ANTIHISTAMINICOS H3 PDF

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In a consensus group on new-generation antihistamines CONGA defined the characteristics required for a third-generation H 1 antihistamine as there had been much controversy about this issue since the early s. One of the antihistamines that had been claimed to belong to such a group is the second-generation antihistamine, ebastine.

The objective of this review is to analyze the pharmacology of ebastine, in light anthistaminicos the CONGA recommendations for the development of new-generation antihistamines: Ebastine seems to have anti-inflammatory properties that help to ameliorate nasal congestion, though this has not yet been conclusively demonstrated. Its pharmacological—therapeutic profile does not differ greatly from that of other second-generation antihistamines.

Its cardiac safety has been widely assessed and no cardiac toxicity has been found at therapeutic antihustaminicos despite initial concerns.

The risk of potentially relevant drug interactions has been investigated antihistaminios ruled out. Ebastine does not produce sedation at therapeutic doses and drug interaction studies with classical CNS depressants have anntihistaminicos demonstrated a synergistic effect.

Pharmacologically, ebastine is an H 1 inverse agonist. Perhaps the answer to the quest for new-generation antihistamines lies not only in H 1 but in a combined approach with other histamine receptors. Allergic diseases are among the commonest causes of g3 ill health. Throughout the last decades, these drugs have been clearly differentiated in first- and second-generation antihistamines.

First-generation antihistamines, such as chlorpheniramine, diphenhydramine, promethazine, and hydroxyzine, are characterized by their high H 1 receptor blocking power, and in spite of their side-effect profile they are still widely used. Second-generation antihistamines, such as terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, levocetirizine, ebastine, rupatadine, and bilastine, do not penetrate the blood—brain barrier and so provoke minimal central nervous system CNS effects.

They have greater receptor specificity, with little or no affinity for muscarinic cholinergic receptors.

In addition, some second-generation antihistamines exhibit properties, such as anti-inflammatory and analgesic activity, on systems other than H 1 receptors. Although second-generation antihistamines have been a clear step forward in the treatment of allergic diseases, they have not been devoid of problems. Cardiotoxicity has been a major issue, provoking the withdrawal of terfenadine and astemizole, for example, from the market 1011 and introducing the requirement of formal cardiac safety assessment in the drug development paradigm.

Antihistaminico : Antihistaminicos – Medicamentos para la alergia

In spite of the knowledge we have acquired over the past few decades, the search for the optimal antihistamine drug continues. As a antihjstaminicos, ina consensus group on new-generation antihistamines CONGAled by Dr Holgate, provided recommendations on the development of new antihistamines.

To date, no antihistamine drug has fulfilled all the criteria proposed by Holgate et al. In this review we look critically at the information available on ebastine in the light antjhistaminicos the CONGA criteria and present current information on the development of new generation antihistamines.

Ebastine 4-diphenylmethoxy[3- 4-terbutylbenzoyl propyl] piperidine, Las-W, CAS 1819 is a long-acting, second-generation, selective H 1 -receptor inverse agonist, discovered and developed by Almirall SA.

After over 18 years of use in more than 80 countries around the globe, the efficacy and safety of ebastine has been extensively demonstrated. Its clinical indications include the treatment of seasonal 20 — 24 and perennial allergic rhinitis 2526 and antihjstaminicos idiopathic urticaria.

The efficacy of H 1 antihistamines in allergic disorders has traditionally been attributed to their effects on the histamine receptor. The allergic cascade is a complex response that is composed of three distinct zntihistaminicos phases: H 1 receptor-dependent mechanisms involve stabilization of the histamine receptor in its b3 conformation.

Both are activated by the H 1 receptor in an agonist-dependent manner, and this activation is inhibited by various H 1 -receptor antihistamines. H 1 receptor-independent mechanisms, however, inhibit histamine release from mast cells and basophils.

Antihistamine

They also inhibit inflammatory cell activation, and possibly eicosanoid generation and oxygen free radical production. The clinical relevance of this effect is still under discussion due to the fact that very high drug concentrations are needed and it is unlikely that these concentrations are achieved with therapeutic doses.

Modulation of adhesion molecule expression is important because molecules, such as inter-cellular adhesion molecule 1 ICAM-1 influence the activity of eosinophils, mast cells, macrophages and lymphocytes, all of which play key roles in the allergic reaction. In vitroit has been shown that antihistamines reduce ICAM-1 expression on nasal and conjunctival epithelial cells, and it has also been observed that they reduce inflammatory infiltration after allergen challenge and during natural exposure.

