 light chain 3 (LC3) in Western blot. In this study, edaravone in both packages showed a similar strong neuroprotection after cerebral ischemia, which was confirmed with in vivo and ex vivo optical imagings for MMPs and annexin V as well as reducing cerebral infarct, inhibiting apoptotic/autophagic mechanisms, and protecting a part of neurovascular unit.
Topics: Animals; Annexin A5; Antipyrine; Apoptosis; Autophagy; Blood-Brain Barrier; Blotting, Western; Cerebral Infarction; Diagnostic Imaging; Edaravone; Fluorescence; Fluorescent Antibody Technique; Fluorescent Antibody Technique, Indirect; Free Radical Scavengers; Immunohistochemistry; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Matrix Metalloproteinases; Mice; Mice, Inbred ICR
PubMed: 21571257
DOI: 10.1016/j.brainres.2011.04.038