Isolation, structure elucidation, and high-performance liquid chromatography quantification of photolytic degradation impurities in acrivastine.

Acrivastine is a second-generation H1-receptor antagonist, and its structure is sensitive to ultraviolet. Four unknown and one reported degradation products can be detected in the ultraviolet radiation solutions of acrivastine. To improve the quality control of acrivastine, the photodegradation impurities were isolated and structurally elucidated. There are four new impurities (1-3 and 5), and one reported compound (4). The isolation strategy was designed as preparative high-performance liquid chromatography using a reversed phase column with volatile acid addition in the mobile phase, combined with preparative thin-layer chromatography using silica gel with alkaline addition in the mobile phase. Using the developed methods, five impurities (1-5) were efficiently purified after two or three chromatography runs with purities > 95%. The structures of compounds 1-5 are elucidated based on spectroscopy analysis of MS, and nuclear magnetic resonance spectroscopy. Using the impurity standard, the high-performance liquid chromatography method was developed and validated. The method was proved to be sensitive, accurate (Recovery% 96.1-107.7%), linear (0.15-0.75 µg/mL, R2 > 0.996), robust, and specific, and it was successfully used to determine the degradation impurities of acrivastine and its formulation.

Development and validation of a rapid stability indicating HPLC-method using monolithic stationary phase and two spectrophotometric methods for determination of antihistaminic acrivastine in capsules.

Simple, rapid and accurate high performance liquid chromatographic (HPLC) and spectrophotometric methods are described for determination of antihistaminic acrivastine in capsules. The first method (method A) is based on accurate, sensitive and stability indicating chromatographic separation method. Chromolith® Performance RP-18e column, a relatively new packing material consisting of monolithic rods of highly porous silica, was used as stationary phase applying isocratic binary mobile phase of ACN and 25 mM NaH2PO4 pH 4.0 in the ratio of 22.5:77.5 at flow rate of 5.0 mL/min and 40°C. A diode array detector was used at 254 nm for detection. The elution time of acrivastine was found to be 2.080±0.032. The second and third methods (methods B and C) are based on the oxidation of acrivastine with excess N-bromosuccinimide (NBS) and determination of the unconsumed NBS with, metol-sulphanilic acid (λmax: 520 nm) or amaranth dye (λmax: 530 nm). The reacted oxidant corresponds to the drug content. Beer's law is obeyed over the concentration range 1.563-50, 2.0-20 and 1.0-10 µg mL(-1) for methods A, B and C, respectively. The limits of detection and quantitation were 0.40, 0.292 and 0.113 µg mL(-1) and 0.782, 0.973 and 0.376 µg mL(-1) for methods A, B and C, respectively. The HPLC method was validated for system suitability, linearity, precision, limits of detection and quantitation, specificity, stability and robustness. Stability tests were done through exposure of the analyte solution for four different stress conditions and the results indicate no interference of degradants with HPLC-method. The proposed methods was favorably applied for determination of acrivastine in capsules formulation. Statistical comparison of the obtained results from the analysis of the studied drug to those of the reported method using t- and F-tests showed no significant difference between them.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of acrivastine and pseudoephedrine in human plasma and its application in pharmacokinetics.

A specific, sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of acrivastine and pseudoephedrine in human plasma samples. Plasma samples were processed and analyzed on a Phenomenex Luna 3 µ CN 100A column (150 mm×2.0 mm) eluted with the mobile phase consisting of methanol and 0.01 mol/L ammonium acetate water solution containing 0.1% formic acid (45:55, v/v) at a flow rate of 0.2 mL/min. The analytes were detected by positive ion electrospray ionization in multiple reaction monitoring mode. The transitions of m/z 349→278, m/z 166→148 and m/z 256→167 were monitored for acrivastine, pseudoephedrine and diphenhydramine (IS), respectively. The method was specific and sensitive with a lower limit of quantitation (LLOQ) of 1.52 ng/mL for acrivastine and 8.13 ng/mL for pseudoephedrine. The method showed good linearity in the range of 1.52~606.0 0 ng/mL for acrivastine and 8.13~813.12 ng/mL for pseudoephedrine (r≥0.996). The mean recovery were ranged 91.82% ~ 98.46% for acrivastine and 90.77% ~ 92.05% for pseudoephedrine. Validation results, such as accuracy, precision and repeatability were within the required limits. The method was successfully applied in a pharmacokinetic study of the acrivastine and pseudoephedrine hydrochloride compound capsule in humans.

Synthesis of aryl(di)azinyl ketones through copper- and iron-catalyzed oxidation of the methylene group of aryl(di)azinylmethanes.

