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At least 865 records · Page 48Linked to original sources
PubMed2001

Deleterious effects of IL-9-activated mast cells and neuroprotection by antihistamine drugs in the developing mouse brain.

Elevated mean IL-9 serum levels have been observed in human neonates who will later develop cerebral palsy. In earlier studies, using a newborn mouse model of excitotoxic lesions mimicking those described in human cerebral palsy, we found that IL-9 pretreatment exacerbated brain damage produced by intracerebral injections of the glutamatergic analog ibotenate. Among its different cell targets, the Th2 cytokine IL-9 is a mast cell growth and differentiation factor that can cause mast cells to release various substances including histamine. In the present study, we sought to determine whether the deleterious effects of IL-9 in our mouse model were mediated by mast cells through histamine release. All mouse pups were pretreated with intraperitoneal injections of IL-9 or saline between postnatal days (P) P1 and P5. Immunohistochemistry for murine mast cell protease-1 performed on P5 showed an increased density of labeled cells in the neopallium of IL-9-treated Swiss pups as compared with controls. Western blot analysis confirmed the increased murine mast cell protease-1 brain content of IL-9-treated Swiss mice. IL-9 pretreatment had no significant effect on ibotenate-induced excitotoxic brain lesions in mast cell-deficient P5 pups (WBB6F1/J kit(W/W-v)), whereas IL-9 exacerbated these lesions in the control littermates with normal mast cell populations. Finally, cromoglycate or antihistamine drugs significantly reduced ibotenate-induced brain lesions in IL-9-treated Swiss pups. Taken together, these data suggest that recruitment of cerebral mast cells with histamine release may contribute to the exacerbation of neonatal excitotoxic brain lesions produced by IL-9. Neuroprotective strategies targeting mast cells may be useful in some neonates at risk for cerebral palsy.

Animals↗
PubMed1999

Inhibitory effects of the antihistamines epinastine, terfenadine, and ebastine on potassium currents in rat ventricular myocytes.

We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (IK) and transient outward potassium current (Ito) of rat isolated ventricular myocytes, using a patch clamp technique. Terfenadine, ebastine and epinastine were found to inhibit IK with IC50 values of 5.96, 15.3 and 145 microM, respectively. Ito was suppressed by epinastine with an IC50 value of 69.5 microM. The order of arrhythmogenicity, assessed by the inhibition of IK, was ranked as terfenadine > ebastine > epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.

Animals↗
PubMed1996

Assessment of antihistaminic and antimuscarinic effects of optical isomers of ephedrine and methylephedrine by receptor binding assay in guinea pig ileal muscle.

Effects of optical isomers of ephedrine (EPH) and methylephedrine (MEP) on histamine H1-receptors and muscarinic receptors in guinea pig ileal muscle were investigated by radioligand binding assay and by measuring the mechanical response to histamine and acetylcholine. EPH and MEP inhibited the specific binding of [3H]mepyramine and [3H]quinuclidinyl benzilate (QNB) to microsomal fractions prepared from this tissue. The rank order of inhibitory potency of [3H]mepyramine and [3H]QNB binding was d-->l-isomer and l-->d-isomer, respectively. Furthermore, the rank order of antagonistic potency in the mechanical response study was the same as that in the binding study. d-MEP competitively antagonized histamine-induced contraction (pA2 value; 5.14). These results suggest that each isomer of EPH and MEP has a distinct affinity for histamine H1-receptors and muscarinic receptors in guinea pig ileal muscle. The antihistaminic and antimuscarinic activity of these compounds may be largely attributed to competition at receptor sites. In addition, it is suggested that d-MEP exhibits a competitive antagonist activity for the histamine H1-receptor.

Acetylcholine↗
PubMed1989

Quantitative structure-activity relationships of H1-antihistaminic benzimidazole derivatives.

The quantitative structure-activity relationships (QSAR) of 2-(4-substituted-1-piperazinyl)benzimidazole derivatives for antihistaminic activity were examined. Taking into consideration the specific conformations of some derivatives, a significant correlation was obtained using Verloop's STERIMOL parameters B3 and L of the substituent at the 1-position of the benzimidazole nucleus. The results indicated that the derivatives having a substituent with a small breadth and an appropriate length at the 1-position showed potent activity. From the results, a model of the binding site is proposed. The QSAR of side effects (anticholinergic activity and central nervous system depressive effect) were also examined and the results showed that a sterically small substituent at the 1-position was required to decrease side effects.

