triprolidine and acrivastine

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.

Topics: Arrhythmias, Cardiac; Astemizole; Benzimidazoles; Butyrophenones; Cetirizine; Cisapride; Heart Diseases; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Serotonin Receptor Agonists; Terfenadine; Triprolidine

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,

Topics: Astemizole; Benzimidazoles; Butyrophenones; Central Nervous System; Cetirizine; Drug Interactions; Heart; Histamine H1 Antagonists; Humans; Hypnotics and Sedatives; Loratadine; Piperidines; Potassium Channel Blockers; Terfenadine; Triprolidine

The new H1 antihistamines are a major therapeutic advancement in the treatment of allergic disorders such as urticaria and allergic rhinitis. Their efficacy combined with greatly reduced sedating and anticholinergic side effects makes the new class of H1 antihistamines the first-line treatment in the management of urticaria and mild angioedema. The choice of a particular low-sedating H1 antihistamine depends on pharmacokinetic considerations, the severity of the problem (systemic steroids and epinephrine are the first-line treatment for severe angioedema), and the requirement for limiting the frequency of administration. The efficacy of the new H1 antihistamines in the treatment of itch due to atopic eczema and systemic disease remains uncertain, and further controlled clinical trials are needed to elucidate their possible role in these conditions.

Topics: Astemizole; Cetirizine; Dermatitis, Atopic; Histamine H1 Antagonists; Humans; Loratadine; Terfenadine; Triprolidine; Urticaria

Acrivastine is a short acting histamine H1-receptor antagonist with a rapid onset of action. Double-blind clinical trials have shown acrivastine (usually 8mg three times daily) to be an effective and well tolerated antihistamine in the treatment of chronic urticaria and allergic rhinitis. Acrivastine was more effective than placebo and similar in efficacy to clemastine or terfenadine in the treatment of seasonal allergic rhinitis. In the treatment of dermatoses in which histamine has a pathogenetic role, the efficacy of acrivastine was superior to that of placebo and similar to that of usual dosages of clemastine, hydroxyzine, chlorpheniramine, cyproheptadine or terfenadine. Acrivastine caused less drowsiness than clemastine, the incidence of adverse effects being indistinguishable from that with placebo or terfenadine. Thus, acrivastine is an effective addition to drugs currently available for the treatment of patients with allergic diseases in whom a histamine H1-receptor antagonist is indicated. Because of its rapid onset of action acrivastine will be particularly useful for 'on demand' therapy in patients with intermittent symptoms.

Topics: Dermatitis, Atopic; Histamine H1 Antagonists; Humans; Rhinitis, Allergic, Seasonal; Triprolidine; Urticaria

Topics: Cetirizine; Cyproheptadine; Histamine H1 Antagonists; Humans; Hydroxyzine; Loratadine; Rhinitis, Allergic, Seasonal; Triprolidine; Urticaria

The general human and skin pharmacology of acrivastine, its clinical utility and some important concepts of the use of H1-antihistamines in dermatology are discussed. The drug has potent H1-antihistamic activity yet a low sedative profile as compared with first generation agents. Acrivastine is rapidly absorbed with peak inhibition of flare areas occurring at 90 min and peak activity against weals at 120 min after drug administration. No accumulation of the drug following multiple dosing has been demonstrated. Due to these effects the drug has a high level of patient acceptability and a high level of useful activity in a range of histamine-mediated dermatoses.

Topics: Histamine H1 Antagonists; Histamine Release; Humans; Pyridines; Triprolidine; Urticaria

Acrivastine is an antihistamine with reduced sedating potential. This comprehensive review of clinical experience with acrivastine in allergic rhinitis considers all currently available data both published and, as yet, unpublished. Unequivocal evidence of the efficacy of 8 mg acrivastine three times daily for the control of symptoms of seasonal allergic rhinitis has been provided by 11 placebo-controlled studies involving almost 1000 patients. Additional trials have generated further supportive data as well as evidence for the use of acrivastine in the treatment of perennial allergic rhinitis. In common with most antihistamines, acrivastine alone has limited effect on the symptom of blocked nose. In a further series of 11 studies, mainly conducted in the USA, the combination of 8 mg acrivastine plus 60 mg pseudoephedrine was found to control not only the histamine-mediated symptoms of allergic rhinitis but also blocked nose. There were few adverse events associated with the use of acrivastine and the small increase in incidence of drowsiness over that found with placebo was similar to that observed for terfenadine. The marked absence of other signs of significant depression of the central nervous system (or anticholinergic activity) suggests that acrivastine will be an important addition for the antihistaminic control of symptoms of allergic rhinitis.

Topics: Clinical Trials as Topic; Histamine H1 Antagonists; Humans; Pyridines; Rhinitis, Allergic, Seasonal; Triprolidine

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.

Topics: Bronchodilator Agents; Calibration; Chromatography, High Pressure Liquid; Cross-Over Studies; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Limit of Detection; Male; Pseudoephedrine; Quality Control; Reference Standards; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Triprolidine; Young Adult

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.. 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.. 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.. 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.. 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.

Topics: Administration, Inhalation; Adult; Allergens; Anti-Allergic Agents; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Histamine; Humans; Male; Methacholine Chloride; Middle Aged; Petasites; Phytotherapy; Plant Extracts; Respiratory Hypersensitivity; Sesquiterpenes; Skin; Skin Tests; Treatment Outcome; Triprolidine

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.. To determine the therapeutic effect of the leukotriene receptor antagonist zafirlukast in patients with chronic urticaria.. 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.. 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.. 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.

Topics: Adolescent; Adult; Aged; Chronic Disease; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Female; Histamine H1 Antagonists; Humans; Indoles; Leukotriene Antagonists; Male; Middle Aged; Phenylcarbamates; Sulfonamides; Tosyl Compounds; Treatment Outcome; Triprolidine; Urticaria

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.. 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.. 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.. 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.. 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.

Topics: Adult; Air Pollutants; Allergens; Anti-Allergic Agents; Double-Blind Method; Drug Combinations; Ephedrine; Female; Histamine H1 Antagonists; Humans; Loratadine; Male; Nasal Decongestants; Pollen; Rhinitis, Allergic, Seasonal; Time Factors; Triprolidine

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.

