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International Journal of Molecular... Dec 2020Antazoline (ANT) was recently shown to be an effective and safe antiarrhythmic drug in the termination of atrial fibrillation. However, the drug is still not listed in...
Antazoline (ANT) was recently shown to be an effective and safe antiarrhythmic drug in the termination of atrial fibrillation. However, the drug is still not listed in clinical guidelines. No data on ANT metabolism in humans is available. We used liquid chromatography coupled with tandem mass spectrometry to identify and characterize metabolites of ANT. We analyzed plasma of volunteers following a single intravenous administration of 100 mg of ANT mesylate and in in vitro cultures of human hepatocytes. We revealed that ANT was transformed into at least 15 metabolites and we investigated the role of cytochrome P450 isoforms. CYP2D6 was the main one involved in the fast metabolism of ANT. The biotransformation of ANT by CYP2C19 was much slower. The main Phase I metabolite was M1 formed by the removal of phenyl and metabolite M2 with hydroxyl in the position of phenyl. Glucuronidation was the leading Phase II metabolism. Further study on pharmacokinetics of the metabolites would allow us to better understand the activity profile of ANT and to predict its potential clinical applications. Ultimately, further investigation of the activity profile of the new hydroxylated M2 metabolite of ANT might result in an active substance with a different pharmacological profile than the parent molecule, and potentially a new drug candidate.
Topics: Antazoline; Chromatography, Liquid; Healthy Volunteers; Hepatocytes; Humans; In Vitro Techniques; Tandem Mass Spectrometry
PubMed: 33353167
DOI: 10.3390/ijms21249693 -
Chemical & Pharmaceutical Bulletin Jan 2006A zero-crossing first-derivative spectrophotometric method is applied for the simultaneous determination of naphazoline hydrochloride and antazoline phosphate in eye...
A zero-crossing first-derivative spectrophotometric method is applied for the simultaneous determination of naphazoline hydrochloride and antazoline phosphate in eye drops. The measurements were carried out at wavelengths of 225 and 252 nm for naphazoline hydrochloride and antazoline phosphate, respectively. The method was found to be linear (r2>0.999) in the range of 0.2-1 microg/ml for naphazoline hydrochloride in the presence of 5 microg/ml antazoline phosphate at 225 nm. The same linear correlation (r2>0.999) was obtained in the range of 1-10 microg/ml of antazoline phosphate in the presence of 0.5 microg/ml of naphazoline hydrochloride at 252 nm. The limit of determination was 0.2 microg/ml and 1 microg/ml for naphazoline hydrochloride and antazoline phosphate, respectively. The method was successfully used for simultaneous analysis of naphazoline hydrochloride and antazoline phosphate in eye drops without any interference from excipients and prior separation before analysis.
Topics: Adrenergic alpha-Agonists; Antazoline; Anti-Allergic Agents; Calibration; Indicators and Reagents; Naphazoline; Ophthalmic Solutions; Reference Standards; Reproducibility of Results; Spectrophotometry, Ultraviolet
PubMed: 16394564
DOI: 10.1248/cpb.54.119 -
Journal of Pharmaceutical and... May 2016Antazoline is a first-generation antihistaminic agent with antiarrhythmic quinidine-like properties. In some countries, it is widely used for termination of cardiac...
Application of a novel liquid chromatography/tandem mass spectrometry method for the determination of antazoline in human plasma: Result of ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study.
