Small occasional doses of azatadine are probably acceptable during breastfeeding. Larger doses or more prolonged use may cause drowsiness and other effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. The nonsedating antihistamines are preferred alternatives.

UDP-glucuronosyltransferase (UGT)1A4 and UGT2B10 are the human UGT isoforms most frequently involved in N-glucuronidation of drugs. UGT2B10 exhibits higher affinity than UGT1A4 for numerous substrates, making it potentially the more important enzyme for metabolism of these compounds in vivo. Clinically relevant UGT2B10 polymorphisms, including a null activity splice site mutation common in African populations, can lead to large exposure differences for UGT2B10 substrates that may limit their developability as marketed drugs. UGT phenotyping approaches using recombinantly expressed UGTs are limited by low enzyme activity and lack of validation of scaling to in vivo. In this study, we describe the use of an efficient experimental protocol for identification of UGT2B10-selective substrates (i.e., those with high fraction metabolized by UGT2B10), which exploits the activity difference between pooled human liver microsomes (HLM) and HLM from a phenotypically UGT2B10 poor metabolizer donor. Following characterization of the approach with eight known UGT2B10 substrates, we used ligand-based virtual screening and literature precedents to select 24 potential UGT2B10 substrates of 140 UGT-metabolized drugs for testing. Of these, dothiepin, cidoxepin, cyclobenzaprine, azatadine, cyproheptadine, bifonazole, and asenapine were indicated to be selective UGT2B10 substrates that have not previously been described. UGT phenotyping experiments and tests comparing conjugative and oxidative clearance were then used to confirm these findings. These approaches provide rapid and sensitive ways to evaluate whether a potential drug candidate cleared via glucuronidation will be sensitive to UGT2B10 polymorphisms in vivo. SIGNIFICANCE STATEMENT: The role of highly polymorphic UDP-glucuronosyltransferase (UGT)2B10 is likely to be underestimated currently for many compounds cleared via N-glucuronidation due to high test concentrations often used in vitro and low activity of UGT2B10 preparations. The methodology described in this study can be combined with the assessment of UGT versus oxidative in vitro metabolism to rapidly identify compounds likely to be sensitive to UGT2B10 polymorphism (high fraction metabolized by UGT2B10), enabling either chemical modification or polymorphism risk assessment before candidate selection.

Loratidine is a piperidine derivative resemble to azatadine long acting non sedating commonly used for the treatment of allergic condition like watery or itchy eyes, runny nose, chronic urticaria or throat itching. In the present study different brands of loratidine were evaluated for the weight variation, hardness, friability, disintegration time and dissolution. Dissolution release study performed by using paddle method (USP 2) in 900 ml of 0.1N HCl at 50 rpm. The physicochemical of loratidine did not give any variation. By this study we conclude that all parameter for physicochemical properties like weight variation, hardness of tablets, friability, their disintegration time and the dissolution release study for all the brands of loratidine that are available in Karachi meet the British pharmacopoeia (BP) and United State pharmacopoeia (USP) specification for quality control analysis.Weight variation, hardness and friability value requirement was complied by all brands .Disintegration time for all brands was less than 15 minutes complying the BP/USP recommendation. All brands showed more than 80% drug release within 45 minutes. The present findings suggest that almost all the brands of loratidine meet the BP/USP specification for QC analysis.

A sensitive method using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) was developed and validated for the analysis of antihistamine drug azatadine in human plasma. Loratadine was used as internal standard (IS). Analytes were extracted from human plasma by liquid/liquid extraction using ethyl acetate. The organic phase was reduced to dryness under a stream of nitrogen at 30 °C and the residue was reconstituted with the mobile phase. 5 μL of the resulting solution was injected onto the LC-MS/MS system. A 4.6 mm × 150 mm, I.D. 5 μm, Agilent TC-C(18) column was used to perform the chromatographic analysis. The mobile phase consisted of ammonium formate buffer 0.010 M (adjusted to pH 4.3 with 1M formic acid)/acetonitrile (20:80, v/v) The chromatographic run time was 5 min per injection and flow rate was 0.6 mL/min. The retention time was 2.4 and 4.4 min for azatadine and IS, respectively. The tandem mass spectrometric detection mode was achieved with electrospray ionization (ESI) iron source and the multiple reaction monitoring (MRM) (291.3 → 248.2m/z for azatadine, 383.3 → 337.3m/z for IS) was operated in positive ion modes. The low limit of quantitation (LLOQ) was 0.05 ng/mL. The intra-day and inter-day precision of the quality control (QC) samples was 8.93-11.57% relative standard deviation (RSD). The inter-day accuracy of the QC samples was 96.83-105.07% of the nominal values.