Topics: Adult; Cetirizine; Cross-Over Studies; Female; Histamine; Histamine H1 Antagonists; Humans; Loratadine; Male; Middle Aged; Single-Blind Method; Triprolidine; Urticaria

Semprex-D capsules contain acrivastine 8 mg (a second generation H1-antagonist) plus pseudoephedrine HCl 60 mg and were developed to satisfy the needs of allergy suffers who prefer combination products designed to provide broader symptom relief. Approval of combination products by the US Food and Drug Administration requires demonstration that each component contributes to the overall effectiveness.. The objective of the study was to demonstrate that both acrivastine and pseudoephedrine share in the efficacy of the combination in relieving allergy symptoms in patients sensitive to ragweed pollen.. This was a double-blind, randomized, placebo-controlled, parallel groups, balanced design, multicenter (13 sites) study. Patients 12 years of age or older with skin test reactivity to ragweed were recruited. Patients who qualified for the study were dispensed either (1) acrivastine + pseudoephedrine, (2) acrivastine, (3) pseudoephedrine, or (4) placebo with instructions to take one capsule 4 times daily and to record allergy symptom scores in a symptom diary 3 times daily for 14 days. Assessments of health, global allergy symptoms, protocol compliance, adverse events, and vital signs were also documented.. A total of 702 patients were enrolled in this study. Over the 2-week period, the combination of acrivastine + pseudophedrine was significantly more effective than acrivastine, pseudoephedrine, and placebo for relief of all symptoms (P range .01 to .001); pseudoephedrine for treating symptoms responsive to antihistamines (P = .003); and acrivastine for treating symptoms responsive to nasal decongestants (P < .001). Relatively small increases in adverse experience rates were observed for the combination relative to the placebo.. These findings in a large clinical trial demonstrate that each component of the combination of acrivastine 8 mg plus pseudoephedrine HCl 60 mg contributes to the overall efficacy, thereby supporting the conclusion that the combination is rational, safe, and effective for the treatment of allergic rhinitis.

Topics: Adolescent; Adult; Aged; Allergens; Child; Child, Preschool; Double-Blind Method; Drug Therapy, Combination; Ephedrine; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Plant Proteins; Pollen; Rhinitis, Allergic, Seasonal; Triprolidine

Acrivastine is a second-generation H1-antagonist chemically related to triprolidine, but more polar and with less central nervous system penetration than triprolidine.. The efficacy of the antihistamine-decongestant combination product (Semprex-D capsules) containing acrivastine 8 mg plus pseudoephedrine HCl 60 mg was evaluated for the treatment of seasonal allergic rhinitis symptoms.. A total of 676 patients sensitive to mountain cedar pollen was enrolled into a 6-center, randomized, double-blind, placebo-controlled, parallel, 4-group study designed to compare acrivastine + pseudoephedrine, acrivastine, pseudoephedrine, and placebo. Patients with demonstrable diary symptom scores at baseline took study medication (4 doses/day) and recorded symptom scores twice daily for 2 weeks. The effectiveness of the acrivastine + pseudoephedrine combination was examined relative to the individual components and placebo in terms of changes in diary symptom scores.. Over the 2-week period, the combination of acrivastine plus pseudoephedrine was significantly more effective than (1) acrivastine, pseudoephedrine, and placebo (P < .001) for relief of all symptoms; (2) pseudoephedrine (P < .001) for relieving allergy symptoms, ie, running nose, sneezing, itchy nose/throat and tearing; and (3) acrivastine (P < .001) for reducing nasal congestion. Relative to placebo, small increases in adverse experience rates were observed with acrivastine + pseudoephedrine for dry mouth, insomnia, somnolence, and headache.. These findings in a large clinical trial demonstrate (1) the efficacy of acrivastine and (2) that each component of the combination of acrivastine 8 mg plus pseudoephedrine HCl 60 mg contributes to the overall efficacy, thereby supporting the conclusion that the combination is rational, safe, and effective for the treatment of allergic rhinitis.

Topics: Adolescent; Adult; Aged; Double-Blind Method; Drug Therapy, Combination; Ephedrine; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Pollen; Rhinitis, Allergic, Seasonal; Trees; Triprolidine

The purpose of this study was to test the hypothesis that learning ability is impaired in patients with seasonal allergic rhinitis relative to untreated individuals and to evaluate a combination compound (acrivastine 8 mg + pseudoephedrine 60 mg) for attenuation of the learning impairment in these patients.. In a previous study employing the same method it was shown that young children (10 to 12 yrs) suffering from seasonal allergic rhinitis performed significantly worse on tests of learning and using knowledge after acute treatment with a sedating antihistamine (diphenhydramine 50 mg) or placebo as compared with nontreated healthy controls. This effect was partially reversed by treatment with loratadine.. Sixty-seven young adults suffering from seasonal allergic rhinitis and 28 matched controls were trained on didactic simulation for three consecutive days. Atopic subjects were treated differentially during training according to a double-blind, randomized, parallel group design with either diphenhydramine hydrochloride 50 mg, a combination compound (acrivastine 8 mg + pseudoephedrine 60 mg, A + P), or placebo, administered qd. After training, all atopic subjects were maintained on A + P treatment for 14 days at which time all groups returned for examination.. Mean performance at the end of training was worse for all atopic subjects combined compared with normal subjects. Subjects treated with diphenhydramine performed significantly worse than either normals (P < .001) or those treated with A + P (P < .001). At the examination, the diphenhydramine group's performance differed significantly from those of the normal (P < .001) and A + P groups (P < .001).. The study supports our previous finding that allergy symptoms reduce learning ability which is further reduced learning ability which is further reduced by diphenhydramine. Atopic subjects with allergies treated with acrivastine + pseudoephedrine learned as well as normal subjects.

Topics: Adolescent; Adult; Diphenhydramine; Double-Blind Method; Drug Combinations; Ephedrine; Female; Histamine H1 Antagonists; Humans; Learning; Learning Disabilities; Male; Memory; Rhinitis, Allergic, Seasonal; Triprolidine

The review summarizes the major results of eight double-blind, placebo-controlled, volunteer studies undertaken by three independent institutions for showing the effects on actual driving performance of "sedating" and "nonsedating" antihistamines (respectively, triprolidine, diphenhydramine, clemastine and terfenadine, loratadine, cetirizine, acrivastine, mizolastine, and ebastine). A common, standardized test was used that measures driving impairment from vehicular "weaving" (i.e., standard deviation of lateral position (SDLP)). Logical relationships were found between impairment and dose, time after dosing, and repeated doses over 4-5 days. The newer drugs were generally less impairing, but differences existed among their effects, and none was unimpairing at doses 1-2x the currently recommended levels. One or possibly two of the newer drugs possessed both performance-enhancing and -impairing properties, depending on dose, suggesting two mechanisms of action.

