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PubMed1989

Loratadine: a nonsedating antihistamine with once-daily dosing.

Loratadine is an addition to the class of nonsedating antihistamines which includes terfenadine, astemizole, and acrivastine. Loratadine is chemically related to the tricyclic antidepressants. Animal data have shown that insignificant amounts of loratadine enter the brain, and it has a threefold greater affinity for peripheral as compared with central histamine 1-receptors. Loratadine has one main metabolite, descarbethoxyloratadine, which is four times more active than the parent drug. Loratadine reaches peak plasma concentration in 1-2 hours; the metabolite does so in 3-4 hours. Their respective elimination half-lives are about 10 and 20 hours. Onset of action is within 1 hour and duration is at least 24 hours. Once-daily dosing is recommended. Generally, loratadine is as efficacious as existing antihistamines in relieving symptoms of allergic rhinitis, urticaria, and in suppressing wheal formation. Reports of sedation and other adverse reactions are no more frequent than found with placebo. Tachyphylaxis has not been noted in humans, and there is minimal potential for drug interactions based on animal data. Loratadine and terfenadine have comparable therapeutic applications. Both have shown minimal adverse effects, but loratadine has a quicker onset and longer duration of action. These two agents are useful for acute allergic reactions. In contrast, astemizole has an onset of action of several days and is most useful for prophylactic treatment of seasonal allergies.

Cyproheptadine↗

PubMed2002

The use of antihistamines in safety-critical jobs: a meeting report.

The use of sedating agents by aircrew and those with safety-critical occupations has raised serious concern and has been extensively debated for several years. This meeting report summarizes the findings of an international panel of experts in aerospace medicine and allergic rhinitis who were brought together to discuss issues related to the use of antihistamines, in particular the selective, H1-receptor antagonist fexofenadine, in pilots. The presentations covered a wide range of topics including methods for accurately assessing sedation and impairment, and the validity of laboratory testing versus simulator assessments. The panel also examined data on sedation and impairment levels with currently available antihistamines and assessed the impact of these data on their use by pilots and aircrew. It was the consensus of the meeting that fexofenadine can be safely recommended for use in individuals involved in skilled activities, such as pilots, without the concern of sedation above recommended therapeutic doses.

Aviation↗

PubMed2004

A direct comparison of the efficacy of antihistamines in SAR and PAR: randomised, placebo-controlled studies with levocetirizine and loratadine using an environmental exposure unit - the Vienna Challenge Chamber (VCC).

OBJECTIVE: The Vienna Challenge Chamber (VCC) is an established method for the controlled exposure of patients to specific allergens, used to make valid comparisons between antihistamines. The aim of the significantly more than loratadine at all time two placebo-controlled, randomised studies reported here was to compare the efficacy and safety of levocetirizine 5 mg od and loratadine 10 mg od in subjects suffering from seasonal allergic rhinitis (SAR) or perennial allergic rhinitis (PAR). SUBJECTS AND METHODS: During each study period, SAR and PAR subjects were exposed to grass pollen or house-dust mite allergens, respectively for 6 h on 2 consecutive days in the VCC. Each day, medications were administered 2 h after the start of the challenge; with a washout of at least 5 days between each period. The main criterion for evaluation of efficacy was the major symptom complex (MSC) for SAR and the complex symptom score (CSS) for PAR. RESULTS: The pattern of patients' response was similar in SAR and PAR. Both levocetirizine and loratadine were superior to placebo in alleviating SAR and PAR symptoms at all time intervals evaluated during the two study days. Levocetirizine decreased the mean MSC score intervals in SAR subjects, with the most marked difference observed on day 2 (p = 0.002). In PAR patients, although with borderline significance (p = 0.08), levocetirizine decreased the mean CSS more than loratadine. Levocetirizine appeared to have a faster onset of action than loratadine in SAR (45 min versus 1 h 15 min) and PAR (1 h versus 1 h 30 min). However, these apparent differences were not tested for statistical significance. Both medications were well tolerated and no treatment-related adverse events were reported. This level of antihistamine efficacy was maintained regardless of whether the subjects' rhinitis was seasonal or perennial. CONCLUSION: This study demonstrated that levocetirizine is superior to loratadine in improving symptoms in SAR and that there is a similar trend in PAR.