Due to the difficulty of monitoring trace levels of cyproheptadine (CYP) residues in complicated biological matrices, specific adsorption materials for the preconcentration and clean-up of CYP are indispensable. In this work, CYP was extracted from urine using dummy molecularly imprinted SPE (DMISPE) to avoid leakage of the imprinting molecules during the desorption phase. For synthesis of DMISPE, azatadine (AZA) was employed as the dummy template, methacrylic acid (MAA) as the monomer, ethylene glycol dimethacrylate (EGDMA) as the cross-linker, 2,2'-azobis(2-methylpropionitrile) (AIBN) as the initiator, and dichloromethane as the porogen solvent. An LC-MS/MS method was used to analyze CYP. Two MRM (multiple reaction monitoring) transitions for each analyte were monitored using diphenylpyraline hydrochloride (DPP.HCl), which was used as an internal standard. The advantages of DMISPE include obtaining less complex chromatograms and reducing ion suppression in ESI. The process efficiencies for DMISPE and SPE were 80% and 12%, respectively. In addition, the demonstrated reusability of the DMISPE cartridges is an advantage compared with single-use SPE cartridges or immunoaffinity materials.

The use of custom-made polymeric materials with high selectivities as target molecules in solid-phase extraction (SPE), known as molecularly imprinted solid-phase extraction (MISPE), is becoming an increasingly important sample preparation technique. However, the potential risk of leakage of the imprinting molecules during the desorption phase has limited application. The use of a mimicking template, called a dummy molecular imprinting polymer (DMIP), that bears the structure of a related molecule and acts as a putative imprinting molecule may provide a useful solution to this problem. In the current study, cyproheptadine (CPH) and azatadine (AZA) were used as templates in the development of an MIP and DMIP for acrylic acid and methacrylic acid monomers. Our results indicate that DMIPs have equal recognition of CPH, avoiding the problem of leakage of original template during the desorption phase relative to MIPs synthesized in presence of the print molecule CPH. Examination of the surface structure of the two polymer products by SEM shows appreciable differences in structural morphology and function of the monomers employed. These results are well supplemented by data obtained for swelling ratios and solvent uptake. Molecular modelling of CPH and AZA suggests that both substrates are similar in shape and volume.

Vestibular neuronitis was described in 1949 and 1952 by Dix and Hallpike. Two groups of patients were described, those with sudden seizures and sensations of blackout (since identified as having vestibular neuritis) and a second group with symptoms of disequilibrium and feelings of top-heaviness or imbalance. The pathology was believed to be central to the inner ear. Arslan labeled these groups as having nucleoreticular vestibular syndrome. Using a suprathreshold stapedial reflex test, Bosatra localized the pathophysiology in the brainstem, an area rich in serotonergic neurons. This author has used antiserotonergic drugs, with success, in treating patients having the symptoms identified by Dix and Hallpike in their second group (which now should be labeled nucleoreticular vestibular syndrome), properly identified as a brainstem affliction. This study describes the characteristics of this disorder, the methods of diagnosis and treatment, and the outcomes in two groups of patients studied. The study concluded that antiserotonin drugs, specifically affecting 5-hydroxytryptamine2, should be considered in the management of nucleoreticular vestibular syndrome.