Animals↗
PubMed1994

Synthesis and structure-activity relationships of antiallergic N-[4-[4-(1H-indol-3-yl)piperidinoalkyl]-2-thiazolyl]alkanamides possessing both antihistaminic and anti slow-reacting substance (SRS) activities.

A series of N-[4-[4-(1H-indol-3-yl)piperidinoalkyl]-2- thiazolyl]alkanamide derivatives were synthesized and tested for in vivo antianaphylactic activity and in vitro anti slow-reacting substance (SRS) activity. Among the compounds synthesized, N-[4-[4-(1H-indol-3-yl)piperidinomethyl]-2- thiazolyl]propanamide (7) was the best balanced compound (antianaphylactic activity, ED50 = 0.92 mg/kg p.o.; anti-SRS activity, IC50 = 0.89 microgram/ml). Regarding the biological activities of 7, we ascribe the antianaphylactic activity to its potent antihistaminic activity and the anti SRS activity to the inhibition of 5-lipoxygenase.

Amides↗
PubMed2002

In vivo evidence for a lack of central effect of ebastine, an antihistaminic agent, in rats: a microdialysis study.

The effects of ebastine and its active metabolite carebastine on brain dopamine uptake and the accessibility to brain were compared with those for a classical antihistaminic agent chlorpheniramine by using the microdialysis technique. Both carebastine and chlorpheniramine potently inhibited brain [(3)H]dopamine uptake and increased the extracellular concentration of dopamine in the striatum after local perfusion via microdialysis probes, although systemic injection of ebastine but not chlorpheniramine did not change the dopamine level. These findings suggest that neither ebastine nor carebastine affects central dopamine metabolism because of a limited access to brain, in spite of having a potent inhibitory action on neuronal dopamine uptake.

Animals↗
PubMed1995

Effect of antihistamines, disodium cromoglycate (DSCG) or methysergide on post-irradiation cerebral blood flow and mean systemic arterial blood pressure in primates after 25 Gy, whole-body, gamma irradiation.

Exposure to ionizing radiation causes hypotension, cerebral ischemia and release of histamine (HA) and serotonin (5-HT). To investigate the relationship among these responses, rhesus monkeys (Macaca mulatta) received physiological saline (i.v.), disodium cromoglycate (DSCG), antihistamines (AH, mepyramine and cimetidine), or methysergide (METH), then were given 25 Gy whole-body irradiation. Monkeys receiving DSCG, AH or METH had higher post-irradiation mean arterial blood pressure (MBP) than saline-treated controls. Compared to levels in controls, post-irradiation hippocampal blood flow (rCBF) levels were higher in monkeys receiving DSCG, AH or METH. Treatment with the 5-HT2 receptor antagonist methysergide was the most effective in maintaining both rCBF and MBP after irradiation. Results support the hypothesis that the irradiation-induced cerebral ischemia and, to some extent, the hypotension is mediated by serotonin through 5-HT2 receptor sites.

Animals↗
PubMed1999

Cardiac effects of ebastine and other antihistamines in humans.

The electrocardiographic effects of ebastine and its active metabolite, carebastine, have been studied alone and in relevant drug-interaction studies in various patient populations. The overall cardiac tolerability of ebastine is excellent. In ebastine dose-ranging studies in adults and children, there were no meaningful dose-related changes in the QTc interval. At high doses of ebastine (5 to 10 times the recommended dose), a modest 10.3 msec increase in QTc was observed. Recommended doses of ebastine had no meaningful effect on QTc in the elderly or in patients with renal or hepatic insufficiency. Interaction studies involving ebastine with ketoconazole revealed a significant increase in the serum ebastine concentration and in the elimination half-life of ebastine, with a modest 18.1 msec increase in QTc (approximately 10 msec above ketoconazole alone) and a plateau QTc-ebastine relationship at higher ebastine levels. Similar, though more minor, QTc findings were observed during coadministration of ebastine with erythromycin. No QTc effects were noted when ebastine was administered with theophylline, and the QTc was similar when ebastine was administered with or without food. These findings indicate that ebastine is well tolerated and, in contrast to terfenadine and astemizole, has no clinically meaningful effect on the QTc interval even at high serum concentrations. As with other 'safe' antihistamines, which have shown similar modest increases in QTc when coadministered with ketoconazole, caution should be exercised when administering ebastine to patients having the long QT syndrome or hypokalaemia, and in patients receiving azole antifungals or macrolide antibacterials.