Cetirizine↗

PubMed2006

Synthesis and pharmacological investigation of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones as a new class of H1-antihistamine agents.

A series of novel 1-substituted-4-(4-substituted phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones was synthesized by the cyclization of 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one with various one-carbon donors. The starting material, 2-hydrazino-3-(4-substituted phenyl)-3H-quinazolin-4-one, was synthesized from 4-substituted aniline by a novel innovative route. When tested for in-vivo H1-antihistamine activity on conscious guinea-pigs, all the test compounds significantly protected the animals against histamine-induced bronchospasm. The compound 1-methyl-4-(4-chloro phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (VII) was more potent (72.71% protection), and 1-methyl-4-(4-methoxy phenyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) was equipotent (71% protection), when compared with the reference standard, chlorpheniramine maleate (71% protection). Compounds II and VII showed negligible sedation (5% and 8% respectively) when compared with chlorpheniramine maleate (25%). Compounds II and VII could serve as prototype molecules for further development as a new class of H1-antihistamines.

Animals↗

PubMed2005

Synthesis and H1-antihistaminic activity of some novel 1-substituted-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones.

A series of novel 1-substituted-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-ones were synthesized by the cyclization of 2-hydrazino-3-(3-methylphenyl) quinazolin-4(3H)-one with various one carbon donors. The starting material 2-hydrazino-3-(3-methylphenyl)quinazolin-4(3H)-one, was synthesized from 3-methylaniline by a novel innovative route. When tested for their in vivo H(1)-antihistaminic activity on conscious guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly, whereas the compound 1-methyl-4-(3-methylphenyl)-1,2,4-triazolo[4,3-a]quinazolin-5(4H)-one II was found to be equipotent (percent protection 70.0%) with the reference standard chlorpheniramine maleate (percent protection 71%). Compound II show negligible sedation (7%) when compared to chlorpheniramine maleate (25%). Hence it could serve as prototype molecule for further development as a new class of H(1)-antihistamines.

Animals↗

PubMed1992

Method for optical resolution of racemic homochlorcyclizine and comparison of optical isomers in antihistamine activity and pharmacokinetics.

A method was developed for semi-preparative scale enantioseparation of racemic homochlorcyclizine (HCZ) by high performance liquid chromatography (HPLC) on Chiralcel OD column. The best resolution was achieved using an eluent composed of n-hexane plus 0.2 M isopropylamine. By this method, about 5.0 mg of racemic HCZ could be resolved completely in one run. The optical purity of the enantiomers were both greater than 99.9%. The studies of antihistamine activity on guinea pig ileum demonstrated that l-HCZ is significantly more potent than d- and racemic HCZ. The pharmacokinetics of d- and l-HCZ after oral administration to rats also differed. The successful resolution of racemic HCZ permits comparison of the pharmacokinetics and antihistamine activity of the enantiomers.

Animals↗

PubMed1997

Synthesis and structure-activity relationships of a new series of benzimidazoles as H1-antihistaminic agents.

New 2-(4-(4-azolylbutyl)piperazinyl)-, 2-(4-(4-azolylbutyl) piperazinylmethyl)-, 2-(4-(-azolylbutyl)homopiperazinyl)- and 2-(4-(4-azolylbutyl)homopiperazinylmethyl)benzimidazoles were synthesized, characterized and tested for in vitro and in vivo H1-antihistaminic activity. Structure-activity relationships implied that the best antihistaminic activity required the simultaneous presence of a homopiperazinylbenzimidazole system (or a methylene linker between the benzimidazole and the piperazine rings) and an unsubstituted pyrazole ring. 1-(2-Ethoxyethyl)-2-¿4-[4-(pyrazol-1-yl)butyl] homopiperazin-1-yl¿benzimidazole (17), as its dimaleate salt, has been chosen for further development.