Data from in vitro, in vivo, and ex vivo studies suggest that second-generation antihistamines have a number of antiallergic, anti-inflammatory properties that appear to be independent of their H1-blockade activity. First-generation antihistamines also have antiallergic, anti-inflammatory properties, as suggested by the studies with azatadine, chlorpheniramine, mepyramine, and promethazine; most other first-generation antihistamines have not been studied for these properties. In vitro studies have shown that H1-antihistamines reduce the release of proinflammatory mediators from mast cells and basophils, the chemotaxis and activation of inflammatory cells (especially eosinophils), and the expression of adhesion molecules induced by immunological and nonimmunological stimuli in epithelial cell lines. Nasal allergen challenge models have similarly demonstrated that H1-antihistamines inhibit mediator release from mast cells and basophils, and that they decrease inflammatory cell infiltration and the expression of adhesion molecules on epithelial cells. The results of published studies of the effects of H1-antihistamines on nasal allergic inflammation in humans have been summarized in this chapter. Recent investigations indicate that H1-antihistamines may modulate airway inflammation by downregulating the activity of airway epithelial cells, which have an important role in allergic airway inflammation. The modulation of adhesion molecules and of inflammatory cell infiltration by H1-antihistamines may be beneficial during long-term treatment in patients with allergic rhinitis. The rationale for this hypothesis is the persistence of inflammation on the nasal epithelial cells even when patients are symptom-free (16). All of the events affected by H1-antihistamines are important in the allergic inflammation cascade. The underlying mechanisms for such effects remain unclear, but are unrelated to H1-antagonist activity. Several studies have demonstrated that H1-antihistamines can form an ionic association with cell membranes and inhibit calcium ion influx into the mast cell or basophil plasma membrane, or inhibit Ca2+ release within the cells, and may therefore influence the signal transduction pathways. However, these effects appear to occur at concentrations higher than those achieved in therapeutic practice (126-128). It has recently been hypothesized that the anti-inflammatory activity of H1-antihistamines may be a consequence of their ability to influence the activation of genes responsible for the expression and synthesis of proinflammatory mediators (129). The contribution of the antiallergic effects of H1-receptor antagonists to their clinical efficacy is not fully understood. There have been no data suggesting that H1-antihistamines with well-documented antiallergic properties are superior to the others for which such properties have not been as extensively investigated. Additional studies are needed to elucidate the mechanisms(s) by which H1-antihistamines exert anti-inflammatory effects. This knowledge might lead to the development of novel therapies with more potent and specific anti-inflammatory effects.

A reversed-phase liquid chromatographic procedure with a micellar mobile phase of sodium dodecyl sulfate (SDS), containing a small amount of pentanol, was developed for the control of 7 antihistamines of diverse action in pharmaceutical preparations (tablets, capsules, powders, solutions, and syrups): azatadine, carbinoxamine, cyclizine, cyproheptadine, diphenhydramine, doxylamine, and tripelennamine. The retention times of the drugs were <9 min with a mobile phase of 0.15M SDS-6% (v/v) pentanol. The recoveries with respect to the declared compositions were in the range of 93-110%, and the intra- and interday repeatabilities and interday reproducibility were <1.2%. The results were similar to those obtained with a conventional 60 + 40 (v/v) methanol-water mixture, with the advantage of reduced toxicity, flammability, environmental impact, and cost of the micellar-pentanol solutions. The lower risk of evaporation of the organic solvent dissolved in the micellar solutions also increased the stability of the mobile phase.

The chromatographic behaviour of binary and ternary mixtures of several phenethylamines (phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine and methoxyphenamine) and antihistamines (pheniramine, carbinoxamine, doxylamine, chlorpheniramine, dexchlorpheniramine, dexbrompheniramine, diphenhydramine, tripolidine, azatadine and phenyltoloxamine), found in cough-cold pharmaceutical preparations, was studied using C8, C18 and cyano columns, micellar mobile phases of sodium dodecyl sulfate (SDS) and pentanol and UV detection. Using a C8 column and mobile phases of 0.05 mol l-1 SDS-6% v/v pentanol or 0.15 mol l-1 SDS-2% v/v pentanol at pH 7, more than 30 different phenethylamine-antihistamine combinations can be resolved in < 15 min. Intra- and inter-day repeatabilities and reproducibilities evaluated at three different drug concentrations (0.5, 5 and 25 micrograms ml-1, n = 10) were below 1.6, 2.5 and 2.4%, respectively. The drug amounts found in 18 formulations agreed with those declared by the manufacturers within the tolerance limits, and with those obtained using a mobile phase of 55% v/v methanol at pH 7. No interference was observed from other accompanying drugs such as acetylsalicylic acid, ascorbic acid, betamethasone, bromhexine, caffeine, codeine, dextromethorphan, paracetamol, prednisolone, salicylamide and tartrazine. The proposed procedure has the advantage over the conventional aqueous-organic procedure of using a small amount of organic solvent, which is highly retained in the SDS solution. The efficiencies are also greater. On the other hand, in the micellar system, the retentions of phenethylamines and antihistamines are similar, although the compounds can be easily resolved. In contrast, using the methanol-water mobile phase, the phenethylamines are weakly retained, whereas the antihistamines usually show a high retention.