Topics: Automobile Driving; Benzimidazoles; Butyrophenones; Cetirizine; Clemastine; Diphenhydramine; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Humans; Loratadine; Netherlands; Piperidines; Psychomotor Performance; Terfenadine; Triprolidine

In a placebo-controlled, randomized, and double-blind 1-day field study, the efficacy and onset of action of capsule acrivastine 8 mg were evaluated in 42 patients suffering from allergic rhinoconjunctivitis elicited by natural grass pollen exposure. Before and for 2 h after treatment, the patients scored the severity of five rhinoconjunctivitis symptoms every 10 min on a 0-5 scale (0 = no symptoms; 5 = very severe symptoms). The number of sneezes was recorded, and every 30 min, measurements of nasal peak flow were made. Before treatment, there was no difference in median total symptom score (mTSS) between the acrivastine group (A) and the placebo group (P) (12 and 12, respectively). Time of onset was estimated by an exponential decay model to be 19 min (95% confidence interval 0-39 min). A statistically significant difference in percent reduction of mTSS between A and P was observed for the first time 46 min after treatment start (A = 22%, P = 0%, P < 0.05). A 50% reduction in total symptom score (TSS) was achieved within 60 min by 38% in A and 17% in P (NS), and within 80 min in 52% and 17%, respectively (P < 0.05). The median time for 50% reduction in TSS (MT50) was 80 min for A and > 120 min for P (P < 0.01). The symptom score of sneezing and number of sneezes were evaluated for periods of 30 min. The difference between A and P became statistically significant from 31-60 and 61-90 min, respectively (P < 0.05 and P < 0.01). Objective and subjective determinants in the different time intervals were well correlated. Improvement of nasal congestion was observed in A at 91-120 min, as measured by nasal peak flow.

Topics: Administration, Oral; Adult; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Pollen; Rhinitis, Allergic, Seasonal; Triprolidine

Renal cell carcinoma exhibits chemoresistance attributable in part to the P-glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic antihistamine that has been shown in vitro to reverse this form of resistance. After five patients were treated on a dose-finding study, seventeen patients with metastatic or unresectable renal cell carcinoma were entered into a phase II study of vinblastine in combination with acrivastine. Patients received oral acrivastine at doses of 400 mg every 4 hours for 6 days and a 96-hour continuous infusion of vinblastine at a dose of 1.6 mg/m2/24 h. Of 15 evaluable patients, no tumor responses were seen. The regimen was well-tolerated with the majority of toxicities being gastrointestinal and hematologic. Serum levels of acrivastine, its principal metabolite (270C81) and vinblastine were measured during the study. Based on in vitro data, the plasma levels of acrivastine were within a range adequate to block P-glycoprotein activity. High doses of acrivastine were well-tolerated clinically, however, the combination of acrivastine and vinblastine was not active against renal cell carcinoma.

Topics: Adult; Aged; Carcinoma, Renal Cell; Drug Resistance, Multiple; Female; Histamine H1 Antagonists; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Triprolidine; Vinblastine

The study was conducted according to a nine-way, observer- and subject-blind, cross-over design. Its purpose was to compare the single-dose effects of the following drugs on driving performance: acrivastine (8, 16 and 24 mg); the combination of acrivastine (8 mg) with pseudoephedrine (60 mg); terfenadine (60, 120 and 180 mg); diphenhydramine-HCl (50 mg); and placebo. The subjects were 18 healthy female volunteers. Drug effects were assessed in two repetitions of two driving tests (highway driving and car-following) after each treatment. Acrivastine's impairing effects in both driving tests were similarly dose-related. The 8-mg dose had a small, but significant, effect on highway driving in the first trial. The 16-mg and 24-mg doses significantly impaired driving in both tests during the first trial and the 24-mg dose did so again during the second trial. Neither the combination of acrivastine with pseudoephedrine nor terfenadine caused any significant impairment of performance. Diphenhydramine significantly impaired driving in both tests during every trial. In conclusion, the normal therapeutic dose of acrivastine (8 mg) had little effect on driving performance, and virtually none when that dose was given in combination with pseudoephedrine (60 mg). Higher doses of acrivastine severely impaired driving performance. Terfenadine had no significant effect on driving performance after any dose while diphenhydramine strongly impaired every important driving parameter.

Topics: Administration, Oral; Adult; Automobile Driving; Cross-Over Studies; Diphenhydramine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Ephedrine; Female; Humans; Infant, Newborn; Middle Aged; Single-Blind Method; Terfenadine; Triprolidine

The purpose of this study was to assess the time of onset of action of acrivastine in suppressing the wheal response to histamine (10 mg/ml) and allergen (10,000 and 100,000 BU/ml) in the skin prick test. Ten subjects with a well-documented allergy to pollen received single doses of 8 mg of acrivastine and placebo according to a randomized, double-blind, placebo-controlled, crossover treatment design. Duplicate skin prick tests were performed 0, 15, 20, 25, 30, and 60 min after medication. The results demonstrated a statistically significant suppression of the wheal reactions 15-20 min after medication, depending on the reaction producers used. The sum of all three producers showed a statistically significant effect on the wheal reaction 15 min after medication. The upper 95% confidence limit for time lag from dosing of acrivastine until reduction from placebo level commences was 6.5 min. The study substantiates that orally administered acrivastine has a rapid onset of action in the skin of allergic subjects. The results indicate that allergen SPT is a more sensitive tool for studying antihistaminergic activity than histamine SPT.

Topics: Administration, Oral; Adult; Allergens; Confidence Intervals; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Middle Aged; Pollen; Skin Tests; Time Factors; Triprolidine; Urticaria

The response to the histamine hydrochloride prick skin test was studied in 24 healthy volunteers who received, in random order and at least four days apart, acrivastine (8 mg), terfenadine (120 mg), and placebo. The tests were performed on either side of the back before and at the time of administration (single dose), then every 30 minutes for two hours, and every hour for the following four hours. Evaluation was based on the mean of two measurements of the surface area of the wheal-and-flare reaction accompanied by assessment of topical pruritus. The response to histamine was decreased markedly in the two active treatment groups. Although within one hour of injection, the activity of both antihistamines was consistently greater than that of placebo, the kinetics of action of the two products nevertheless differed; indeed acrivastine was active against flare and wheal earlier (within 30 minutes); terfenadine proved to be more active than acrivastine only on flare and only at the later times (four, five, and six hours). The safety study primarily demonstrated drowsiness in one-fourth of the patients receiving placebo and active treatment.

