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At least 469 records · Page 26Linked to original sources

PubMed2005

Histamine H1 receptor occupancy and pharmacodynamics of second generation H1-antihistamines.

The predictive efficacy of drugs in humans is frequently estimated from both a high affinity for their receptor as measured in vitro and a long plasmatic half-life. This is grossly misleading since one key parameter is missing: drug concentration at the receptor site in vivo. As a case study we compared the efficacies of three H(1) antihistamines in inhibiting histamine-induced wheal and flare in humans at two different time points with the above mentioned parameters. It is concluded that estimating in vivo receptor occupancy, which takes into account both the affinity of the drug for the receptor and its free plasma concentration, is a far better predictor for human pharmacodynamics and hence antihistamine potency, than considering in vitro affinity and plasmatic half-life only.

Animals↗

PubMed2003

Characteristics of the antihistamine effect of TAK-427, a novel imidazopyridazine derivative.

OBJECTIVE AND DESIGN: The characteristics of the antihistamine effect of the new antiallergic compound TAK-427 were investigated. MATERIALS AND METHODS: In vitro binding assay of [(3)H] pyrilamine was performed using recombinant human histamine H(1) receptors (rhH(1)R). In vivo studies were performed in male ICR mice or Hartley guinea pigs. Drugs were administered orally 1 h before examinations. Determinations were made of histamine-induced skin reaction, ex vivo measured radioligand binding to brain and lung H(1) receptors, pentobarbital-induced sleeping time, passive cutaneous anaphylaxis (PCA) reaction, and antigen-induced itch-scratch responses (ISRs). RESULTS: TAK-427 inhibited ligand binding to rhH(1)R with an IC(50) value of 17.3 nmol/l. TAK-427 inhibited histamine-induced skin reactions in guinea pigs and mice with an ID(50) value of 0.884 and 0.450 mg/kg, p.o., respectively; significant inhibition associated with 10 mg/kg of TAK-427 was still observed 24 h after dosing in guinea pigs. TAK-427 showed as high selectivity for peripheral H(1) receptors as terfenadine and epinastine did, which was evaluated by ex vivo measured radioligand binding. Even at 300 mg/kg, TAK-427 did not affect pentobarbital-induced sleeping time in mice. TAK-427 significantly inhibited PCA in mice and guinea pigs, and also inhibited antigen-induced ISRs in guinea pigs. CONCLUSIONS: These results suggest that TAK-427 may have a long-lasting antihistamine activity with minimum sedative side effect and suppress acute phase allergic reactions.

Algorithms↗

PubMed1996

[Antipruritic effect of antihistaminic and local anesthetic topical agents after iontophoretic histamine stimulation].

No adequate topical therapy is available for pruritus. As little is known about the local influence of antihistamines and topical anaesthetics on the pruritic effect of histamine, we studied these agents in 12 volunteers. The antipruritic effect of 15-min topical application of dimethindene maleate (Fenistil gel) and different agents (Optiderm, EMLA, Xylocaine-Salbe 5%) on subsequent focal histamine stimulus (20 mC) given by iontophoresis was evaluated. The results were compared with those of pretreatment with the corresponding placebo creams and observations on skin. Wheal and flare areas were evaluated planimetrically. Itch or pain ratings were entered on a scale every minute over a 24-min period. The examination also comprised alloknesis, i.e. elicitation of perifocal itch sensation by usually non-itch-inducing (e.g. mechanical) stimuli. Remarkably, all topically applied substances, regardless of antihistaminic or anaesthetic potential, reduced the area of alloknesis significantly. This is likely to be a result of diminished excitability of the cutaneous mechanoreceptors. Itching was significantly reduced by all active substances, including the placebo cream corresponding to Optiderm, which might be due to the presence of urea.

Adult↗

PubMed1998

[Effect of topical corticosteroids and topical antihistaminics on ciliary epithelium of human nasal mucosa in vitro].

A normal ciliary beat frequency of ciliated cells is necessary for the mucociliary clearance of the nose and paranasal sinuses. An in vitro investigation was performed to evaluate the influence of topical corticosteroids and antihistamines on the ciliary beat frequency of human nasal mucosa. The nasal sprays examined contained the corticosteroids budesonide or fluticasone propionate and the topical antihistamines azelastine or levocabastine. All tests were performed on cell cultures of human nasal mucosa during constant conditions. Three of the four nasal sprays tested contained benzalkonium chloride as preservative. An irreversible cessation of ciliary movement was observed in all cells exposed to nasal sprays containing benzalkonium chloride in a 50 per cent solution. The nasal spray containing budesonide was benzalkonium chloride-free and caused minor but fully reversible decreases in ciliary beat frequency after 20 min. As benzalkonium chloride can cause complete standstill of ciliary beat frequency in vitro in human nasal mucosa, we recommend that this preservative should not be used anymore in topical nasal medications.

Administration, Topical↗

PubMed1994

Risk of developing life-threatening ventricular arrhythmia associated with tefenadine in comparison with over-the-counter antihistamines, ibuprofen and clemastine.