The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (specifically, the H1-receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H1-receptor and provide clinical benefit. However, H1-receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classified as H1-receptor antagonists have long been recognized to have additional pharmacological properties. Most first-generation H1-antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classified as H1-receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic infiltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H1-receptor antagonist, has been shown to have additional actions that should help reduce the allergic response. In animal models, mizolastine inhibits antigen-induced eosinophil infiltration into mouse skin and into the nasal cavity of guinea-pigs. Mizolastine also significantly inhibits antigen-induced neutrophil infiltration into the bronchoalveolar lavage fluids of guinea-pigs. In addition, it inhibits arachidonic acid-induced paw oedema in rats without affecting carrageenin-induced rat paw oedema, suggesting an effect on LT generation. In man, mizolastine inhibits early and late antigen-induced soluble intercellular adhesion molecule 1 (ICAM-1) levels in skin blisters. It also inhibits anaphylactic release of histamine from rodent mast cells, LTC4 and LTB4 release from mouse bone-marrow-derived mast cells, LTC4 release from rat intestinal mast cells, and 5-lipoxygenase activity of polymorphonuclear neutrophils of guinea-pig intestines and rat basophilic leukaemia cells. It is clear that a number of H1-antihistamines have multiple effects on the allergic inflammatory response. It is equally clear that these antiallergic effects are not uniformly shared among all drugs of this class. The assessment of the clinical significance of these results and research regarding the parts of the molecules responsible for these activities are underway.

The effect of a number of pharmacological agents on the enhancement of antimalarial activity of chloroquine was evaluated against chloroquine resistant line of Plasmodium yoelii nigeriensis (N-67). The response after combination therapy was monitored on the basis of alteration in the course of parasitaemia, the extension of mean survival time and the percent cure rate in different groups. The study was designed to compare the in vivo efficacy of a number of resistance modulating agents found effective in several in vitro studies against chloroquine resistant P. falciparum isolates. Based on their efficacy in this rodent model, the response of combination of chloroquine with agents representing diverse chemical moieties has been categorised as curative, moderately active and inactive. Out of the 22 agents evaluated, only cyproheptadine-chloroquine combination produced curative response. Ketotifen, azatadine, pheniramine, amitriptyline, fluoxetine, verapamil, penfluridol and trifluoperazine demonstrated moderate activity while loratadine, terfenadine, promethazine, ranitidine, nifedipine, diltiazem, chlorpromazine, amiodarone, tamoxifen, dipyridamol, propranolol, acyclovir and amantidine were inactive. The study advocates the suitability of proposed rodent model to shortlist potential resistance reversal agents.

The causal prophylactic activity of five tricyclic anti-histaminic agents (histamine H1-receptor antagonists) cyproheptadine, ketotifen, loratadine, azatadine and terfenadine was evaluated in an experimental murine malaria model. Sporozoite induced infections with Plasmodium yoelii nigeriensis (N-67), a strain innately resistant to choloroquine, were employed for the efficacy test and pyrimethamine and primaquine were used as standard reference drugs. Treatment with cyproheptadine or ketotifen at 5 mg/kg and terfenadine at 50 mg/kg, orally for 3 days (-1, 0, +1) completely prevented the establishment of patent infection in mice inoculated with 1 x 10(5) sporozoites on day 0. Partial activity was recorded with lower doses of the above agents as well as with azatadine and loratadine at 10 mg/kg as indicated by marginal delay in the development of patent infection after sporozoite challenge. None of these agents showed blood schizontocidal activity at doses found effective in the causal prophylactic test, though initial suppression of parasitaemia was observed with cyproheptadine and ketotifen at higher doses. This study is the first report on efficacy of antihistaminic agents for growth inhibition of pre-erythrocytic stages of any malaria parasite.

The metabolism of the antihistamine azatadine by the zygomycete fungus Cunninghamella elegans ATCC 9245 was investigated. Within 72 h from the addition of the drug to 48-h-old cultures grown in Sabouraud dextrose broth, 95% of azatadine was biotransformed. Two major metabolites, 7-hydroxyazatadine (25%) and 8-hydroxyazatadine (50%), and two minor metabolites, N-desmethylazatadine and 9-hydroxyazatadine, were isolated by high-performance liquid chromatography and characterized by mass spectrometric and proton nuclear magnetic resonance spectroscopic analyses.