Topics: Drug Hypersensitivity; Histamine; Histamine H1 Antagonists; Humans; Pruritus; Skin; Skin Tests; Terfenadine; Triprolidine

The initiation of the antihistamine effect of a single dose of acrivastine (8 mg) or cetirizine (10 mg) on wheals and itch induced by histamine dihydrochloride (10 mg/ml) in the prick test was studied in a randomized cross-over design employing 20 healthy medical students. The prick test was performed before ingestion of the drug and after 15, 20, 25, 30, 60 and 90 min and 2, 3 and 4 h. Local symptoms (itching) were recorded on a visual analogue scale. The inhibitory effect of acrivastine on the histamine wheal was first noticed 20 min (p < 0.01) after ingestion of the drug and that of cetirizine after 60 min (p < 0.001). The maximum effect of cetirizine, at 4 h, was greater than that of acrivastine, at 3 h (p < 0.001). The suppression of itching was first noticed 25 min after ingestion with both drugs.

Topics: Adult; Cetirizine; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Skin Tests; Time Factors; Triprolidine

In a double-blind, two-period crossover study, 24 healthy volunteers were evaluated to establish the time of onset of action of activity of acrivastine in suppressing the weal and flare response to intradermally injected histamine. Volunteers received single doses of 8 mg acrivastine and placebo according to a fully randomized, balanced treatment plan. Acrivastine significantly (P less than 0.002) reduced the flare response induced by 0.4 micrograms histamine challenge 15 min after oral acrivastine dosing when compared with placebo. A significant (P less than 0.001) reduction of the weal response was noted at 25 min, although trends in this direction were already present at earlier time points.

Topics: Administration, Oral; Adult; Double-Blind Method; Female; Histamine; Histamine H2 Antagonists; Humans; Hypersensitivity, Immediate; Male; Placebos; Random Allocation; Skin; Triprolidine

Acrivastine is a short acting histamine H1-receptor antagonist with a rapid onset of action. Double-blind clinical trials have shown acrivastine (usually 8mg three times daily) to be an effective and well tolerated antihistamine in the treatment of chronic urticaria and allergic rhinitis. Acrivastine was more effective than placebo and similar in efficacy to clemastine or terfenadine in the treatment of seasonal allergic rhinitis. In the treatment of dermatoses in which histamine has a pathogenetic role, the efficacy of acrivastine was superior to that of placebo and similar to that of usual dosages of clemastine, hydroxyzine, chlorpheniramine, cyproheptadine or terfenadine. Acrivastine caused less drowsiness than clemastine, the incidence of adverse effects being indistinguishable from that with placebo or terfenadine. Thus, acrivastine is an effective addition to drugs currently available for the treatment of patients with allergic diseases in whom a histamine H1-receptor antagonist is indicated. Because of its rapid onset of action acrivastine will be particularly useful for 'on demand' therapy in patients with intermittent symptoms.

Topics: Dermatitis, Atopic; Histamine H1 Antagonists; Humans; Rhinitis, Allergic, Seasonal; Triprolidine; Urticaria

In a four period, double-blind cross-over study, forty patients with moderate to severe symptoms of seasonal allergic rhinitis received in randomised order 8 mg acrivastine, 60 mg pseudoephedrine, 8 mg acrivastine plus 60 mg pseudoephedrine and placebo. Each treatment was given three times daily for six days with a one day washout period between treatments. Acrivastine alone significantly reduced all the symptom severity scores when compared to placebo or pseudoephedrine alone (p less than 0.01). These severity scores were assigned daily by patients for itchy nose/throat, sneezing, running nose, blocked nose, watery eyes, itchy eyes and overall symptoms. The combination of acrivastine and pseudoephedrine was significantly better than either placebo or pseudoephedrine alone in controlling all symptom scores (p less than 0.01) and it was also superior to acrivastine alone (p less than 0.05) in controlling all symptoms except itchy eyes. The results confirm the expected additive rather than synergistic effect of acrivastine and pseudoephedrine in combination. The control of symptoms assessed at the end of each treatment period was considered either excellent or good by 79% of patients and 84% of investigators for acrivastine plus pseudoephedrine and, for acrivastine alone, by 69% of patients and 67% of investigators. Both acrivastine alone and acrivastine and pseudoephedrine in combination were well tolerated. There was no significant difference in the number of adverse experiences reported in either of these two groups compared to the number of adverse experiences reported in the placebo group.

Topics: Adolescent; Adult; Double-Blind Method; Drug Therapy, Combination; Ephedrine; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Pyridines; Rhinitis, Allergic, Seasonal; Triprolidine

Topics: Clinical Trials as Topic; Histamine H1 Antagonists; Humans; Pyridines; Triprolidine

The onset of effect of acrivastine, a new H1-antagonist, has been assessed using antagonism of histamine-induced bronchoconstriction in sensitive volunteers. Acrivastine administered 30, 45, 60 or 90 min before challenge produced a right-shift of the histamine dose-response curve of at least 8-fold indicating that a clinically desired degree of H1-antagonism was present within 30 min of ingestion of the recommended therapeutic dose.

Topics: Administration, Oral; Adult; Bronchi; Double-Blind Method; Female; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Humans; Male; Maximal Expiratory Flow Rate; Triprolidine

Topics: Adolescent; Adult; Benzhydryl Compounds; Clinical Trials as Topic; Dermatitis, Atopic; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Pruritus; Pyridines; Random Allocation; Terfenadine; Triprolidine

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.

Topics: Administration, Oral; Adult; Histamine H1 Antagonists; Humans; Male; Pyridines; Suppositories; Triprolidine

A total of 21 patients with a diagnosis of chronic idiopathic urticaria were assessed in a fully randomized, double-blind, crossover study to investigate the efficacy of 8 mg acrivastine versus 20 mg hydroxyzine and placebo administered three times daily. Both acrivastine and hydroxyzine were found to be effective, and significantly better than placebo, in controlling signs and symptoms of urticaria. No significant differences were found between the active preparations. Hydroxyzine was associated with significantly more reports of drowsiness than was placebo.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Hydroxyzine; Male; Placebos; Pyridines; Triprolidine; Urticaria

Patients (n = 56) with a diagnosis of chronic idiopathic urticaria were assessed in a fully randomized, double-blind, crossover study to investigate the efficacy of acrivastine at two doses (8 and 4 mg) versus 60 mg terfenadine and placebo administered three times daily. All three active preparations were found to be effective, and significantly better than placebo, in controlling the signs and symptoms of urticaria. No significant differences were found between the active preparations, although in some cases efficacy trends favoured 8 mg acrivastine and terfenadine over 4 mg acrivastine. No significant differences were noted between the active treatments and placebo with regard to reports of drowsiness.