Animals↗

PubMed1999

The effect of antihistamine, endothelin antagonist and corticosteroid prophylaxis on contrast media induced bronchospasm.

Bronchospasm is a well recognized adverse reaction to radiographic contrast media (RCM) and may occur more frequently in asthmatics and atopics. This study was designed to identify RCM which are most likely to cause bronchospasm and to investigate underlying mechanisms mediating this response. Guinea pigs (mean body weight 550 g, n = 46) were anaesthetized with Hypnorm (5 ml kg-1) and Hypnovel (2 ml kg-1) and tracheal, jugular and pleural cannulae introduced. Total airways resistance (Raw) was calculated from the slope of the pressure/flow relationship. The effects of RCM (diatrizoate 370 mgI ml-1, ioxaglate 320 mgI ml-1, iotrolan 300 mgI ml-1 and iopromide 300 mgI ml-1) at a dose of 4 ml kg-1 body weight or control solutions matched for volume, pH and osmolarity administered via the jugular vein on Raw were studied. The effects of pre-treatment (30 min before the administration of RCM) with antihistamine (Mepyramine (30 mg kg-1 i.p.)) or non-selective endothelin receptor antagonist (SB209670 (1 mg kg-1 i.v.)) were investigated. The effectiveness of corticosteroids prophylaxis (prednisolone (20 mg kg-1 i.p.)) administered 18-24 h and 1 h pre-RCM was also assessed. Control animals received normal saline pre-treatment before RCM administration. Lungs were taken for histological examination 30-40 min post-administration of RCM. Only ioxaglate caused a significant (p < 0.05) increase in Raw (5.19 +/- 0.58 to 13.95 +/- 3.53 mmHg ml-1 min-1). Neither mannitol nor saline control solutions had any effect on Raw. Pre-treatment with Mepyramine, SB209670 or prednisolone caused no significant change in the ioxaglate induced increase in Raw. Histological examination of lung tissue from ioxaglate treated animals showed no important abnormalities. In summary, only the ionic dimer ioxaglate caused an increase in Raw. This effect was independent of osmolarity and could be the result of the chemical composition of the contrast agent. It was not an inflammatory response and could not be prevented by prophylactic treatment with antihistamine, endothelin antagonist or corticosteroids. The mechanisms responsible for the increase in Raw remain uncertain.

Airway Resistance↗

PubMed1980

Etiology of otitis media with effusion: antihistamines--decongestants.

In an attempt to find a causative factor for the increased incidence of otitis media with effusion, a detailed study of 50 cases was conducted. This study included 50 cases of nonpurulent otitis media with effusion requiring ventilating tubes without tonsilloadenoid pathology. A study of these cases revealed an interesting pattern which suggests that antihistamines and decongestants may be causative or precipitating factors in the etiology of otitis media with effusion. A pilot study on the effects of these drugs on mucociliary activity was conducted and revealed further evidence that antihistamines and decongestants interfere with normal mucociliary activity which probably is a factor in abnormal Eustachian tube physiology.

Adolescent↗

PubMed1995

The effect of antihistamines on the laryngeal chemoreflex.

The laryngeal chemoreflex (LCR) consists of apnea, laryngospasm, and cardiovascular changes in neonates after laryngeal irritation and has been implicated in sudden infant death syndrome and apnea of infancy. Antihistamines attenuate a similar vagally mediated pulmonary chemoreflex. The intravenous antihistamine effect on the LCR was studied in neonatal piglets. Laryngeal muscle activity, respiration, blood pressure, and pulse were measured during water stimulation of the LCR. After baseline LCR recordings, intravenous diphenhydramine (2.5 mg/kg) or cimetidine (20 mg/kg) was bolused (control group received saline). LCR measurements were repeated over 7 hours. Diphenhydramine significantly shorted apneas (P < .05) 3 to 7 hours after drug bolus, which is believed to be secondary to central atropinic effects. Cimetidine demonstrated no attenuation of the LCR.

Administration, Intranasal↗

PubMedDate not supplied

Effects of an increase in prescription copayment on utilization of low-sedating antihistamines and nasal steroids.