Loratadine is a long-acting antihistamine agent, exhibiting partial selectivity for peripheral histamine H1-receptors. To date, loratadine has been evaluated in allergic rhinitis, urticaria and, to a limited extent, in asthma. In several large controlled comparative clinical studies, loratadine was superior to placebo, faster acting than astemizole and as effective as azatadine, cetirizine, chlorpheniramine (chlorphenamine), clemastine, hydroxyzine, mequitazine and terfenadine in patients with allergic rhinitis and chronic urticaria. The clinical effectiveness of loratadine in asthma is at present unclear. Loratadine is well tolerated. At dosages of 10 mg daily, commonly reported adverse events were somnolence, fatigue and headache. Sedation occurred less frequently with loratadine than with azatadine, cetirizine, chlorpheniramine, clemastine and mequitazine. Serious ventricular arrhythmias, as reported with some other second generation histamine H1-receptor antagonists, have not been observed with loratadine to date. Thus, loratadine, with its attributes of once daily administration, fast onset of action and essentially nonsedating properties, would appear to be an appropriate first-line agent for the treatment of allergic rhinitis or urticaria.

Antihistamines are believed to reduce the sneezing and rhinorrhea associated with allergic rhinitis, primarily by competitive antagonism of histamine for H1 cellular receptors, but additional mechanisms of action may contribute to their clinical efficacy. To improve our understanding of H1 antihistamine action, we studied the effects of pretreatment with terfenadine, cetirizine, ketotifen, azatadine, diphenhydramine, and azelastine on increases in vascular permeability, mast cell activation, and sneezing induced by nasal challenge with antigen. All studied antihistamines reduced sneezing, indicating that they all effectively antagonize histamine after its release. In addition, terfenadine and topically administered azatadine blocked the release of histamine. Studies with cetirizine and azelastine revealed that these antihistamines significantly reduced sulfidopeptide leukotriene levels. Terfenadine and azelastine also reduced kinin production. These results confirm that antihistamines are effective in reducing sneezing and, in some cases, vascular permeability. The findings of these studies also illustrate that the various antihistamines have multiple and different mechanisms of action that may have implications for their clinical uses.

From a series of amide analogs of the histamine H1 antagonist, azatadine, a potent, orally active, dual platelet-activating factor (PAF) and histamine antagonist, Sch 37370, namely 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo- [5,6]cyclohepta[1,2-b]pyridin-11-ylidine)piperidine, was discovered. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets in vitro (IC50 = 0.6 microM), and in vivo inhibits PAF- and histamine-induced bronchospasm in guinea pigs with ED50 values of 6.0 and 2.4 mg/kg p.o., respectively. Sch 37370 is expected to be more efficacious than single mediator antagonists in allergic diseases, such as asthma.

Tricyclic antihistaminics have relatively few side-effects compared to other agents that enhance the susceptibility to chloroquine of chloroquine-resistant strains of Plasmodium falciparum. Their efficacy was tested in vitro against resistant and sensitive culture-adapted strains of P. falciparum. Isobologram analysis showed that both cyproheptadine and azatadine exert a marked synergistic action on chloroquine against chloroquine-resistant, but not against chloroquine-sensitive, strains of parasites. Cyproheptadine was about twice as effective as azatadine in reversing chloroquine resistance. Loratadine had no effect on chloroquine against both resistant and sensitive strains of parasites. Our in vitro study showed that cyproheptadine and azatadine may be promising candidates for potentiating chloroquine against resistant malaria parasites.

The efficacy and safety of loratadine 10 mg once daily were compared with azatadine 1 mg twice daily in controlling symptoms of seasonal allergic rhinitis. The study was a randomized, double-blind, parallel-group design involving 34 patients receiving either loratadine or azatadine for 14 days. Both treatments were effective in relieving the histamine-mediated symptoms of seasonal allergic rhinitis. At baseline, 100% and 93% of the patients in the loratadine and azatadine treatment groups, respectively, had moderate or severe symptoms of disease; at endpoint of treatment 80% of the patients in the loratadine treatment group and 92% of those in the azatadine treatment group had mild or no disease symptoms. Sedation was reported by fewer patients in the loratadine treatment group than in the azatadine group. Thus loratadine is an effective and safe antihistamine when given once daily for the symptomatic relief of seasonal allergic rhinitis.

