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British Journal of Clinical Pharmacology Jun 1977
Review
Topics: Aging; Anemia, Hypochromic; Antipyrine; Chemical Phenomena; Chemistry; Drug Interactions; Half-Life; Humans; Kinetics; Liver Diseases; Saliva; Sex Factors; Thyroid Diseases
PubMed: 332216
DOI: 10.1111/j.1365-2125.1977.tb00710.x -
The Lancet. Neurology Jul 2017In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria.
METHODS
In this phase 3, randomised, double-blind, parallel-group study, patients aged 20-75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1-4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686.
FINDINGS
Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was -5·01 (SE 0·64) in the edavarone group and -7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal.
INTERPRETATION
Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria.
FUNDING
Mitsubishi Tanabe Pharma Corporation.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Antipyrine; Double-Blind Method; Edaravone; Female; Free Radical Scavengers; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Severity of Illness Index; Young Adult
PubMed: 28522181
DOI: 10.1016/S1474-4422(17)30115-1 -
Nihon Rinsho. Japanese Journal of... Oct 2006
Review
Topics: Antipyrine; Cerebral Infarction; Edaravone; Free Radical Scavengers; Humans
PubMed: 17461204
DOI: No ID Found -
The Journal of Pharmacology and... Jul 1995As space flight becomes more commonplace, the influence of physiologic changes associated with the microgravity environment become of greater concern. Exposure to...
As space flight becomes more commonplace, the influence of physiologic changes associated with the microgravity environment become of greater concern. Exposure to weightlessness has been shown to have numerous effects on body composition and organ function in animals and humans. However, studies examining possible alterations in drug metabolism and pharmacokinetics are not readily available. Antipyrine is a marker of hepatic oxidative function and total body water. The purpose of our study was to examine the effects of simulated weightlessness on the pharmacokinetics of antipyrine. Weightlessness was simulated through the use of the tail-suspended rat model. Rats were suspended for a total of 7 days. During the study period, antipyrine pharmacokinetics, after a single 20 mg/kg i.v. or p.o. dose, were evaluated at base line (day-1) and 1, 3 and 7 days after the initiation of suspension. Total body clearance was significantly elevated in the tail suspended rats from both the i.v. and p.o. dosing groups after 3 and 7 days of simulated weightlessness. In addition, clearance was elevated after 1 day of tail-suspension in the p.o. dosing group. Steady-state volume of distribution was not statistically different over the entire study period in either dosing group. Data from the present study suggest that brief periods of tail-suspension may markedly alter the pharmacokinetics of drugs in the rat and that more studies are required in models of weightlessness and actual space flight to understand the complex interaction between microgravity and hepatic metabolic activity.
Topics: Administration, Oral; Animals; Antipyrine; Infusions, Intravenous; Liver; Male; Models, Biological; Organ Size; Rats; Rats, Sprague-Dawley; Spleen; Tail; Weightlessness
PubMed: 7616419
DOI: No ID Found -
British Journal of Clinical Pharmacology Oct 1986The kinetic parameters of antipyrine obtained from saliva samples and the appearance of major antipyrine metabolites (4-hydroxyantipyrine, norantipyrine and...
The kinetic parameters of antipyrine obtained from saliva samples and the appearance of major antipyrine metabolites (4-hydroxyantipyrine, norantipyrine and 3-hydroxymethylantipyrine) in urine samples were measured in 10 patients with psoriasis (six nonsmokers and four smokers) and in 20 healthy subjects (11 nonsmokers and nine smokers). The volume of distribution and total clearance of antipyrine were not significantly different between psoriatric patients and control subjects subdivided according to smoking habit. However, antipyrine half-life was significantly (P less than 0.05) shorter in nonsmoking psoriatrics than in nonsmoking controls. There were no significant differences in mean values for the amounts (% dose) and partial clearances for production of major antipyrine metabolites between non-smoking patients and non-smoking controls, between smoking patients and smoking controls, and between patients overall and controls overall. The total clearance of antipyrine and the partial clearances of antipyrine to its three main metabolites were significantly (P less than 0.05 to 0.01) greater in smoking controls than in nonsmoking controls, and the total clearance of antipyrine and the partial clearance to 4-hydroxyantipyrine were significantly (P less than or equal to 0.05) greater in smoking patients than in nonsmoking patients. These findings provide no evidence that psoriasis is associated with an alteration in hepatic microsomal monooxygenase activity, at least insofar as the formation of major antipyrine metabolites is concerned.
Topics: Aged; Aged, 80 and over; Antipyrine; Aryl Hydrocarbon Hydroxylases; Edaravone; Female; Half-Life; Humans; Male; Middle Aged; Psoriasis; Saliva; Smoking
PubMed: 3768257
DOI: 10.1111/j.1365-2125.1986.tb02917.x -
Photochemical & Photobiological... May 2020A simple antipyrine based fluorescent probe, 4-[(2-hydroxy-3-methoxy-benzylidene)-amino]-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (OVAP), has been successfully...