BACKGROUND: Health plans are using 3-tier copayment designs and other methods to control utilization that shifts drug costs to plan members. There is a need to determine the effects of increased member cost sharing on drug utilization and drug costs. OBJECTIVE: To assess the impact of a 10 US dollars increase in prescription copayment in a public employer health plan for 2 classes of drugs used for allergic rhinitis. METHODS: Changes in the number of prescriptions dispensed for 2 therapeutic classes.low-sedating antihistamines (LSAs) and nasal steroids (NSs).were examined 1 year prior to and 1 year after copayment increase. Relative price effects were measured as arc price elasticity, the ratio of the percent change in prescription utilization over the percent change in price, an indicator of how responsive patients are to the copayment increase. RESULTS: Of 8,643 continuously enrolled health plan beneficiaries, 2,150 patients (24.8%) received at least 1 NS or LSA during the 2-year period of the study, from January 1, 1998, through December 31, 1999. An average 10 US dollars increase in copayment per prescription was associated with no statistically significant change in utilization of combined LSA and NS prescriptions, 2.89 per patient in 1998 and 2.94 in 1999 (P = 0.597). Health plan costs for study drugs, unadjusted for inflation, decreased by 16.3% from 86.86 US dollars per patient in 1998 to 72.68 US dollars in 1999 (P = 0.004). Health plan costs per patient per month (PPPM) for all drugs for the 2,150 allergic rhinitis patients decreased by 13% from 41.33 US dollars PPPM in 1998 to 35.93 US dollars in 1999 (P<0.001), and health plan drug costs for all 8,643 members decreased by 13% from 14.93 US dollars per member per month (PMPM) in 1998 to 12.99 US dollars in 1999 (P<0.001). The actual average copayment increase was 7.23 US dollars (a 41% increase) for LSAs, which was associated with a 14.8% increase in utilization of LSAs and an 11.8% increase in the number of patients using LSAs; the number of LSA prescriptions per patient per year was unchanged at 2.68 in 1999 versus 2.61 in 1998 (P = 0.429). The actual average copayment increase was 10.98 US dollars (71%) for NSs, which was associated with an 11.3% decrease in utilization of NSs and a 10.2% decrease in the number of users of nasals steroids in 1999; the number of nasal steroid prescriptions per patient per year was unchanged at 2.05 in 1999 versus 2.07 in 1998 (P =.842). The combined utilization of LSA and NS prescriptions increased by 8.9% following the increase in copayments for these 2 therapeutically interchangeable drugs for allergic rhinitis. LSA prescriptions were less elastic, with an unadjusted arc elasticity of 0.39, while nasal steroid prescriptions were more responsive to the copayment change, with an unadjusted arc elasticity of.0.22. CONCLUSIONS: An average 10 US dollars increase in patient cost sharing per prescription (46.9% copayment increase) was associated with an increase in combined utilization of 2 drug classes used for allergic rhinitis (LSAs and NSs) but no change in the number of prescriptions per patient. Health plan costs decreased significantly for allergic rhinitis drugs, all drugs used by allergic rhinitis patients, and all drugs used by continuously enrolled health plan members. NSs exhibited a greater arc price elasticity compared with low-sedating oral antihistamines.

Administration, Intranasal↗

PubMed1999

Cardiotoxicity of histamine and the possible role of histamine in the arrhythmogenesis produced by certain antihistamines.

Since 1990 it has repeatedly been reported that some histamine H1 receptor antagonists (e.g. terfenadine and astemizole) are able to produce ventricular arrhythmias (e.g. torsade de pointes) when they are given at dosages above the therapeutic range and/or administered together with cytochrome P-450 3A4 inhibitors, such as ketoconazole or erythromycin. Although the mechanism by which these arrhythmias are produced remains unclear, the recently reported ability of these drugs to block outward K+ currents has been suggested as the cause of their arrhythmogenic effects. Alternatively, we have observed that some H1 antihistamines, including terfenadine and astemizole, are able to release histamine from guinea-pig cardiac mast cells. Thus, we have proposed that the liberated histamine, acting through an H2 receptor-stimulating mechanism, can prolong the action potential duration and hence induce arrhythmogenic effects. This paper describes experimental observations supporting the hypothesis that some H1 antihistamines can induce severe cardiac arrhythmias via the local release of histamine.