Sustainable Oxidations: an oxidation method to transform aryl(di)azinylmethanes into aryl(di)azinyl ketones is described. Base metals (copper and iron) as catalysts in combination with O(2) as the oxidant are used, which makes this method sustainable. The utility of this method is illustrated by the synthesis of 6-(4-methylbenzoyl)pyridine-2-carbaldehyde, which is an intermediate in the preparation of the drug Acrivastine.

Chromatographic separation and spectroscopic characterization of the E/Z isomers of acrivastine.

A reverse phase high performance liquid chromatography (HPLC) method has been developed for the separation of two geometric isomers of Acrivastine using crude reaction mixture. The resolution between two isomers was found more than 2.9. The geometric isomers have been isolated by preparative HPLC and characterized by spectroscopic techniques, such as NMR, infrared, and MS. The developed method has been validated for the determination of Z-isomer in Acrivastine. The limit of detection and limit of quantification of the Z-isomer were 0.05 and 0.2 µg/ml, respectively. The developed method is precise, linear, accurate, rugged and robust for its intended use.

Quantification of antihistamine acrivastine in plasma by solid-phase extraction and high-performance liquid chromatography.

An automated solid-phase extraction method was developed for the determination of the H1-antihistamine acrivastine in plasma samples. Acrivastine was analyzed at the wavelength of 254 nm using a reversed-phase HPLC assay. Both extraction procedure and analytical condition were optimized and validated for maximum recovery and resolution. The developed method was further applied to plasma samples collected from an in vivo pharmacokinetic study in rabbits. The assay was found to be simple, specific, accurate and reproducible.

The butterbur extract petasin has no effect on skin test reactivity induced by different stimuli: a randomized, double-blind crossover study using histamine, codeine, methacholine, and aeroallergen solutions.

BACKGROUND: Petasin (Ze 339) was recently introduced on the market as a potent herbal antiallergic drug for treatment of respiratory allergies such as hay fever. Few clinical studies have been performed so far addressing the clinical effectiveness of Ze 339. OBJECTIVE: To evaluate the antiallergic properties of Ze 339 using skin prick tests with different stimuli, such as codeine, histamine, methacholine, and a relevant inhalant allergen. METHODS: A randomized, double-blind, placebo-controlled study was performed in which Ze 339 was compared to acrivastine, a short-acting antihistamine, in 8 patients with respiratory allergy and in 10 nonatopic, healthy volunteers. Antiallergic activity of Ze 339 was determined by analyzing inhibitory potency in skin prick tests with codeine, histamine, methacholine, and an inhalant allergen. Wheal-and-flare reactions were assessed 90 minutes after a double dose of Ze 339, acrivastine, or placebo. An interval of at least 3 days was left between the skin tests. RESULTS: Acrivastine was identified as the only substance that significantly inhibited skin test reactivity to all solutions analyzed in all study subjects. In contrast, no significant inhibition could be demonstrated for Ze 339 with any test solution. Moreover, the results of Ze 339 did not differ significantly from placebo. CONCLUSIONS: In this study we found no antiallergic, particularly antihistaminic, effect of Ze 339 in skin tests using a variety of stimuli often used to evaluate immediate skin test reactivity. The mechanism by which Ze 339 is effective in the treatment of seasonal allergic rhinitis still needs to be elucidated.

Spectrophotometric determination of some antihistaminic drugs using 7,7,8,8-tetracyanoquinodimethane (TCNQ).

A simple and sensitive spectrophotometric method is suggested for analysis of 3 antihistaminic drugs, acrivastine (I), mequitazine (II), and dimethindene maleate (III). The method is based on reaction of the drugs with 7,7,8,8-tetracyanoquinodimethane (TCNQ) in acetonitrile to form highly stable colored products that are measured at 750, 766, and 844 nm for I and II, and 480 and 618 nm for III. Beer's law is obeyed in the ranges of 5-60 microg/mL for 1, 5-50 microg/mL for II, and 10-70 microg/mL for III. The optimum assay conditions and their applicability to the determination of the cited drugs in pharmaceutical formulations are described. The method is statistically analyzed as compared with the European Pharmacopoeia (2001) method for the analysis of dimethindene maleate and reference methods for acrivastine and mequitazine drugs revealing good accuracy and precision.

Simultaneous analysis of the H1-antihistamine acrivastine and the decongestant pseudoephedrine hydrochloride by high-performance liquid chromatography.