Topics: Adult; Benzhydryl Compounds; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Placebos; Pyridines; Terfenadine; Triprolidine; Urticaria

Twenty patients of mean age 41.3 years, with a diagnosis of chronic idiopathic urticaria were assessed in a fully randomized, double-blind, crossover study to investigate the efficacy of acrivastine at two doses (8 mg and 4 mg) versus 1 mg clemastine and placebo, given three times per day. All active preparations were found to be effective, and significantly better than placebo, in controlling the signs and symptoms of urticaria. There was a higher incidence of sedation with clemastine than with either acrivastine or placebo, although this difference did not achieve statistical significance in this small study.

Topics: Adult; Chronic Disease; Clemastine; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Placebos; Pyridines; Pyrrolidines; Random Allocation; Triprolidine; Urticaria

A total of 20 patients with a diagnosis of chronic idiopathic urticaria were entered into a fully randomized, double-blind, crossover study to investigate the efficacy of 8 mg acrivastine versus 4 mg chlorpheniramine three times daily. Data from 16 patients were available for analysis. Both acrivastine and chlorpheniramine were found to be effective in relieving the signs and symptoms of urticaria. There were no significant differences between the two treatments, although efficacy trends were generally in favour of acrivastine over chlorpheniramine throughout the study.

Topics: Adult; Chlorpheniramine; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Pyridines; Random Allocation; Triprolidine; Urticaria

Twenty-four healthy volunteers were entered into a double-blind, crossover study conducted to establish the time of onset of action and the time to peak activity of acrivastine in suppressing the weal and flare responses to intradermally injected histamine. Volunteers received single doses of 8 mg acrivastine and placebo according to a fully randomized, balanced treatment plan. Acrivastine significantly (P less than 0.001) reduced both the weal and flare responses induced by histamine challenge 30 min after oral dosing, as compared with placebo. Peak inhibition of the flare response was seen at 90 min, and maximal suppression of the weal response occurred at 120 min after administration of acrivastine.

Topics: Clinical Trials as Topic; Double-Blind Method; Histamine; Histamine H1 Antagonists; Humans; Pyridines; Random Allocation; Triprolidine; Urticaria

In a double-blind, placebo-controlled multicentre study, the antihistamine acrivastine, was used over prolonged periods for the treatment of seasonal allergic rhinitis. After the initial treatment period of 10 days, 8 mg acrivastine three times daily was significantly superior to placebo in controlling the symptoms of sneezing, itchy nose, running nose, watery eyes, itchy eyes and itchy throat. The benefit from acrivastine was also apparent in the second (14 days) and third (28 days) treatment periods, although the difference no longer reached statistical significance. This was probably due to the large proportion of non-responders in the placebo group who withdrew from the study owing to lack of efficacy. The investigators rated symptom control with acrivastine to be 'good' in comparison to 'poor' control with placebo treatment (P = 0.01) for all three periods. There were no significant differences between acrivastine and placebo in the incidence of adverse experiences at the end of each treatment period. Acrivastine is effective and well tolerated over prolonged periods (up to 52 days) for the treatment of seasonal allergic rhinitis.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Multicenter Studies as Topic; Pyridines; Rhinitis, Allergic, Seasonal; Triprolidine

The speed of onset of H1-antagonism by 8 mg acrivastine and 60 mg terfenadine was compared by bronchial challenge of volunteers with histamine. Active treatments or placebo were administered 1 or 2 h before challenge in a double-blind, randomized, balanced crossover manner to 10 subjects. Acrivastine and terfenadine significantly attenuated the response to inhaled histamine compared to placebo. The effects of acrivastine at 1 and 2 h before challenge, and terfenadine at 2 h were indistinguishable, but that of terfenadine at 1 h was significantly less, indicating that acrivastine has a faster onset of action than terfenadine.

Topics: Adult; Aerosols; Benzhydryl Compounds; Female; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Lung; Male; Pyridines; Receptors, Histamine H1; Terfenadine; Triprolidine; Vital Capacity

Acrivastine is an antihistamine with reduced sedating potential. This comprehensive review of clinical experience with acrivastine in allergic rhinitis considers all currently available data both published and, as yet, unpublished. Unequivocal evidence of the efficacy of 8 mg acrivastine three times daily for the control of symptoms of seasonal allergic rhinitis has been provided by 11 placebo-controlled studies involving almost 1000 patients. Additional trials have generated further supportive data as well as evidence for the use of acrivastine in the treatment of perennial allergic rhinitis. In common with most antihistamines, acrivastine alone has limited effect on the symptom of blocked nose. In a further series of 11 studies, mainly conducted in the USA, the combination of 8 mg acrivastine plus 60 mg pseudoephedrine was found to control not only the histamine-mediated symptoms of allergic rhinitis but also blocked nose. There were few adverse events associated with the use of acrivastine and the small increase in incidence of drowsiness over that found with placebo was similar to that observed for terfenadine. The marked absence of other signs of significant depression of the central nervous system (or anticholinergic activity) suggests that acrivastine will be an important addition for the antihistaminic control of symptoms of allergic rhinitis.

Topics: Clinical Trials as Topic; Histamine H1 Antagonists; Humans; Pyridines; Rhinitis, Allergic, Seasonal; Triprolidine

In this double-blind, multicentre study the antihistamine acrivastine was compared with terfenadine for the treatment of seasonal allergic rhinitis. The study was divided into three periods which together lasted 56 days. Patients (n = 83) were randomly assigned treatment with either 8 mg acrivastine three times daily or 60 mg terfenadine twice daily. Both agents were equally efficacious in reducing the severity of sneezing, itchy nose, blocked nose, running nose, itchy eyes, watery eyes and itchy throat as recorded daily by patients, and as rated by both the patients and their physicians at the end of each treatment period. Acrivastine and terfenadine were equally well tolerated with no serious side-effects. Both effectively controlled the symptoms of seasonal allergic rhinitis in otherwise healthy individuals.