Antazoline is a first-generation antihistaminic agent with antiarrhythmic quinidine-like properties. In some countries, it is widely used for termination of cardiac arrhythmias, especially atrial fibrillation (AF). However, no human pharmacokinetic studies have been conducted with intravenous antazoline. The aim of our study was to develop and validate a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the determination of antazoline in human plasma: the ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study. Antazoline was extracted from plasma using liquid-liquid extraction. The concentration of the analyte was measured by LC-MS/MS with xylometazoline as an internal standard. The method was validated for linearity, precision, accuracy, stability (freeze/thaw stability, stability in autosampler, short and long term stability), dilution integrity and matrix effect. The analyzed validation criteria were fulfilled. The method was applied to a pharmacokinetic study involving 10 healthy volunteers. Following a single intravenous dose of antazoline mesylate (100 mg), the plasma concentration profile showed a relative fast elimination with a terminal elimination half-life of 2.29 h. A relatively high volume of distribution was observed (Vss=315 L). The values of mean residence time (MRT∞), area under the curve (AUC∞) and clearance were 3.45 h, 0.91 mg h L(-1) and 80.5 L h(-1), respectively. One volunteer showed significant differences in pharmacokinetic parameters. In conclusion, the proposed new LC-MS/MS method was successfully used for the first time for the determination of antazoline in human plasma.
Topics: Adult; Antazoline; Chromatography, Liquid; Drug Stability; Female; Half-Life; Hemodynamics; Humans; Liquid-Liquid Extraction; Male; Mesylates; Plasma; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 26895496
DOI: 10.1016/j.jpba.2016.01.060 -
Journal of Pharmaceutical and... Oct 2023This work implements a stability indicating HPLC method developed to simultaneously determine xylometazoline (XYLO) and antazoline (ANT) in their binary mixture, rabbit...
Exquisite integration of quality-by-design and green analytical approaches for simultaneous determination of xylometazoline and antazoline in eye drops and rabbit aqueous humor, application to stability study.
This work implements a stability indicating HPLC method developed to simultaneously determine xylometazoline (XYLO) and antazoline (ANT) in their binary mixture, rabbit aqueous humor and cited drug's degradates by applying analytical quality-by-design (AQbD) combined with green analytical chemistry (GAC) experiment for the first time. This integration was designed to maximize efficiency and minimize environmental impacts, as well as energy and solvent consumption. Analytical quality-by-design was applied to achieve our aim starting with evaluation of quality risk and scouting analysis, tracked via five parameters chromatographic screening using Placket-Burman design namely: pH, temperature, organic solvent percentage, flow rate, and wavelength detection. Recognizing the critical method parameters was done followed by optimization employing central composite design and Derringer's desirability toward assess optimum conditions that attained best resolution with satisfactory peak symmetry with short run time. Optimal chromatographic separation was attained by means of an XBridge® C18 (4.6 × 250 mm, 5 µm) column through isocratic elution using a mobile phase consists of phosphate buffer (pH 3.0): ethanol (60:40, by volume) at a 1.6 mL/min flow rate and 230.0 nm UV detection. Linearity acquired over a concentration range of 1.0-100.0 µg/mL and 0.5-100.0 µg/mL for XYLO and ANT, respectively. Furthermore, imperiling cited drugs' stock solutions to stress various conditions and satisfactory peaks of degradation products were obtained indicating that cited drugs are vulnerable to oxidative degradation and basic hydrolysis. Degradates' structures were elucidated using mass spectrometry. Applying various assessment tools; namely: analytical greenness (AGREE), green analytical procedure index (GAPI), analytical eco-scale, and national environmental method index (NEMI), Greenness method's evaluation was applied and proved to be green. In fact, the developed method is established to be perceptive, accurate, and selective to assess cited drugs for routine analysis.
Topics: Animals; Rabbits; Antazoline; Ophthalmic Solutions; Aqueous Humor; Limit of Detection; Solvents; Chromatography, High Pressure Liquid
PubMed: 37516064
DOI: 10.1016/j.jpba.2023.115598 -
Trials Sep 2012Rapid conversion of atrial fibrillation (AF) to sinus rhythm may be achieved by the administration of class IA, IC and III antiarrhythmic drugs or vernakalant... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical efficacy of antazoline in rapid cardioversion of paroxysmal atrial fibrillation--a protocol of a single center, randomized, double-blind, placebo-controlled study (the AnPAF Study).