Animals↗

PubMed1999

Effects of H1 antihistamines on animal models of QTc prolongation.

OBJECTIVE: The clinical use of some nonsedating H1 antihistamines (histamine H1 receptor antagonists) has been associated with a rare but life-threatening type of arrhythmia, torsade de pointes, especially when these drugs are coadministered with cytochrome P450 (CYP) 3A4 enzyme inhibitors. On the basis of the latter observation and the fact that most of these H1 antihistamines undergo extensive first-pass metabolism to active metabolites apparently devoid of cardiovascular adverse effects, this arrhythmogenicity has been attributed to the parent drug. The objective of this study was to find an animal model with the ability to predict the proclivity of drugs to produce torsade de pointes. DESIGN: Two experimental approaches were used: (i) blockade of CYP3A4 metabolism by coadministration of ketoconazole to increase the plasma concentrations of the parent compound in the conscious guinea-pig, and (ii) administration of the compound directly into the coronary circulation of the anaesthetised dog in order to circumvent first-pass metabolism. RESULTS: The first approach demonstrated that terfenadine administered in the presence of ketoconazole prolongs the corrected QT (QTc) interval of the electrocardiogram, whereas ebastine does not. Similarly, when terfenadine was administered through the coronary circulation, a statistically significant increase in the QTc interval was also seen, whereas ebastine and carebastine were without effect. Thus, it is clear that ebastine was much better tolerated than terfenadine from a cardiovascular standpoint, since ebastine and its metabolite are devoid of effects on cardiac repolarisation, as measured by the QTc interval in these animal models.

Animals↗

PubMed1989

Rational use of antihistamines in allergic dermatological conditions.

For many years, the use of antihistamines in dermatological conditions has been closely linked to the treatment of urticarias and to the symptomatic relief of pruritus. H1-receptor antagonists are the first-line drugs for urticarias. Those urticarias of type I immunological origin respond better than physical urticarias. H2-receptor antagonists may be added for refractory patients but are rarely effective alone. Conventional H1-blockers are frequently associated with somnolence and anticholinergic effects. Therefore, new antihistamines without depressive effects on the central nervous system have recently been introduced. In other pruritic conditions such as atopic dermatitis the limited effects of these drugs suggest that histamine is not the only mediator involved in pruritus. In these cases, their beneficial effects seem to be due mainly to their sedative properties; recently available nonsedative H1-blockers are less effective.

Dermatitis, Contact↗

PubMed1999

Second-generation antihistamines: a comparative review.

Second-generation histamine H1 receptor antagonists (antihistamines) have been developed to reduce or eliminate the sedation and anticholinergic adverse effects that occur with older H1 receptor antagonists. This article evaluates second-generation antihistamines, including acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, loratadine, mizolastine and terfenadine, for significant features that affect choice. In addition to their primary mechanism of antagonising histamine at the H1 receptor, these agents may act on other mediators of the allergic reaction. However, the clinical significance of activity beyond that mediated by histamine H1 receptor antagonism has yet to be demonstrated. Most of the agents reviewed are metabolised by the liver to active metabolites that play a significant role in their effect. Conditions that result in accumulation of astemizole, ebastine and terfenadine may prolong the QT interval and result in torsade de pointes. The remaining agents reviewed do not appear to have this risk. For allergic rhinitis, all agents are effective and the choice should be based on other factors. For urticaria, cetirizine and mizolastine demonstrate superior suppression of wheal and flare at the dosages recommended by the manufacturer. For atopic dermatitis, as adjunctive therapy to reduce pruritus, cetirizine, ketotifen and loratadine demonstrate efficacy. Although current evidence does not suggest a primary role for these agents in the management of asthma, it does support their use for asthmatic patients when there is coexisting allergic rhinitis, dermatitis or urticaria.

Asthma↗

PubMed1997

Quality-of-life outcomes and the use of antihistamines in a French national population-based sample of patients with perennial rhinitis.