Aged↗
PubMed2005

Pharmacological management of allergic rhinitis in the elderly: safety issues with oral antihistamines.

An increasing number of elderly persons in our society experience allergic rhinoconjunctivitis. Different agents are used in the pharmacological treatment of allergic rhinitis, with histamine H1 receptor antagonists (antihistamines) being the most frequently prescribed class. However, drug therapy of aged persons differs to a degree from that in other age groups primarily because of quantitative pharmacotherapeutic problems. The main problems are co-morbidities and polymedication, which may lead to drug-drug interactions. H1 receptor antagonists block the action of histamine at specific receptors and are available for both topical and systemic administration. First-generation H1 receptor antagonists are lipophilic and therefore may cross the blood-brain barrier; they also lack specificity for the H1 receptor. Second-generation H1 receptor antagonists have reduced capacity to cross the blood-brain barrier and greater specificity for the H1 receptor. Use of first-generation H1 receptor antagonists in the elderly should be considered carefully because of the large number of adverse effects and potential for interactions with these agents. Second-generation H1 receptor antagonists such as desloratadine, levocetirizine and ebastine provide good selective H1 receptor blockade without anticholinergic or alpha-adrenoceptor antagonist activity. Furthermore, they inhibit proinflammatory cytokines and are safe. Second-generation H1 receptor antagonists also offer therapeutic possibilities in patients with severe liver and/or renal dysfunction.

Administration, Oral↗
PubMedDate not supplied

Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines).

This article reviews clinical pharmacokinetic data on the H1-receptor antagonists, commonly referred to as the antihistamines. Despite their widespread use over an extended period, relatively little pharmacokinetic data are available for many of these drugs. A number of H1-receptor antagonists have been assayed mainly using radioimmunoassay methods. These have also generally measured metabolites to greater or lesser extents. Thus, the interpretation of such data is complex. After oral administration of H1-receptor antagonists as syrup or tablet formulations, peak plasma concentrations are usually observed after 2 to 3 hours. Bioavailability has not been extensively studied, but is about 0.34 for chlorpheniramine, 0.40 to 0.60 for diphenhydramine, and about 0.25 for promethazine. Most of these drugs are metabolised in the liver, this being very extensive in some instances (e.g. cyproheptadine and terfenadine). Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg (for astemizole, brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine and triprolidine), while their elimination half-lives range from about 3 hours to about 18 days [cinnarizine about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole and its active metabolites about 7 to 20 days (after long term administration); flunarizine about 18 to 20 days]. They also have relatively large apparent volumes of distribution in excess of 4 L/kg. In children, the elimination half-lives of chlorpheniramine and hydroxyzine are shorter than in adults. In patients with alcohol-related liver disease, the elimination half-life of diphenhydramine was increased from 9 to 15 hours, while in patients with chronic renal disease that of chlorpheniramine was very greatly prolonged. Little, if any, published information is available on the pharmacokinetics of these drugs in neonates, pregnancy or during lactation. The relatively long half-lives of a number of the older H1-receptor antagonists such as brompheniramine, chlorpheniramine and hydroxyzine suggest that they can be administered to adults once daily.

Astemizole↗
PubMed1991

Levocabastine. A review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis.

Levocabastine is a long acting, highly potent and selective histamine H1-receptor antagonist, which has been developed for nasal and ocular administration. In controlled trials performed to date levocabastine was effective and well tolerated in the treatment of allergic rhinitis and allergic conjunctivitis. Comparative studies have demonstrated that levocabastine is superior to placebo and at least as effective as sodium cromoglycate (cromolyn sodium) in alleviating symptoms associated with seasonal allergic conditions. Although levocabastine appears to be less effective than the topical corticosteroid beclomethasone with regard to relieving runny and blocked nose, further comparative trials between these 2 agents would be desirable. Similar to other antihistamines, levocabastine provides minimal relief of nasal blockage, but this symptom is believed to be mediated by receptors other than histamine H1. The prompt onset of antiallergic activity after application differentiates levocabastine from the reference topical antiallergic, sodium cromoglycate, which has an onset of efficacy characterised by a lag period, thereby necessitating maintenance treatment. The incidence of adverse effects associated with levocabastine therapy is low and is similar to that observed with placebo and sodium cromoglycate. Levocabastine provides prophylactic protection as well as acute relief from nasal and ocular symptoms in patients with seasonal allergic disorders. With the ever increasing trend towards topical therapy for the treatment of allergic rhinitis and allergic conjunctivitis, levocabastine is a useful addition to the range of drugs currently available. Possible avenues for additional research should include determining whether the antiallergic efficacy of topical levocabastine is superior to that of oral agents such as astemizole and terfenadine, and whether topical therapy is indeed preferred, considering the relative ease of administration of effective oral antiallergic agents.