BACKGROUND
Rapid conversion of atrial fibrillation (AF) to sinus rhythm may be achieved by the administration of class IA, IC and III antiarrhythmic drugs or vernakalant hydrochloride. However, that treatment may be related to potential pro-arrhythmia, lack of efficacy or the exceptionally high cost of a compound used. Antazoline is a first generation antihistaminic agent with chinidin-like properties. When administered intravenously, antazoline exerts a strong antiarrhythmic effect on supraventricular arrhythmia, especially on AF, facilitating rapid conversion to sinus rhythm. Despite a relative lack of published data antazoline has been marketed in Poland and widely used in cardiology wards and emergency rooms for many years due to its efficacy, safety and rapid onset of action within minutes of administration.
METHODS/DESIGN
A randomized, double blind, placebo-controlled, superiority clinical trial was designed to assess clinical efficacy of antazoline in rapid conversion of AF to sinus rhythm. Eligible patients will present AF lasting less than 43 hours, will be in stable cardio-pulmonary condition and will have no prior history of advanced heart failure or significant valvular disease. Long-term antiarrhythmic therapy is not considered an exclusion criterion. Subjects who fulfill selection criteria will be randomly assigned to receive intravenously either antazoline or placebo in divided doses and observed for 1.5 hours after conversion to sinus rhythm or after the last i.v. bolus. Primary end point will be the conversion of AF to sinus rhythm confirmed in an electrocardiogram (ECG) during the observation period. Secondary end points will be comprised of time to conversion and return of AF during the observation period. Special consideration will be given to the observation of any adverse events. A sample size of 80 patients was calculated based on the following assumptions: two-tailed test, a type I error of 0.01, a power of 90%, efficacy of placebo 5%, efficacy of antazoline 50% and 20% drop-out rate to fulfill the criteria of intention-to-treat analysis. Due to the presumed lack of statistical power, the secondary end points and safety endpoints will be considered exploratory.
CLINICAL TRIALS REGISTRY
ClinicalTrials.gov, NCT01527279.
Topics: Adult; Aged; Antazoline; Anti-Arrhythmia Agents; Atrial Fibrillation; Double-Blind Method; Electrocardiography; Female; Humans; Injections, Intravenous; Male; Middle Aged; Poland; Time Factors; Treatment Outcome
PubMed: 22967497
DOI: 10.1186/1745-6215-13-162 -
Biomedical Chromatography : BMC Dec 2013A reversed-phase ion pair chromatography method with liquid-liquid extraction analytical method was developed and validated for the determination of antazoline...
A reversed-phase ion pair chromatography method with liquid-liquid extraction analytical method was developed and validated for the determination of antazoline hydrochloride in plasma and excreta of rat. The aim of our study was to characterize the preclinical pharmacokinetics and excretion profiles of antazoline hydrochloride in rats after intravenous injection at the dose of 10 mg/kg. Plasma and excreta samples were extracted with ethyl acetate, and phenacetin was used as the internal standard. The result showed that the method is suitable for the quantification of antazoline hydrochloride in plasma and excreta samples. Analysis of accuracy (90.89-112.33%), imprecision (<7.1%) and recovery (>82.5%) showed adequate values. After a single intravenous administration at 10 mg/kg to rats, plasma concentration profile showed a relative fast elimination proceeding with a terminal elimination half-life of 3.53 h. Approximately 61.8 and 14.2% of the administered dose were recovered in urine and bile after 72 and 24 h post-dosing respectively; 5.9% of the administered dose was recovered in feces after 72 h post-dosing. The above results show that the major elimination route is urinary excretion.
Topics: Animals; Antazoline; Bile; Chromatography, Reverse-Phase; Feces; Female; Linear Models; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity
PubMed: 23847054
DOI: 10.1002/bmc.2965 -
Combinatorial Chemistry & High... 2020Allergic rhinitis, acute nasal congestion and sinusitis are one of the most common health problems and have a major effect on the quality of life. Several medications...