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One of these involves the H 1 receptor referred to earlier in this articleand the other is independent from this receptor. These authors also provided evidence that azelastine represses AP-1 activity via the same mechanisms.

The inhibition of mediator release is another mechanism whereby antihistamines affect the allergic inflammatory reaction, independently of their anti- H 1 activity. In vitro studies have consistently established that H 1 antihistamines inhibit the release of mediators from both mast cells and basophils. Nevertheless, these results are difficult to replicate in vivo as 3- or 4-fold therapeutic concentrations of antihistamines would be needed.

The inflammatory modulation of ebastine has been reported in various in vitroand in vivo studies. Regarding the secretion of cytokines, Nori et al evaluated the effect of ebastine on the production of T helper 2 T h 2 type cytokines. Serum eosinophil cationic protein ECP levels, peripheral blood eosinophil counts, morning peak expiratory flow rate PEFR and thresholds for airway hyper-responsiveness were determined before and after treatment.

PEFR was significantly increased in the atopic patients No changes were found in the nonatopic patients and there was no change in the threshold for airway hyper-responsiveness. The results of another in vivo study by Ciprandi et al have been published recently. Clinical changes were assessed by subjective total nasal symptom score and visual analogue scales [VAS] and objective rhinomanometry evaluations.

Nasal obstruction is the leading symptom in patients with allergic rhinitis, with allergic inflammation, mucosal congestion and mucus hypersecretion playing key roles. The decongestant activity of ebastine was first suggested by Ratner et al 52 after they performed 3 double-blind, randomized, placebo-controlled, parallel group studies that compared ebastine 20 mg, ebastine 10 mg, loratadine 10 mg and placebo in the control of symptoms of ragweed-induced rhinitis.

Although the results showed that ebastine at both doses reduced nasal congestion as compared to placebo, nasal congestion was measured subjectively ie nasal congestion symptom scores. Although a double-blind, randomized controlled trial with active comparators and placebo would be the most suitable design to obtain conclusive evidence, this pilot study showed that nasal obstruction can be affected in a positive way by antihistamine treatment with ebastine.

antihistaminicos by Moises Angel Ortega on Prezi

Presently available evidence indicates that some second antihistamlnicos antihistamines possess properties that modulate the allergic inflammatory cascade by means of H 1 receptor dependent and independent mechanisms. All in all, in vitroin vivo and clinical studies using subjective and objective measurements seem to indicate that ebastine possesses this characteristic and ameliorates nasal congestion to some degree.

However, to clarify this effect a clinical trial including a comparator devoid of modulator effect should be carried out. Until this piece of the puzzle is put in place we can not conclusively claim that ebastine complies with the first requirement exposed in the CONGA. Ebastine was initially conceptualized as the combination of the structural elements of the very potent, yet sedative antihistamine, diphenyl-pyraline and the less potent, but nonsedative, terfenadine.

The receptor-binding affinity and receptor-dissociation rate for antihistamines on peripheral H 1 receptors help to antihistaminiocs characterize novel anti-H 1 antihistajinicos drugs.

They also allow an appraisal of the likely in vitro potency at the H 1 receptor anntihistaminicos relationship to known standards, and provide potential information on duration of action. The binding characteristics of an H 1 receptor antihistamine determine the extent to which histamine can be blocked from binding to antihisgaminicos H 1 receptor.

These binding characteristics are an integral component for the efficacy and safety of an antihistamine. However, specific characteristics of an H 1 receptor antihistamine may influence its potency, and high in vitro H 1 binding activity does not necessarily imply good clinical efficacy because many other factors such as uptake, metabolism, and pharmacokinetics are also relevant.

Moreover, some H 1 receptor antihistamines may lack specificity and bind to other receptors, causing unwanted side effects. Ebastine has a potent and selective H 1 antihistamine activity, as assessed by in vitro and in vivo studies. Contrary to the properties of other antihistamines, the anticholinergic and anti-serotonergic properties of ebastine have proved to be negligible. In vitro potency has been demonstrated in a series of experiments performed by Almirall. Their results showed that ebastine inhibits histamine-induced contractions in an isolated ileum model.