High-performance liquid chromatography (HPLC) was used for the simultaneous quantification of the H(1)-antihistamine acrivastine and the decongestant pseudoephedrine hydrochloride. Both compounds were detected at the wavelength of 214 nm. The influence of the mobile phase and the detection wavelength was evaluated and optimized. This method was used to assay various samples from studies of the commercial preparation Semprex-D capsules. The method was found to be accurate, specific, selective, rapid, and versatile for use in routine quality control analyses.

Evaluation and comparison of five matrix excipients for the controlled release of acrivastine and pseudoephedrine.

For treatment of allergic rhinitis, acrivastine with pseudoephedrine in Semprex-D conventional capsules requires dosing every 6-8 hours. This study was designed to develop a controlled release matrix tablet of acrivastine and pseudoephedrine and evaluate 5 different matrix excipients for their in vitro controlled-release profiles. Compritol 888ATO, Eudragit RS, Methocel K100M, Polyox WSR301 and Precirol ATO5 were used alone or in varying combinations for the formulation of controlled release matrix tablets. In vitro drug dissolution and mathematical modeling were used to characterize drug release rate and extent. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. Due to the aqueous solubility of pseudoephedrine and the size of the dose, none of the matrix excipients used alone prolonged drug release significantly to meet the desired twice-daily administration frequency. The use of two excipients in combination, however, significantly decreased the dissolution rate of both active ingredients. A combined lipid-based Compritol and hydrophilic Methocel produced optimal controlled drug release for longer than 8 hours for both acrivastine and pseudoephedrine.

Homology modelling and binding site mapping of the human histamine H1 receptor.

Three-dimensional model of the human histamine H1 receptor was developed by homology modelling using the high resolution structure of bovine rhodopsin as template. Genetic algorithm based docking calculations were used to identify the role of several amino acids having an effect on agonist or antagonist binding. Binding mode analyses of mepyramine, desloratidine, loratidine and acrivastine allowed us to rationalise their binding affinity. Binding site mapping resulted in seven new potential aromatic interaction points (Tyr 108, Phe 184, Phe 190, Phe 199, Phe 424, Trp 428, Tyr 431), that took part in forming the lipophilic pocket of the antagonist binding cavity.

Electrochemical behaviour and determination of acrivastine in pharmaceuticals and human urine.

The differential pulse polarography, DC-tast polarography and cyclic voltammetry behaviour of acrivastine was studied in Britton-Robinson buffer solutions (pH 2-11.7). In acidic media, a non-reversible diffusion controlled reduction process involving four electrons takes place. Two reduction waves appear at a E(1/2)=-0.6 and -0.99 V. The reduction mechanism is discussed. The linear relationship between peak current height and acrivastine concentration allowed the differential pulse polarographic determination of acrivastine over a wide concentration range, from 0.35 to 26.1 mg l(-1)at pH 2.5. The procedure was applied to determination of the drug in pharmaceutical formulations and human urine samples.

Cardiotoxicity of new antihistamines and cisapride.

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Zafirlukast has no beneficial effects in the treatment of chronic urticaria.

BACKGROUND: Leukotriene receptor antagonists have shown some efficacy in t he treatment of asthma. Injection of LTC4, LTD4 and LTE4 into the skin leads to a weal-and-flare reaction, suggesting an involvement of leukotrienes in the pathogenesis of urticaria. Indeed, various reports have indicated a beneficial effect for leukotriene receptor antagonists in patients with chronic urticaria. OBJECTIVE: To determine the therapeutic effect of the leukotriene receptor antagonist zafirlukast in patients with chronic urticaria. METHODS: The study was a double-blind, placebo-controlled, cross-over study lasting for 12 weeks. Fifty-two patients with chronic urticaria were investigated at a university hospital. The patients were randomized to receive 20 mg zafirlukast b.i.d. or placebo and cross-over was scheduled after 6 weeks. The efficacy of the treatment was evaluated by a daily symptom score, six physical examinations, the requirement of rescue antihistamines (acrivastine) and an overall assessment by the patient andthe investigating physician. RESULTS: Forty-six patients completed the study: zafirlukast was well tolerated without alteration of the investigated laboratory parameters. In comparison with placebo, treatment with zafirlukast resulted in no significant positive effect for any of the efficacy measures. Moreover, we were unable to identify any subgroup of patients with chronic urticaria responding with a therapeutic benefit. CONCLUSIONS: The leukotriene receptor antagonist zafirlukast does not provide a significant therapeutic benefit at a dose of 20 mg b.i.d. in patients with chronic urticaria.

Lipophilicity behaviour of the Zwitterionic antihistamine cetirizine in phosphatidylcholine liposomes/water systems.