The Development of Spectrophotometric and Validated Stability- Indicating RP-HPLC Methods for Simultaneous Determination of Ephedrine HCL, Naphazoline HCL, Antazoline HCL, and Chlorobutanol in Pharmaceutical Pomade Form.
BACKGROUND
Allergic rhinitis, acute nasal congestion and sinusitis are one of the most common health problems and have a major effect on the quality of life. Several medications are used to improve the symptoms of such diseases in humans. Pharmaceutical pomade form containing Ephedrine (EPD) HCl, Naphazoline (NPZ) HCl, Antazoline (ANT) HCl, and Chlorobutanol (CLO) is one of them.
OBJECTIVE
For these reasons, this study includes the development of spectrophotometric and chromatographic methods for the determination of EPD HCl, NPZ HCl, ANT HCl, and CLO active agents in the pharmaceutical pomade.
METHOD
In the spectrophotometric method, third-order derivative of the amplitudes at 218 nm n=5 and the first-order derivative of the amplitudes 254 nm n=13 was selected for the determination of EPD, ANT, respectively while NPZ was determined by the second derivative at 234 nm and n=21. Colorimetric detection was applied for assay analysis of CLO at 540 nm. Furthermore, a reverse phase high performance liquid chromatographic (RP- HPLC) method has been developed and optimized by using Agilent Zorbax Eclipse XDB C18 (75 mm x 3.0 mm, 3.5μm) column. The column temperature was 40°C, binary gradient elution was used and the mobile phase consisted of 15 mM phosphate buffer in distilled water (pH 3.0) and methanol, and the flow rate was 0.6 mL min and the UV detector was detected at 210 nm. The linear operating range was obtained as 11.97-70, 0.59-3, 2.79-30, and 2.92-200 μg mL for EPD HCl, NPZ HCl, ANT HCl, and CLO respectively.
RESULTS
The LOD values were found to be 3.95, 0.19, 0.92 and 0.96 μg mL for EPD HCl, NPZ HCl, ANT HCl, and CLO in the spectrophotometric method, respectively. The linear ranges in the RP-HPLC method were 8.2-24.36 μg mL, 0.083 - 0.75 μg/mL, 2.01-7.5 μg mL and 2.89-24.4 μg mL for EPD HCl, NPZ HCl, ANT HCl, and CLO, respectively. The LOD values in the validation studies were 2.7, 0.025, 0.66 and 0.86 μg mL for EPD HCl, NPZ HCl, ANT HCl, and CLO in RP-HPLC method respectively.
CONCLUSION
The results of the spectrophotometric and chromatographic methods were compared and no differences were found between the two methods.
Topics: Antazoline; Chlorobutanol; Chromatography, High Pressure Liquid; Ephedrine; Equipment Design; Molecular Structure; Naphazoline
PubMed: 32691707
DOI: 10.2174/1386207323666200720101835 -
Journal of Pharmaceutical and... May 2016Capillary electrophoretic (CE) and high performance liquid chromatographic (HPLC) methods were developed and optimized for the determination of antazoline (ANT) and...
Capillary electrophoretic (CE) and high performance liquid chromatographic (HPLC) methods were developed and optimized for the determination of antazoline (ANT) and tetrahydrozoline (TET) in ophthalmic formulations. Optimum electrophoretic conditions were achieved using a background electrolyte of 20mM phosphate buffer at pH 7.0, a capillary temperature of 25°C, a separation voltage of 22 kV and a pressure injection of the sample at 50 mbar for 17s. HPLC analysis was performed with Kinetex (150 × 4.6mm ID × 5 μm) (Phenomenex, USA) analytical column with 1 mL min(-1) flow rate of mobile phase which consisted of 0.05% TFA in bidistilled water (pH adjusted to 3.0 with 5M NaOH) and acetonitrile/buffer in the ratio of 63:37 (v/v) at room temperature. Injection volume of the samples was 10 μL and the wavelength of the detector was set at 215 nm for monitoring both analytes. Calibration graphs showed a good linearity with a coefficient of determination (R(2)) of at least 0.998 for both methods. Intraday and interday precision (expressed as RSD%) were lower than 2.8% for CE and 0.92% for HPLC. The developed methods were demonstrated to be simple and rapid for the determination of ANT and TET in ophthalmic solutions providing recoveries in the range between 97.9 and 102.70% for CE and HPLC.