Administration, Topical↗
PubMed1993

New data concerning the antianaphylactic and antihistaminic activity of nimesulide.

The time to respiratory crisis in ovalbumin-sensitised guinea-pigs following exposure to aerosol administered antigen was dose dependently delayed by inhalation of nimesulide (0.1% to 1%), whereas indomethacin had no effect. At the same time, nimesulide significantly reduced blood histamine concentrations, in contrast to the slight increase observed with indomethacin. In human bronchial muscle preparations, nimesulide, but not indomethacin, antagonised H1-histamine-receptor activation by histamine and was without effect on acetylcholine-induced responses. Bronchoconstriction was also elicited in anaesthetised guinea-pigs by intravenous acetaldehyde (5% in saline, 1 ml/kg). This effect, which is paralleled by a rise in blood histamine concentrations, was significantly attenuated by inhaled nimesulide (0.1% to 1%), but not by indomethacin (1%). These data, which further support the antihistaminic and antiallergic activity of nimesulide, may have therapeutic relevance in patients who are affected by inflammation of the respiratory tract and who also have a history of allergic bronchoconstriction.

Anaphylaxis↗
PubMed2004

Cost-benefit analysis of first-generation antihistamines in the treatment of allergic rhinitis.

BACKGROUND: The majority of individuals with allergic rhinitis in the US take first-generation antihistamines (FGAs). Although FGAs have been proven effective in alleviating allergic rhinitis symptoms, they have been associated with an increased risk of motor vehicle, aviation and occupational injuries and deaths, reduced productivity and impaired learning. OBJECTIVE: The objective of this analysis was to quantify the total costs and benefits of FGA use in the US from the societal perspective. METHODS: We used a decision-analytic model to quantify the annual societal costs and benefits of treatment with FGAs compared with the hypothetical alternative of no treatment for the population of individuals with allergic rhinitis and taking FGAs in the US in 2001. The benefit associated with FGA use was estimated using the willingness-to-pay framework and projected to the US population using published estimates of the prevalence of allergic rhinitis. The costs of FGA-associated sedation included lost productivity and the direct and indirect cost of unintentional injuries (including motor vehicle, occupational, public and home injuries and fatalities). The incidence of injuries and fatalities associated with FGA use was estimated using the risk of injury attributable to the sedentary effects of FGAs in the allergic rhinitis population. To evaluate uncertainty in the model assumptions, a probabilistic sensitivity analysis was conducted using Bayesian second-order Monte Carlo simulation. Costs and benefits are expressed in 2001 US dollars, using a 3% discount rate. RESULTS: Based on current utilisation, the total societal benefit (95% credible interval) associated with the use of FGAs for the treatment of allergic rhinitis was US 7.7 billion dollars (US 1.3 billion dollars to US 21 billion dollars). The societal cost of purchasing FGAs was only US 697 million dollars. However, the societal cost of FGA-associated sedation was US 11.3 billion dollars (US 2.4 billion dollars to US 50.8 billion dollars). The annual societal net benefit of FGA use for the treatment of allergic rhinitis in the US was -US4.2 billion dollars (-US 36 billion dollars to +US 0.296 billion dollars). The net benefit was negative in 97% of the 10,000 Monte Carlo simulations. CONCLUSIONS: The societal benefits of FGA use in alleviating the symptoms of allergic rhinitis are significant. However, based on the assumptions, probability distributions and parameter estimate ranges used in the current model, it is very likely that the costs associated with sedation exceed the benefits of FGA use in the US. The cost of FGA-associated sedation is comparable to estimates of the cost of all medical care expenditures on respiratory conditions in the US (US 12.1 billion dollars to US 31.3 billion dollars) [1996 values] and provides compelling evidence of the economic burden of sedation associated with FGA use.

Accidents↗
PubMed2002

Mechanisms of antihistamines and mast cell stabilizers in ocular allergic inflammation.