PURPOSE: The partitioning of cetirizine in a phosphatidylcholine liposomes/water system was compared with that of hydroxyzine and acrivastine to gain insight into the mechanisms of interaction of its various electrical species with membranes. METHODS: The lipophilicity profiles of the compounds were obtained from equilibrium dialysis and potentiometry, and compared with changes in NMR relaxation rates. RESULTS: The neutral form of hydroxyzine interacted mainly via hydrophobic interactions with the bilayer lipid core of the membrane, whereas for the cationic form both hydrophobic and electrostatic interactions were involved. Zwitterionic and anionic cetirizine were less lipophilic than its cation, which behaved like the corresponding species of hydroxyzine. Zwitterionic cetirizine interacted more by weak electrostatic interactions with the polar headgroups of phospholipids than by hydrophobic interactions with the membrane interior. The lipophilicity of its anion reflected the balance of repulsive electrostatic interactions between the carboxylate and phosphate groups and the hydrophobic interactions with the lipid core. CONCLUSION: The study confirms that various mechanisms influence the interaction of solutes with liposomes. Combining experimental techniques and using suitable reference compounds proves useful.

Onset-of-action for antihistamine and decongestant combinations during an outdoor challenge.

BACKGROUND: Medications containing a combination antihistamine-decongestant are commonly used for allergic rhinitis yet onset-of-action comparisons for symptom relief after a single dose have not been performed. OBJECTIVE: To determine the onset of symptom relief and efficacy of antihistamine-decongestant medications (acrivastine-pseudoephedrine and loratadine-pseudoephedrine) compared with placebo in an outdoor park. METHODS: This study was conducted during the spring of 1997 using a double-blind, placebo-controlled design. Patients completed baseline rhinitis symptom diaries from 7:30 to 9:30 AM. Subjects with qualifying symptom scores received one dose of either acrivastine-pseudoephedrine, loratadine-pseudoephedrine, or placebo at 10:00 AM. Symptom diaries were recorded for the next 4 hours. RESULTS: Of 593 patients randomized to treatment, 592 were included in efficacy analysis. Acrivastine-pseudoephedrine and loratadine-pseudoephedrine demonstrated a mean onset-of-action by 45 and 30 minutes respectively for total symptom and rhinitis symptom scores for the five sites. Onset-of-action for nasal congestion scores was 45 minutes for both medications. Sites having higher pollen exposure (>100 pollen grains over 6 hours) demonstrated a difference between the antihistamine combinations: acrivastine-pseudoephedrine had an onset of action at 45 minutes for total symptom and rhinitis symptom scores, and 15 minutes for nasal congestion scores whereas loratadine-pseudoephedrine had onset-of-action for nasal congestion score of 105 minutes but failed to reach significance at any timepoint for total symptom and rhinitis symptom scores. CONCLUSIONS: Both antihistamine-decongestant combinations demonstrate an onset-of-action within 60 minutes of administration but under conditions of higher pollen exposure, the acrivastine combination was more effective for total symptoms, rhinitis symptoms, and nasal congestion with an onset-of-action within 45 minutes for rhinitis symptoms and 15 minutes for congestion.

Sedation with "non-sedating" antihistamines: four prescription-event monitoring studies in general practice.

OBJECTIVES: To investigate the frequency with which sedation was reported in post-marketing surveillance studies of four second generation antihistamines: loratadine, cetirizine, fexofenadine, and acrivastine. DESIGN: Prescription-event monitoring studies. SETTING: Prescriptions were obtained for each cohort in the immediate post-marketing period. SUBJECTS: Event data were obtained for a total of 43 363 patients. MAIN OUTCOME MEASURES: Reporting of sedation or drowsiness. RESULTS: The odds ratios (adjusted for age and sex) for the incidence of sedation were 0.63 (95% confidence interval 0.36 to 1.11; P=0.1) for fexofenadine; 2.79 (1.69 to 4.58; P<0.0001) for acrivastine, and 3.53 (2.07 to 5.42; P<0.0001) for cetirizine compared with loratadine. No increased risk of accident or injury was evident with any of the four drugs. CONCLUSIONS: Although the risk of sedation was low with all four drugs, fexofenadine and loratadine may be more appropriate for people working in safety critical jobs.

Effects of acrivastine, loratadine and cetirizine on histamine-induced wheal and flare responses.