Topics: Adult; Benzhydryl Compounds; Clinical Trials as Topic; Double-Blind Method; Female; France; Histamine H1 Antagonists; Humans; Male; Multicenter Studies as Topic; Pyridines; Random Allocation; Rhinitis, Allergic, Seasonal; Terfenadine; Triprolidine

Twelve patients with symptomatic dermographism were entered into a double-blind, crossover study. Patients received 8 mg acrivastine three times daily, 60 mg terfenadine three times daily or placebo, according to a fully randomized balanced treatment plan. Subjective clinical assessments were performed and the response to experimentally induced dermographism was assessed. Both active treatments were well tolerated and were shown to be significantly more effective than placebo in the treatment of symptomatic dermographism and in reducing the signs and symptoms of wealing induced by a dermographometer.

Topics: Adult; Benzhydryl Compounds; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Pyridines; Random Allocation; Terfenadine; Triprolidine; Urticaria

In a placebo controlled, randomised, multicentre study the efficacy and safety of multiple doses of acrivastine, a derivative of the antihistamine tripolidine (Actidil) were evaluated in patients exhibiting symptoms of seasonal allergic rhinitis. Over the 10 day treatment period, 103 patients received, twice daily, either 4 mg and 8 mg of acrivastine or a placebo. Three patients withdrew from the study due to poor symptom control and two due to adverse experiences. The reporting of adverse experiences was evenly distributed between the treatment and placebo periods. Acrivastine did not affect the haematological, biochemical or urinalysis screens. Both 4 mg and 8 mg acrivastine alleviated the symptoms of seasonal allergic rhinitis with significant improvements in the symptom scores for sneezing, running nose and the calculated overall score. In addition, 8 mg acrivastine reduced the symptom scores for watery eyes and itchy throat. Acrivastine was both well tolerated and effective in the treatment of seasonal allergic rhinitis.

Topics: Adolescent; Adult; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Multicenter Studies as Topic; Pyridines; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Seasonal; Triprolidine

Ten patients with cholinergic urticaria (CU) were entered into a double-blind, placebo-controlled, cross-over study. They were scheduled to receive acrivastine 8 mg t.d.s., hydroxyzine hydrochloride 20 mg t.d.s. and placebo according to a fully randomized, balanced treatment plan. Subjective clinical assessments and objective measurements following exercise challenge were performed during the study period. Both acrivastine and hydroxyzine were shown to be effective and well tolerated in the treatment of cholinergic urticaria. In addition, a trend was demonstrated for both active agents to improve peak expiratory flow rate (PEFR) following exercise, when compared with placebo, and this trend reached statistical significance in the case of acrivastine (p less than 0.05).

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Exercise; Female; Histamine H1 Antagonists; Humans; Hydroxyzine; Male; Middle Aged; Peak Expiratory Flow Rate; Placebos; Pyridines; Triprolidine; Urticaria

A double-blind, crossover trial with a new triprolidine derivative, acrivastine (BW 825C; 8 mg 3 times daily), cyproheptadine (4 mg 3 times daily) and placebo was carried out in 18 patients suffering from idiopathic cold urticaria. Acrivastine and cyproheptadine significantly (p less than 0.01) reduced weal areas following ice cube challenge when compared to placebo. Acrivastine was found to be significantly more effective (p less than 0.01) than cyproheptadine in reducing weal areas. Furthermore, cyproheptadine caused significantly more drowsiness than acrivastine (p = 0.021) or placebo (p = 0.013), which did not differ from each other. This study shows that acrivastine is an effective agent in the treatment of cold urticaria and suggests that acrivastine in the dose used lacks adverse effects, such as drowsiness, traditionally associated with antihistamine therapy.

Topics: Adult; Clinical Trials as Topic; Cold Temperature; Cyproheptadine; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Placebos; Pyridines; Random Allocation; Sleep Stages; Triprolidine; Urticaria

Two studies were performed to measure the effects of acrivastine (BW825C), an antihistamine, in combination with alcohol on the central nervous system. In one study acrivastine 8 mg, diphenhydramine 50 mg and alcohol 32 ml were administered alone and in combination and compared with placebo. In a second study terfenadine 60 and 120 mg and acrivastine 4 and 8 mg combined with alcohol 32 ml were compared with placebo and alcohol alone. Each study was a double-blind, randomised cross-over design using twelve healthy volunteers. Adaptive tracking, reaction time, body sway, eye movements and subjective effects were measured at intervals after treatments. Acrivastine 8 mg alone did not affect any of these measures in contrast with diphenhydramine. Acrivastine in combination with alcohol caused significantly more impairment of some of the tests than placebo or alcohol alone, but significantly less than diphenhydramine/alcohol, which also affected more tests. In the second study no significant differences were seen between the effects of alcohol alone and combinations of either terfenadine or acrivastine with alcohol. It was concluded that acrivastine 8 mg alone did not impair CNS performance in the tests used. In combination with alcohol significant impairment was seen, but this was less pronounced than after diphenhydramine/alcohol. The second study failed to demonstrate differences between drug/alcohol combinations and alcohol alone confirming that the effect of acrivastine in combination with alcohol is small.

Topics: Adolescent; Adult; Benzhydryl Compounds; Brain; Diphenhydramine; Double-Blind Method; Drug Synergism; Ethanol; Eye Movements; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Psychomotor Performance; Pyridines; Reaction Time; Terfenadine; Triprolidine

Topics: Adolescent; Adult; Aged; Chronic Disease; Clemastine; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Pyridines; Pyrrolidines; Random Allocation; Triprolidine; Urticaria

The new H1-receptor antagonist BW 825C and triprolidine (2.5 and 5 mg) were administered to 12 healthy male volunteers in a double blind placebo controlled, balanced, crossover design. Histamine antagonism was measured by assessment of flare and weal areas after intradermal injection of histamine. The 2 compounds were approximately equipotent in blocking the flare and weal response to intradermal histamine and had a similar duration of action. Triprolidine impaired performance of vigilance and reaction time (p less than 0.05) compared with placebo while BW 825C did not. Drowsiness measured using visual analogue scales followed both triprolidine treatments, but not BW 825C. BW 825C had a plasma half-life (t1/2) of 1.7 +/- 0.2 h and triprolidine of 4.6 +/- 4.3 h. The peak plasma level of BW 825C was approximately 6 times that of triprolidine. It was concluded that BW 825C might be a clinically active H1-antagonist with reduced sedative side-effects.