Mast cells play a central role in allergic reactions and inflammation. Successful anti-allergic therapies have typically targeted mast cell mediators, particularly histamine. Antihistaminic compounds interact with the various histamine receptors found on many cells, whereas other compounds such as disodium cromoglycate, are referred to as mast cell stabilizers, as they inhibit degranulation. Some of the most successful compounds developed recently are dual-action, in that they have both anti-histaminic and mast cell stabilizing activities. Recent trends in pharmaceutical intervention, however, have been focused on the secondary effects of mast cell mediators on epithelial cell adhesion molecule expression and mediator release in the process of allergic inflammation. Since, the ocular mucosa is highly exposed to environmental allergens it is commonly involved in allergic reactions and, as such, has been a useful and accessible model in which to test new therapies in vivo. These ocular allergen provocation studies permit analysis of ocular surface cells and evaluation of tear film mediators. Furthermore, techniques to purify conjunctival mast cells have facilitated the study of the effects of mast cell stabilizing compounds on other mast cell mediators, such as cytokines, and the direct effects of mast cell mediators on epithelial cells in vitro. This review will discuss current understanding of how anti-histamines and mast cell stabilizers work, particularly in the context of molecular mechanisms of ocular allergic inflammation.

Animals↗
PubMed2006

Inhibition of the antigen provoked nasal reaction by second-generation antihistamines in patients with Japanese cedar pollinosis.

BACKGROUND: Epinastine hydrochloride and fexofenadine hydrochloride, the second-generation antihistamines, are largely used in the indication of allergic rhinitis in Japan. The purpose of this study was to compare the protective efficacy of epinastine hydrochloride or fexofenadine hydrochloride using a nasal provocation test with Japanese cedar pollen allergen. METHODS: A single-dose, placebo-controlled, single-blind crossover clinical study was conducted in patients with Japanese cedar pollinosis. The pollen exposure was done by the antigen provocation by disc method and involved repeated provocation five times per day. RESULTS: Among the active agents studied-epinastine hydrochloride and fexofenadine hydrochloride-epinastine hydrochloride significantly decreased the number of sneezing attacks and the quantity of nasal discharge for 3 hours after drug administration compared with placebo, a finding supported by the quantity of nasal discharge in the nasal findings. In this study, fexofenadine hydrochloride showed no significant difference compared with placebo. CONCLUSIONS: This study demonstrates better protection with epinastine hydrochloride than with fexofenadine hydrochloride or placebo in a nasal provocation test with Japanese cedar pollen allergen.

Adolescent↗
PubMed1985

The development of a new antihistamine: astemizole.

As compared with reference antihistamines, the action of astemizole is characterized by several unusual properties: highly pronounced and very specific histamine H1 antagonism, long duration of action and absence of central and sedative effects.

Administration, Oral↗
PubMed1991

N(+)-glucuronidation of aliphatic tertiary amines, a general phenomenon in the metabolism of H1-antihistamines in humans.

1. Representative drugs of the various structural classes of H1 antihistamines were chosen for study. The drugs chosen (class name in parentheses) were chlorpheniramine maleate and pheniramine maleate (alkylamines), diphenhydramine hydrochloride and doxylamine succinate (ethanolamines), pyrilamine maleate and tripelennamine hydrochloride (ethylenediamines), promethazine hydrochloride (phenothiazine), cyclizine lactate (piperazine) and terfenadine (miscellaneous). In each case oral dose(s) were administered over no more than 6 h to two healthy volunteers and the total urine collected for 36 h. 2. Metabolites from urine were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis in the fast atom bombardment mode. The structure of each metabolite identified as a quaternary ammonium-linked glucuronide metabolite was confirmed by direct comparison of its mass spectrum and chromatographic behaviour with that of a synthetic authentic compound. 3. For eight of the nine drugs studied, metabolism by the N(+)-glucuronidation pathway was observed in each of the volunteers. Terfenadine was the exception. 4. The amount of each N(+)-glucuronide in the urine was estimated by h.p.l.c. analysis. The mean proportion of dose excreted as the metabolite was 14.3%, 6.5% and 4.0% for cyclizine, tripelennamine and diphenhydramine, respectively. Promethazine was the only case where the N(+)-glucuronide accounted for less than 1.0% of the administered dose in both volunteers examined.

Adult↗
PubMed1978

Tardive dyskinesia and antihistamines.

A case of tardive dyskinesia due to the prolonged administration of antihistamines is reported. Clinical features are discussed, as well as the alleviation of these by haloperidol.

Dyskinesia, Drug-Induced↗