A simple antipyrine based fluorescent probe, 4-[(2-hydroxy-3-methoxy-benzylidene)-amino]-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (OVAP), has been successfully synthesized using a one-step condensation method. It exhibits dual sensing properties toward Al3+ and Zn2+ in the presence of other relevant metal ions and also displays novel aggregation induced emission enhancement (AIEE) characteristics in its aggregated/solid state. Aggregated OVAP microstructures with interesting morphologies have been synthesized using SDS as a morphology directing agent. Morphologies of the particles are characterized using optical microscopy. Photophysical properties of the as-synthesized OVAP hydrosol are studied using UV-Vis absorption, steady state and time resolved fluorescence spectroscopy. The 'turn on' luminescence property of OVAP is used for the selective detection of trace amounts of Al3+ and Zn2+ and a significant turn on fluorescence enhancement over ∼100-fold is triggered via chelation-enhanced fluorescence (CHEF) through complex formation. The 1 : 1 stoichiometry of each sensor metal ion complex is observed from Job's plot based on UV-Vis absorption titration. The LODs for Al3+ and Zn2+ are found to be 1.05 nM and 2.35 nM, respectively. Notably, the sensor, OVAP, is further demonstrated using a molecular INHIBIT logic gate.
Topics: Aluminum; Antipyrine; Fluorescent Dyes; Spectrometry, Fluorescence; Zinc
PubMed: 32329762
DOI: 10.1039/c9pp00472f -
Pharmacology 1981A high-performance liquid chromatography method is described which allows for the simultaneous determination of antipyrine, 4-hydroxyantipyrine, norantipyrine and...
A high-performance liquid chromatography method is described which allows for the simultaneous determination of antipyrine, 4-hydroxyantipyrine, norantipyrine and 3-hydroxyantipyrine. Hydrolysis conditions with respect to source glucuronidase, amount of glucuronidase, pH of incubation and addition of antioxidant to the incubation medium proved to be very critical for norantipyrine and to a lesser extent 4-hydroxyantipyrine. The method is of good sensitivity, accuracy and reproducibility. Thus, the method is well suited for detailed metabolic studies.
Topics: Antioxidants; Antipyrine; Chromatography, High Pressure Liquid; Edaravone; Humans; Hydrogen-Ion Concentration; Hydrolysis; Time Factors
PubMed: 7323136
DOI: 10.1159/000137550 -
Journal of Hepatology Jan 1995Our aim was to study whether chronic hepatitis C affects the three metabolic pathways of the model drug antipyrine differently.
BACKGROUND/AIMS
Our aim was to study whether chronic hepatitis C affects the three metabolic pathways of the model drug antipyrine differently.
METHODS
We measured antipyrine clearance from saliva as well as urinary excretion of its main metabolites 4-hydroxy-antipyrine, 3-hydroxy-methyl-antipyrine, and nor-antipyrine in 24 patients with chronic hepatitis C and in 21 healthy control subjects. Due to incomplete urine collection, 12 liver patients and three controls were excluded.
RESULTS
Antipyrine clearance (mean +/- SD) was significantly lower in patients with chronic hepatitis C, 1.2 +/- 0.7 l.h-1 (n = 12), than in controls (n = 18), 2.2 +/- 1.0 l.h-1 (p = 0.006). The urinary excretion of each of the metabolites was depressed to an equal extent in liver patients. The severity of the liver disease, as assessed by Child Pugh score, serum albumin and bilirubin, correlated significantly with antipyrine clearance and urinary excretion of the metabolite 3-hydroxy-methyl-antipyrine. The hepatitis activity index (Knodell) correlated with 3-hydroxy-methyl-antipyrine and 4-hydroxy-antipyrine, only.
CONCLUSIONS
Moderate-severe chronic hepatitis C does not seem to depress the three main metabolic pathways of antipyrine differently.
Topics: Adult; Antipyrine; Chronic Disease; Edaravone; Female; Hepatitis C; Humans; Male; Middle Aged; Reference Values
PubMed: 7751582
DOI: 10.1016/0168-8278(95)80254-1 -
European Journal of Clinical... 1985In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral...
In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides the parent drug, 3-hydroxymethylantipyrine (HMA) was present in plasma in the free and conjugated forms, whereas 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) were found only in the conjugated form. The same was true for urine. The plasma concentrations of these metabolites are too low to be measured in subjects with normal renal function. Plasma antipyrine clearance in the patients was in the same range as in healthy subjects. Investigation of metabolite kinetics, however, revealed that the rate of formation of NORA was preferentially decreased, whereas that of OHA and HMA were unaltered. Renal clearance of the metabolites of antipyrine was severely impaired in patients with renal insufficiency, and the resulting accumulation made it possible for the first-time to measure the antipyrine metabolites in plasma. Mean residence times of metabolites were longer than that of the parent compound. Renal clearances of the conjugates were correlated with the creatinine clearance, but were somewhat higher. Renal clearance of free HMA was lower and was also correlated with creatinine clearance. The mean clearance for glucuronidation of HMA was 93.1 ml/min. The results suggest that in healthy subjects Phase I metabolism is the rate-limiting step in the elimination of antipyrine, which is essential for its application as a model drug in metabolism studies.
Topics: Adult; Aged; Antipyrine; Edaravone; Female; Half-Life; Humans; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Time Factors
PubMed: 4043202
DOI: 10.1007/BF00544072 -
Amyotrophic Lateral Sclerosis &... Nov 2017
Review
Topics: Amyotrophic Lateral Sclerosis; Antipyrine; Decision Making; Edaravone; Free Radical Scavengers; Humans; Treatment Outcome
PubMed: 28975816
DOI: 10.1080/21678421.2017.1369125