Topics: Adult; Auditory Perception; Histamine H1 Antagonists; Humans; Kinetics; Male; Pyridines; Reaction Time; Triprolidine

The new H1-antagonist acrivastine (BW825C) in doses of 4, 8, and 16 mg was compared with triprolidine HCl (2.5 and 5 mg) in a double-blind crossover study in 12 subjects. Adaptive tracking performance 1.5 hours after dosing was impaired by triprolidine, 2.5 and 5 mg; the impairment was still detectable 3.5 hours after 5 mg. Acrivastine did not impair adaptive tracking after any of the doses. Triprolidine increased reaction times after 1.5 hours (2.5 and 5 mg) and 3 hours (5 mg), but acrivastine did not have any effect on reaction time at any dose. Both doses of triprolidine caused subjective central nervous system effects after 1.5 hours, and triprolidine, 5 mg, still had some detectable effects on subjective rating scales after 3 hours. No subjective effects were noted after acrivastine. We conclude that acrivastine at doses causing more peripheral H1-antagonism than triprolidine has considerably reduced central nervous system activity.

Topics: Administration, Oral; Adult; Double-Blind Method; Drug Evaluation; Female; Humans; Male; Middle Aged; Pyridines; Reaction Time; Triprolidine

20 patients with a diagnosis of chronic idiopathic urticaria were entered into a double-blind placebo-controlled cross-over study. All patients completed the trial and during the assessment period they were treated with placebo, BW 825C (4 mg) and BW 825C (8 mg) according to a fully randomised and balanced treatment plan. Both doses of BW 825C were found to be highly effective and significantly better than placebo in controlling signs and symptoms of urticaria. Few adverse reactions were reported and in this small group of patients there was no significant difference from placebo in reports of drowsiness or any other side-effects.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Pyridines; Random Allocation; Sleep Stages; Triprolidine; Urticaria

The aim: This study aimed to develop mouth-dissolving tablets of Acrivastine, an antihistamine medication, in order to increase its oral bioavailability.. Materials and methods: Different super disintegrants, such as crospovidone, croscarmellose sodium, and sodium starch glycolate, were used to make Acrivastine oral dispersible tablets (ODTs). These super disintegrants were utilized in various concentrations. The formulation (F3) with 6% w/w crospovidone had a fast disintegration time (less than 30 seconds) and practically total drug release within 10 minutes. All of the formulations were made using the direct compression method and proper diluents, binders, and lubricants. Fourier transform infrared spectroscopy (FTIR) tests were used to investigate the drug-ex¬cipient interaction, and all formulations demonstrated improved drug-excipient compatibility.. Results: The average weight of all formulations was between 175 and 180 mg. All formulations' hardness and friability were within acceptable ranges. Direct compression tablets had a hardness of 3.2 to 4 kg/cm2. All formulations were determined to have a friability of less than 1.0%. For oral dissolving tablets, the in vitro disintegration time is critical, and this time preferred to be < 60 seconds. The results also showed that crospovidone disintegrated after 24 seconds and sodium starch glycolate disintegrated in 40 seconds in vitro.. Conclusions: When compared to croscarmellose sodium and sodium starch glycolate, crospovidone performs better as a super disintegrant. In comparison to other formula, tablets breakdown in the mouth in 30 seconds and have a maximum in vitro drug release time in 1-3 minutes.

Topics: Carboxymethylcellulose Sodium; Humans; Povidone; Tablets; Triprolidine

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, R

Topics: Chromatography, High Pressure Liquid; Drug Contamination; Magnetic Resonance Spectroscopy; Photolysis; Silica Gel; Triprolidine; Ultraviolet Rays

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.

Topics: Bromosuccinimide; Calibration; Capsules; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Chromatography, Liquid; Histamine Antagonists; Hydrogen-Ion Concentration; Oxygen; Reproducibility of Results; Spectrophotometry; Spectrophotometry, Ultraviolet; Temperature; Time Factors; Triprolidine

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.

Topics: Catalysis; Copper; Iron; Ketones; Methane; Oxidation-Reduction; Pyridines; Triprolidine

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.

Topics: Chromatography, High Pressure Liquid; Reproducibility of Results; Spectrum Analysis; Stereoisomerism; Triprolidine

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.

Topics: Animals; Area Under Curve; Calibration; Chromatography, High Pressure Liquid; Data Interpretation, Statistical; Half-Life; Histamine H1 Antagonists; Rabbits; Reference Standards; Reproducibility of Results; Spectrophotometry, Ultraviolet; Triprolidine

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.

Topics: Calibration; Capsules; Chromatography, High Pressure Liquid; Ephedrine; Histamine H1 Antagonists; Nasal Decongestants; Pharmaceutical Solutions; Reference Standards; Reproducibility of Results; Solubility; Triprolidine

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.

Topics: Algorithms; Amino Acid Sequence; Animals; Binding Sites; Cattle; Computer Simulation; Drug Interactions; Histamine Agonists; Histamine Antagonists; Humans; Loratadine; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Protein Conformation; Pyrilamine; Receptors, Histamine H1; Rhodopsin; Sequence Homology, Amino Acid; Triprolidine

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.

Topics: Canada; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Evaluation, Preclinical; Ephedrine; Excipients; Fatty Acids; Isomerism; Methylcellulose; Polymethacrylic Acids; Solubility; Tablets; Technology, Pharmaceutical; Triprolidine

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.

Topics: Electrochemistry; Humans; Pharmaceutical Preparations; Triprolidine

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.. The lipophilicity profiles of the compounds were obtained from equilibrium dialysis and potentiometry, and compared with changes in NMR relaxation rates.. 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.. The study confirms that various mechanisms influence the interaction of solutes with liposomes. Combining experimental techniques and using suitable reference compounds proves useful.