Topics: Antazoline; Chromatography, High Pressure Liquid; Electrophoresis, Capillary; Imidazoles; Ophthalmic Solutions
PubMed: 26952922
DOI: 10.1016/j.jpba.2016.02.032 -
British Medical Journal Jul 1965
Topics: Agranulocytosis; Antazoline; Anti-Allergic Agents; Drug Therapy; Histamine H1 Antagonists; Humans; Lead Poisoning; Penicillamine
PubMed: 14304069
DOI: 10.1136/bmj.2.5454.171 -
Neuroprotective activity of antazoline against neuronal damage induced by limbic status epilepticus.Neuroscience 2003Imidazoline drugs exert neuroprotective effects in cerebral ischaemia models. They also have effects against mouse cerebellar and striatal neuronal death induced by... (Comparative Study)
Comparative Study
Imidazoline drugs exert neuroprotective effects in cerebral ischaemia models. They also have effects against mouse cerebellar and striatal neuronal death induced by N-methyl-D-aspartate (NMDA) through the blockade of NMDA currents. Here, we investigated the effects of antazoline on NMDA toxicity and current in rat hippocampal neuronal cultures, and on an in vivo model of status epilepticus. In hippocampal cultures, antazoline (30 microM) decreased NMDA-mediated neurotoxicity and also blocked the NMDA current with voltage-dependent and fast-reversible action (inhibition by 85+/-3% at -60 mV). Status epilepticus was induced by injecting pilocarpine (200 nmol) directly into the right pyriform cortex of male adult rats. The rats then received immediately three consecutive i.p. injections at 30-min intervals of either PBS (control group) or antazoline at 10 mg/kg (low-dose group) or at 45 mg/kg (high-dose group). During the 6-h recording, status epilepticus lasted more than 200 min in all groups. In the high-dose group only, seizures completely ceased 1 h after the third injection of antazoline, then started again 1 h later. Rats were killed 1 week later, and Cresyl Violet-stained sections of their brain were analysed for damage quantification. On the ipsilateral side to the pilocarpine injection, pyriform cortex and hippocampal CA1 and CA3 areas were significantly protected in both antazoline-treated groups, whilst prepyriform and entorhinal cortices were only in the high-dose group. On the contralateral side to the pilocarpine injection, only the hippocampal CA3 area was significantly protected in the low-dose group, but all investigated structures were in the high-dose group. In conclusion, antazoline is a potent neuroprotective drug in different models of neuronal primary culture, as previously shown in striatal and cerebellar granule neurons [Neuropharmacology 39 (2000) 2244], and here in hippocampal neurons. Antazoline is also neuroprotective in vivo in the intra-pyriform pilocarpine-induced status epilepticus model.
Topics: Animals; Animals, Newborn; Antazoline; Cell Count; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Conductivity; Electroencephalography; Excitatory Amino Acid Agonists; Female; Hippocampus; Histamine H1 Antagonists; In Vitro Techniques; Male; Muscarinic Agonists; N-Methylaspartate; Neurons; Patch-Clamp Techniques; Pilocarpine; Pregnancy; Rats; Rats, Sprague-Dawley; Status Epilepticus; Time Factors; Trauma, Nervous System
PubMed: 12890517
DOI: 10.1016/s0306-4522(03)00268-9