Our primary objective in designing the first large-scale nationwide population-based survey in France was to assess the impact of perennial rhinitis on quality of life. Our secondary objective was to describe the use of drug treatment, including histamine H1 antagonists, in that population. A pollbase of 20,000 households was screened for symptoms of rhinitis. 16,786 households responded, including 35,615 patients aged over 15 years, giving an overall response rate of 84%. Using an algorithm, 1367 patients with probable perennial rhinitis were selected for a cross-sectional collection of data about the history of their condition, comorbidity, use of medical resources, sick leave and nasal symptom-related quality of life [according to the Medical Outcomes Study 36-Item Short-Form Questionnaire (SF-36)]. Finally, multivariate regression techniques were used to describe the relationship between quality-of-life scores and treatment subgroups, controlling for some other confounding factors. The point prevalence of perennial rhinitis was estimated to be 4.1% [95% confidence interval (CI): 3.9 to 4.3%]. Association of perennial rhinitis with a history of asthma was highly significant (13.4% in those with perennial rhinitis vs 3.8% in those without; odds ratio 3.26; p < 0.001). 38% of the patients with perennial rhinitis reported having taken regular medication during the last 3 months. Antihistamine use was associated with use of decongestant or topical nasal products in about one-third of patients. Four SF-36 dimensions (physical functioning, role physical, bodily pain, social functioning) showed significantly higher mean scores (indicating better quality of life) in patients receiving non-anticholinergic histamine H1 antagonist therapy, relative to those receiving other treatments, a difference that was maintained after controlling for gender, age, level of nasal symptoms, medical history of asthma and number of general practitioner visits. These results established the long term impact of perennial rhinitis on quality of life (generic and specific), and raised questions about appropriate therapy, since a positive association between current use of non-anticholinergic antihistamines with improvements on some SF-36 dimensional scores in patients with perennial rhinitis was observed.

Adult↗

PubMed2006

Acute eosinophilic pneumonia caused by calcium stearate, an additive agent for an oral antihistaminic medication.

A 70-year-old man was admitted to our hospital because of dyspnea after taking an antihistaminic agent (homochlorcyclizine hydrochloride) for itching. Chest roentgenogram showed infiltration in the left lung field, and laboratory data revealed eosinophilia. Examination of the bronchoalveolar lavage fluid revealed an increased eosinophil count. A drug lymphocyte stimulation test was positive only for calcium stearate, an additive contained in the homochlorcyclizine hydrochloride tablet. The pulmonary infiltration and clinical symptoms subsided after withdrawal of all drugs and initiation of glucocorticoid therapy. Therefore, we concluded that this patient's pulmonary disease was caused by calcium stearate, an additive for an antihistaminic drug. An allergic reaction to a drug's additive material should be considered as a rare cause of drug-induced acute eosinophilic pneumonia.

Acute Disease↗

PubMed1999

Physiological and behavioral effects of an antivertigo antihistamine in adults.

12 neurologically normal adults were tested before and after administration of meclizine, an over-the-counter medication for motion sickness. A battery of four tests was used: (1) distortion-product otoacoustic emissions, (2) the Repeated Evoked Potentials version of the Auditory Brainstem Response, (3) quantitative electroencephalography measured over the left and right sides of the auditory cortex, and (4) a hand-eye coordination task. The battery required approximately 1.5 hr. to complete. Each subject was tested with the battery in each of eight longitudinal sessions: three times on a control day (9 am, 1 pm, 3 pm--no medication); the same times on a second day one week later (medication at approximately 11:30 am), and 24- and 48-hr. check-up sessions following the medication day. Analysis indicated changes in all components, with details suggesting the site(s) of action of this type of antihistamine. The cross-section of the auditory system yielded by this battery makes it possible to observe effects at the periphery, in the brainstem, and in the cortex, including evidence linking otoacoustic emissions with central auditory physiology. Implications range from cautions regarding the use of antihistamines to physiological support for employing such medications to enhance patients' response to vestibular rehabilitation as well as to improve performance in learning-disordered children.

Adult↗