Potency in vivo has mainly been studied in guinea pigs. In another in vivo study, ebastine reversed the changes in pulmonary resistance induced by leukotriene C 4 in anesthetized guinea pigs, whereas cetirizine and loratadine were devoid of activity in this model. Potency in humans can be assessed by evaluating distinct biomarkers that may be related to histamine activity. Examples of biomarkers in this setting are the wheal and flare response after a skin-prick test, the measurement of inflammatory mediators after nasal challenge with histamine or allergens, and the inhibition of histamine-induced brochospasm.

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The histamine wheal-and-flare response provides information on the preliminary efficacy of the H 1 receptor antihistamine following oral dosing and has been widely used. It is sometimes criticized, however, because it does not mimic the late phase response of the allergic process, mast cell degranulation, and inflammatory mediator release.

It has also been stated that it does not correlate with results in patients. This reduction reaches its peak around 6 to 12 hours after drug administration. In children, ebastine 5 and 10 mg has shown to reduce histamine-induced wheal and flare compared with baseline values for up to 28 hours. Overall, ebastine 10 mg has shown to be as effective at inhibiting the histamine-induced wheal response as several other antihistamines, whilst ebastine 20 mg proved to be more effective than others eg, loratadine, cetirizine, and fexofenadine.

The effect of ebastine has been also assessed by cutaneous and nasal challenge with allergens, and through the measurement of inflammatory mediators. The inhibitory effect of ebastine on wheal disappeared by day 4 after discontinuing treatment, and the effect on flare by day 3.

A marked inhibitory effect of ebastine was seen on the histamine-induced wheal surface area at 6 and 24 hours after treatment completion compared to placebo. There was no residual effect of ebastine compared to placebo 5 days after treatment discontinuation. The effect on inflammatory mediators has also been tested. Antonijoan et al performed two double-blind, double-dummy, randomized, placebo-controlled, 3-period crossover clinical trials 1462 to assess the pharmacodynamics of a fast-dissolving tablet FDT of ebastine.

This relatively new formulation facilitates administration to patients who have problems swallowing tablets and hard gelatine capsules, such as geriatric patients and those who are ill in bed or those who may not have access to water to aid swallowing. In these studies ebastine 10 mg in the first and 20 mg in the second study was compared with desloratadine 5 mg or placebo.

Besides assessing the inhibition of wheal response to cutaneous histamine challenge using a histamine skin-prick test, both included subjective assessments of itching, flare and pain by means of VAS, tolerability assessments, as well as acceptability and convenience evaluation, measured by a questionnaire. The main outcome was inhibition of the response to the histamine challenge, defined as the percentage reduction from baseline in the wheal area of the skin intradermal test conducted 24 hours after the fifth dose of study medication.

In the second trial 14 FDT ebastine 20 mgthe mean percentage reduction from baseline in wheal area 24 hours after 5 days of treatment was significantly greater with ebastine compared with desloratadine, and placebo These studies showed that, after 5 days of administration, inhibition of the response to histamine injection was significantly greater with FDT ebastine 10 and 20 mg than with desloratadine 5 mg.

As denoted by the authors, this test does not necessarily correlate with clinical responses. However, it is important to assess and compare the pharmacodynamic effects of antihistamines. Concerning the therapeutic index, evidence supports the notion that ebastine has a wide therapeutic index. The toxicology profile also showed that ebastine is free of toxic effects in animals, even at doses representing extremely high multiples of the recommended therapeutic dose in humans 0.

As well as all of the pharmacodynamic characteristics described above, ebastine has shown to be effective for the relief of symptoms in adults and adolescents with allergic rhinitis or chronic idiopathic urticaria. The efficacy of ebastine for the treatment of seasonal and perennial allergic rhinitis has been evaluated in five pivotal trials 20252664 — 66 and several supporting trials.

Four of the trials lasted 3 weeks and the other lasted 12 weeks. The goal was to show superiority of ebastine over placebo. Ebastine 10 and 20 mg were used. The primary goal of the comparative efficacy in supporting studies was to show the superiority of ebastine over other H 1 receptor antihistamines.

Overall, ebastine has shown superiority over placebo in the treatment of seasonal and perennial allergic rhinitis and ebastine 10 mg has shown to be at least as effective as loratadine 10 mg and cetirizine 10 mg at reducing symptoms in patients with allergic rhinitis, whereas ebastine 20 mg was generally more effective than the comparator antihistamines at the used dosages.

For chronic idiopathic urticaria, the efficacy of ebastine has been evaluated in 2 randomized, double-blind, controlled trials, one compared to placebo 2872 and the other to terfenadine and placebo.