The inherent blood schizontocidal activities of five antihistaminic compounds, cyproheptadine hydrochloride (CYP), ketotifen hydrogen fumarate (KET), pizotyline hydrogen maleate (PIZ), azatadine maleate (AZAT) and loratadine (LOR) were examined against the following organisms: chloroquine-sensitive (CS) Plasmodium berghei and chloroquine-resistant (CR) P. yoelii ssp. NS in mice; and CS Tak 9 clone 96 and CR K1 strain of P. falciparum in vitro. Chloroquine, verapamil and desipramine were used as comparison standards. CYP, KET, PIZ were active against the CS strain in vivo with ED90 levels between 20 and 30 mg kg-1 (given sc daily for four days). They were slightly more active against the CR strain. AZA was active, but much less so than the other compounds. LOR, verapamil and desipramine were inactive in vivo at the doses tested. Against CS P. falciparum in vitro, all five antihistaminics and desipramine were active at EC50 concentrations ranging from about 50-80 mumol l-1, while verapamil was only active at 175 mumol l-1. Against the CR strain of this parasite, CYP, PIZ and LOR were slightly more active than against the CS strain, but KET, AZAT, desipramine and verapamil were significantly less active. The action of all these compounds in combination with chloroquine was then examined both in vivo and in vitro. The ability of verapamil and desipramine to reverse chloroquine resistance in vitro was confirmed, but only a low level of reversal was seen with these compounds in vivo. However, CYP, KET, PIZ and AZAT produced a marked reversal of chloroquine resistance both in vivo and in vitro. The implications of these observations in relation to further laboratory and clinical research are discussed.

Antigen and cold dry air were used to challenge the upper and lower airways, skin, and conjunctiva. In each of these four systems an immediate and late-phase reaction to antigen is well characterized. Although the pattern of mediator release is different in these four areas, the degree of infiltration of basophils and eosinophils in the late-phase reaction appears to be constant. Of a number of drugs that can influence these mediators and cell responses, the steroids represent a typical mode of action. Steroids block the late-phase response and ablate the eosinophil and basophil infiltration. Although the effects of antihistamines appear to be similar, they do not appear to be caused by H1 antagonism; the mechanism of their action is unknown. This discussion will focus on these non-H1 antagonist effects of antihistamines in four challenge models, particularly the upper airways and skin.

Fifty-six patients with ragweed seasonal rhinitis were challenged intranasally with ragweed. A clinical score (0-12)--including measurements of rhinomanometry, secretions, and sneezes--was generated. Each patient then received either azatadine (A), terfenadine (T), astemizole (AS), or nothing (control), for 1 week. Repeat challenges revealed changes in clinical score with A 3.6 (P less than .01), AS 3.1 (P less than .02), and T 2.7 (P less than .05). All three antihistamines similarly inhibited the nasal provocation response to ragweed.

A nasal antigen challenge model of allergic individuals was used to evaluate whether antihistamines could inhibit human mast cell and basophil mediator release in vivo. In placebo-controlled trials, topically applied azatadine base, a tricyclic antihistamine with in vitro antirelease action, effectively reduced symptoms and mediator levels in nasal lavage fluids after antigen challenge, suggesting mast cell inhibition. Both terfenadine and cetirizine, systemically administered antihistamines, were clinically effective in reducing sneezing and changes in vascular permeability. Only terfenadine significantly reduced histamine in antigen-induced nasal secretions. However, cetirizine did reduce the level of leukotriene C4 in these fluids. These results indicate that some antihistamines may be capable of suppressing mediator release from nasal mast cells. The significance of this property in those compounds' overall clinical effect is unclear because of their other concomitant activities.