It is accepted that studies evaluating histamine-induced wheal and flare reactions in the skin represent a simple and reliable method for demonstrating pharmacodynamic activity and pharmacokinetics of the H1-receptor antagonists. In this study, the effects of single oral doses of acrivastine (8 mg), loratadine (10 mg) and cetirizine (10 mg) on the histamine-induced wheal and flare reactions were compared in 60 healthy volunteers. The wheal and flare responses were produced by prick test using 1% histamine solution. Measurements were performed before the ingestion of antihistamines (baseline values) and afterwards at 15, 30, 90, 240, 360 min and 24 h. The values obtained for each antihistamine were compared with each other and with baseline values. Cetirizine was found to be superior to acrivastine and loratadine for the suppression of wheal and flare responses at 240, 360 min and 24 h (P < 0.05) and acrivastine was superior to the other two antihistamines for the suppression of flare response at 30 min (P < 0.05). Our results indicate that a single dose of cetirizine provides a more effective and long acting suppression on wheal and flare reactions in urticaria when compared to acrivastine and loratadine.

Mutational analysis of the antagonist-binding site of the histamine H(1) receptor.

We combined in a previously derived three-dimensional model of the histamine H(1) receptor (Ter Laak, A. M., Timmerman, H., Leurs, H., Nederkoorn, P. H. J., Smit, M. J., and Donne-Op den Kelder, G. M. (1995) J. Comp. Aid. Mol. Design. 9, 319-330) a pharmacophore for the H(1) antagonist binding site (Ter Laak, A. M., Venhorst, J., Timmerman, H., and Donné-Op de Kelder, G. M. (1994) J. Med. Chem. 38, 3351-3360) with the known interacting amino acid residue Asp(116) (in transmembrane domain III) of the H(1) receptor and verified the predicted receptor-ligand interactions by site-directed mutagenesis. This resulted in the identification of the aromatic amino acids Trp(167), Phe(433), and Phe(436) in transmembrane domains IV and VI of the H(1) receptor as probable interaction points for the trans-aromatic ring of the H(1) antagonists. Subsequently, a specific interaction of carboxylate moieties of two therapeutically important, zwitterionic H(1) antagonists with Lys(200) in transmembrane domain V was predicted. A Lys(200) --> Ala mutation results in a 50- (acrivastine) to 8-fold (d-cetirizine) loss of affinity of these zwitterionic antagonists. In contrast, the affinities of structural analogs of acrivastine and cetirizine lacking the carboxylate group, triprolidine and meclozine, respectively, are unaffected by the Lys(200) --> Ala mutation. These data strongly suggest that Lys(200), unique for the H(1) receptor, acts as a specific anchor point for these "second generation" H(1) antagonists.

Variations among non-sedating antihistamines: are there real differences?

Most of the modern non-sedating H1 receptor antagonists (antihistamines) penetrate the brain poorly, allowing the use of doses large enough to counteract allergic processes in peripheral tissues without important central effects. The antihistamines reviewed here are acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine. However, these drugs are not entirely free from central effects, and there are at least quantitative differences between them. Although psychomotor and sleep studies in healthy subjects in the laboratory may predict that an antihistamine does not cause drowsiness, the safety margin can be narrow enough to cause a central sedating effect during actual treatment. This might result from a patient's individual sensitivity, disease-induced sedation, or drug dosages that are for various reasons relatively or absolutely larger (patient's weight, poor response, reduced drug clearance, interactions). Mild to even moderate sedation is not necessarily a major nuisance, particularly if stimulants need be added to the regimen (e.g. in perennial rhinitis). Furthermore, patients can adjust doses themselves if needed. Sedating antihistamines are not needed for long-term itching, because glucocorticoids are indicated and more effective. It is wise to restrict or avoid using antihistamines (astemizole, terfenadine) that can cause cardiac dysrhythmias, because even severe cardiotoxicity can occur in certain pharmacokinetic drug-drug interactions. Histamine H1 receptor antagonists (antihistamines) are used in the treatment of allergic disorders. The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects causing dry mouth and blurred vision. Non-specific "quinidine-like" or local anaesthetic actions often led to cardiotoxicity in animals and man. Although such adverse effects varied from drug to drug, there was some degree of sedation with all old antihistamines. Non-sedating antihistamines have become available during the past 15 years. Some of them also have antiserotonin or other actions that oppose allergic inflammation, and they are not entirely free from sedative effects either. In small to moderate "clinical" concentrations they are competitive H1 receptor antagonists, although large concentrations of some of them exert non-competitive blockade. Daytime drowsiness and weakness are seldom really important, and they restrict patients' activities less than the old antihistamines. Some new antihistamines share with old antihistamines quinidine-like effects on the cardiac conducting tissues, and clinically significant interactions have raised the question of drug safety. This prodysrhythmic effect has also been briefly mentioned in comparisons of non-sedative H1 antihistamines.