Topics: Cetirizine; Chemical Phenomena; Chemistry, Physical; Dialysis; Emulsions; Fluoresceins; Histamine H1 Antagonists; Hydroxyzine; Indicators and Reagents; Liposomes; Magnetic Resonance Spectroscopy; Phosphatidylcholines; Potentiometry; Triprolidine; Water

To investigate the frequency with which sedation was reported in post-marketing surveillance studies of four second generation antihistamines: loratadine, cetirizine, fexofenadine, and acrivastine.. Prescription-event monitoring studies.. Prescriptions were obtained for each cohort in the immediate post-marketing period.. Event data were obtained for a total of 43 363 patients.. Reporting of sedation or drowsiness.. 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.. 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.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Cetirizine; Child; Child, Preschool; Consciousness Disorders; Female; Histamine H1 Antagonists; Humans; Infant; Infant, Newborn; Loratadine; Male; Middle Aged; Product Surveillance, Postmarketing; Sleep Stages; Terfenadine; Triprolidine

To quantify and compare the incidence of ventricular arrhythniias associated with the use of five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were also examined.. We carried out a cohort study with a nested case-control analysis using the UK-based General Practice Research database (GPRD). The study cohort included persons aged less than 80 years old who received their first prescription for any of the five study drugs between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as compared with non use.. The study cohort included 197425 persons who received 513012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias were detected. Nine occurred during the current use of any antihistamine, resulting in a crude incidence of 1.9 per 10000 person-years (95%CI: 1.0-3.6) and a relative risk of 4.2 (95%CI: 1.5-11.8) as compared with non use. Astemizole presented the highest relative risk (RR= 19.0; 95%CI: 4.8-76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5-8.5) was in the range of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular arrhythmias (RR=7.4; 95%CI: 2.6-21.4) and seemed to increase the effect of antihistamines (RR=6.4; 95%CI: 1.7-24.8). The proportions of high dose terfenadine and the concomitant use with P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study period with no single case of ventricular arrhythmias occurring in the presence of these two risk factors.. The use of nonsedating antihistamines increases the risk of ventricular arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low requiring 57000 prescriptions, or 5300 person-years of use for one case to occur. The risk associated with terfenadine was no different from that with other nonsedating antihistamines.

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Astemizole; Case-Control Studies; Cetirizine; Child; Child, Preschool; Cohort Studies; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Female; Histamine H1 Antagonists; Humans; Infant; Infant, Newborn; Information Systems; Loratadine; Male; Middle Aged; Risk Factors; Tachycardia, Ventricular; Terfenadine; Triprolidine

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.

Topics: Animals; Cell Line; Cell Membrane; Cetirizine; Guinea Pigs; Histamine; Histamine H1 Antagonists; Humans; Inositol Phosphates; Ligands; Lysine; Models, Molecular; Mutagenesis, Site-Directed; Receptors, Histamine H1; Triprolidine

In this study, fourth derivative spectrophotometry and high performance liquid chromatography (HPLC) have been used and described for the quantitative determination of acrivastine (I) and pseudoephedrine hydrochloride (II) in their pharmaceutical capsules form (Duact). In the former method, d4A/d gamma 4 values were measured in methanol at 315 and 269 nm for (I) and (II) respectively. The relative standard deviations (RSD) for the method were found to be 1.16% for (I) and 0.94% for (II). The latter method based on reversed phase HPLC system using LiChrosorb C18 analytical column. The mobile phase used for separation of (I), (II) and internal standard (p-hydroxymethylbenzoate) were the water/acetonitrile/methanol/perchloric acid/n-octylamine (500:130:25:13:0.3 v/v) and the detection of the compounds in the capsules were at 260 nm using UV detector. The RSD for the HPLC method were determined to be 0.79 and 0.88% for (I) and (II) respectively. The proposed methods, which give thoroughly comparable data, are simple, rapid, and allow precise and accurate results and could be used for commercial formulations containing acrivastine and pseudoephedrine hydrochloride in combination.

Topics: Capsules; Chromatography, High Pressure Liquid; Ephedrine; Reproducibility of Results; Spectrophotometry, Ultraviolet; Triprolidine

Topics: Adverse Drug Reaction Reporting Systems; Astemizole; Cetirizine; Histamine H1 Antagonists; Humans; Loratadine; Terfenadine; Triprolidine

Topics: Adverse Drug Reaction Reporting Systems; Cetirizine; Histamine H1 Antagonists; Humans; Risk; Triprolidine

Topics: Drug Combinations; Ephedrine; Histamine H1 Antagonists; Humans; Rhinitis, Allergic, Seasonal; Triprolidine

Topics: Animals; Cetirizine; Histamine H1 Antagonists; Imidazoles; Male; Mast Cells; Peritoneal Cavity; Phthalazines; Pyridines; Rats; Rats, Sprague-Dawley; Triprolidine

Topics: Drug Combinations; Ephedrine; Histamine H1 Antagonists; Humans; Rhinitis, Allergic, Seasonal; Triprolidine

Acrivastine and terfenadine are second-generation antihistamines with similar pharmacologic profiles and comparable clinical efficacies for allergic rhinitis. However, terfenadine therapy has been associated with cardiovascular side effects that include prolonged QT interval, torsades de pointes, and ventricular fibrillation (VF). We examined the adverse effects induced by terfenadine on evoked action potentials (APs) in isolated canine cardiac Purkinje fibers and determined whether acrivastine causes similar disturbances in this preparation. Terfenadine produced a statistically significant decrease in the maximal rate of increase in the AP (dV/dt) at 10(-7) M, which corresponds to the highest plasma concentration observed clinically. The IC50 (mean +/- SEM) value for terfenadine-induced inhibition of dV/dt was 1.3 +/- 0.3 x 10(-6) M. The decrease in dV/dt caused by terfenadine became more pronounced with faster rates of stimulation. Acrivastine at a concentration of 10(-5) M, a value 10 times higher than plasma concentrations observed in clinical studies, caused no significant changes in AP duration (APD) or dV/dt. The IC50 (mean +/- SEM) value for the acrivastine-induced inhibition of dV/dt was estimated to be 8.0 +/- 3.7 x 10(-3) M. Terfenadine blocked the evoked AP at 3 x 10(-6) M, whereas no block was observed with acrivastine at 10(-3) M. The effective serum concentration of acrivastine is approximately 100 times higher than that of terfenadine. Because the IC50 value for inhibition of dV/dt for acrivastine is approximately 6,000 times greater than that for terfenadine, we estimate that acrivastine is approximately 60-fold less likely to cause disturbances in cardiac conduction than terfenadine.

Topics: Action Potentials; Animals; Dogs; Dose-Response Relationship, Drug; Female; Histamine H1 Antagonists; In Vitro Techniques; Male; Purkinje Fibers; Terfenadine; Triprolidine

Topics: Histamine H1 Antagonists; Humans; Hypersensitivity, Immediate; Pyridines; Triprolidine

Topics: Gas Chromatography-Mass Spectrometry; Histamine H1 Antagonists; Humans; Pyridines; Radioimmunoassay; Triprolidine