Intravenous injection of arabinogalactan or dextran together with pontamine sky-blue dye into mice increased vascular permeability and led to marked blueing of the ears. Arabinogalactan caused a rapidly progressing ear blueing (maximal coloration 20-30 min after injection). This response was suppressed by pretreating the animals with the histamine H1-antihistamines levocabastine and loratadine. In contrast, dextran induced a slowly evolving ear inflammation (maximal coloration 60-90 min after injection), which was blocked by the 5-HT-serotonin antagonists cinanserin, metergoline and ritanserin. Furthermore, the dextran reaction was inhibited by the lipoxygenase (LO)/cyclooxygenase (CO) inhibitors BW540C, BW755C and phenidone and by the specific 5-LO inhibitor AA-861. Both arabinogalactan and dextran responses were inhibited by aprotinin, a kallikrein inhibitor, and the mixed H1/5-HT antagonists astemizole and azatadine. The inflammogenic activity of the polysaccharides was not affected by administration of the CO inhibitors indomethacin and suprofen, the thromboxane synthetase inhibitor dazoxiben, the H2-antihistamines cimetidine and ranitidine, the anticholinergics isopropamide or the PAF-antagonist L-652, 731. These data indicate the existence of distinctive endogenous molecules that mediate the pinnal extravasation reaction to both polysaccharides: histamine for arabinogalactan, serotonin and lipoxygenase-derived arachidonic acid metabolites for dextran.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosages of the nonsedating histamine H1-receptor antagonists terfenadine, astemizole, loratadine, and acrivastine are reviewed. Terfenadine and astemizole are chemically unrelated to histamine H1-receptor antagonists such as diphenhydramine and chlorpheniramine. Loratadine is structurally related to the antihistamine azatadine, and acrivastine is a side-chain-reduced metabolite of the antihistamine triprolidine. Like other histamine H1-receptor antagonists, they competitively block histamine receptor sites rather than inhibiting histamine release. All four drugs have relatively long half-lives and are rapidly absorbed after oral administration. Terfenadine, astemizole, and loratadine are metabolized extensively in the liver; terfenadine and astemizole are both 97% protein bound. Terfenadine 60 mg twice daily has been shown to be as effective as conventional antihistamines for the treatment of seasonal allergic rhinitis. In clinical trials, astemizole 10 mg daily was comparable to or better than chlorpheniramine for treatment of chronic rhinitis. Both terfenadine and astemizole were effective for treatment of chronic urticaria. For treatment of seasonal allergic rhinitis, loratadine combined with pseudoephedrine may be preferable to triprolidine-pseudoephedrine and acrivastine-pseudoephedrine combinations that require more frequent dosing. Acrivastine must be administered more frequently than the other nonsedating antihistamines. None of these four agents impairs psychomotor activity. Infrequently reported adverse effects include dry mouth, skin reactions, and weight gain. The absence of substantial sedative effects and the less-frequent dosing schedules make these agents good alternatives to the classic antihistamines for treatment of seasonal and chronic rhinitis and chronic urticaria.

A group of 32 patients with perennial allergic rhinitis sensitized exclusively to house dust and mites were evaluated for "in vivo" modifications (skin tests for histamine, house dust and mites) and "in vitro" alterations (seric IgE, specific IgE, histamine release curve to different concentrations of Dermatophagoides pteronyssinus and histamine release curve to this pneumoallergen after incubation with H1 receptor antagonists) to four antihistamines (astemizole, azatadine, mequitazine and terfenadine). The patients were divided into 4 groups of 8 and the "in vivo" and "in vitro" tests were performed on days -1, +15 and +30 of administration of these drugs. The reduction in the size of the wheal (prick test) for histamine when comparing days -1 and +15 and -1 and +30 was 69% and 79% (astemizole), 64% and 71% (azatadine), 69% and 64% (mequitazine) and 61% and 64% (terfenadine), respectively. The difference in the mean size of the wheal in mm2 for house dust, Dermatophagoides pteronyssinus and farinae was statistically significant (p less than 0.001) except when comparing the results obtained for mequitazine on days -1 and +15. This was also the case on days -1 and +30 for terfenadine. The values of the serum IgE and specific IgE did not attain statistical significance (p greater than 0.05) in the various tests carried out. After incubation with H1 receptor antagonists an inhibition curve of the histamine release in the presence of Dermatophagoides pteronyssinus was obtained. The inhibition of this curve on day -1 was higher for terfenadine and mequitazine than for azatadine and astemizole.(ABSTRACT TRUNCATED AT 250 WORDS)

Loratadine is a long acting antihistamine which has a high selectivity for peripheral histamine H1-receptors and lacks the central nervous system depressant effects often associated with some of the older antihistamines. Results from controlled clinical trials have shown that loratadine (usually 10mg once daily) is a well-tolerated and effective antihistamine which will be beneficial in patients with allergic rhinitis and chronic urticaria. It was found to be significantly superior to placebo, faster acting than astemizole and as effective as usual dosages of terfenadine, clemastine, mequitazine and azatadine in eliciting relief of symptoms. Importantly, loratadine is associated with a lower incidence of sedation than azatadine, clemastine, chlorpheniramine and mequitazine. Thus, loratadine, with its convenience of once daily administration, will be a useful addition to those drugs currently available for the treatment of patients with allergic diseases in whom a histamine H1-receptor antagonist is indicated. Indeed, it is likely to find a place as one of the newer 'agents of choice' in this setting.