An observational, historical cohort evaluation was performed to examine the hypothesis that terfenadine (Seldane) exposure increases the risk of developing life-threatening ventricular arrhythmias. The study population consisted of Medicaid recipients from 4 states that were included in the Computerized On-Line Medical Pharmaceutical Analysis and Surveillance System (COMPASS). The drug exposure period was defined prospectively as 30 days in all treatment cohorts. The primary end point was the development of life-threatening ventricular arrhythmias (ventricular tachycardia, fibrillation and flutter, and cardiac arrest and sudden death). The comparison cohorts included terfenadine (n = 181,672), over-the-counter antihistamines (n = 150,689), ibuprofen (n = 181,672) and clemastine (Tavist; n = 83,156). Over the exposure period, a total of 317 life-threatening ventricular arrhythmic events occurred, 244 of which were cardiac arrests. The incidence of total life-threatening ventricular arrhythmic events and cardiac arrests were more frequent in patients receiving over-the-counter antihistamines (relative risk 0.36) than in those receiving terfenadine, a finding that was consistent across all subgroups. There was no increased risk of life-threatening ventricular arrhythmias in the terfenadine cohort as compared with the ibuprofen cohort (relative risk 0.62), and in some analyses, the ibuprofen cohort had a significantly higher arrhythmic event rate. In all comparisons with the clemastine cohort, the terfenadine cohort had a statistically indistinguishable relative risk (1.08). Age, race, sex and cardiovascular risk were all considered in the adjusted relative-risk analyses. No baseline historical characteristic or imbalance of baseline medications explained the differences between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1978

The effects of an antihistamine and/or a glucocorticoid on the prolactin response to surgical procedures.

Prolactin (PRL) release in response to surgical stress has been demonstrated in a variety of species. Previous studies in rats indicate this response is blunted or blocked by pretreatment with either glucocorticoids or antihistamines. The present study was designed to investigate this phenomenon in man. Serum PRL levels before, during, and after major gynecologic surgery were measured in 20 women randomly assigned to one of four pretreatment regimens: (1) dexamethasone, (2) promethazine, (3) both agents, and (4) neither agent. Type of operation, preanesthetic medication, anesthetic agents, and estrogen status of patients were similar in all groups. Untreated controls exhibited the expected five- to tenfold increase in serum PRL concentration with surgery. Pretreatment with either dexamethasone or promethazine alone failed to suppress this response (in contrast to reported findings in the rat) and in fact promethazine appeared to cause an augmented response. However, patients given dexamethasone and promethazine together exhibited only a two- to threefold PRL increase, a significantly lesser response than that in any of the other groups. Thus, PRL release in response to general anesthesia and surgery is inhibited by the combination of an antihistamine (H-l) receptor antagonist and a glucocorticoid, whereas either agent alone has no suppressive effect.

Adult↗

PubMed1993

Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics.

Based on molecular cloning studies, five different muscarinic receptor subtypes exist: m1, m2, m3, m4, and m5. We determined the affinity and selectivity of binding for sixteen antidepressants, two of their metabolites, and three antihistaminics (H1) at these subtypes. Using Chinese hamster ovary cells (CHO-K1) transfected with genes for the human muscarinic receptor subtypes, we obtained equilibrium dissociation constants (Kds) from competitive radioligand binding studies with [3H]-quinuclidinyl benzilate ([3H]QNB) and membranal preparations of these cells. QNB was the most potent compound studied (Kd 30-80 pM). Mequitazine (Kd 6-14 nM) and amitriptyline (Kd 7-16 nM) exhibited the highest affinity among the antihistaminics and antidepressants, respectively. Among the antidepressants examined were the serotonin-selective drugs sertraline and fluoxetine, both of which displayed Kd values > 1 microM. The remaining antidepressants were moderate to weak antagonists with some eliciting no radioligand competition at high concentrations. The compounds studied showed no significant selectivity among the five cloned subtypes.

Animals↗

PubMed1986

Antihistamine, anticholinergic and cardiovascular effects of 2-substituted-4-phenylquinoline derivatives.

Eleven new derivatives of 4-phenylquinoline, having various substituents at the 2-position of the quinoline ring, were previously synthesized. The antidepressant activities of these derivatives were demonstrated by their antagonism to reserpine-induced hypothermia in mice. The ED50 values were found to be in the range of 12-42 mg/kg (imipramine is 21.0 mg/kg). In the present work, comparative studies of the effects of these new drugs on the cholinergic and histaminergic (H1) systems, as well as their effects on the cardiovascular system, are presented. Both imipramine and trazodone were utilized as standards representing typical and atypical antidepressant drugs, respectively. All these new compounds have very low antihistaminic (H1) activities, as compared to imipramine. In addition, a clear cut separation of the antidepressant activity from the antihistaminic (H1) activity was observed. These compounds have weak anticholinergic (atropine-like properties) activity as compared to imipramine, using the isolated guinea-pig ileum. Animal studies of the cardiac toxicity of these compounds showed reduced lethality for some of them as compared to imipramine. Arrhythmias commonly associated with imipramine were absent for most of these compounds. The effects of these compounds on the heart conduction were determined by electrocardiographic studies. Although some of these compounds do not interfere with heart conduction, as compared to imipramine most were inferior to trazodone. Correlation between the pharmacological activities and structural modifications of these derivatives has also been observed.

Acetylcholine↗

PubMed1990

H1 antihistamines interact with central sigma receptors.

Several antihistamines were evaluated for their ability to interact with sigma, muscarinic and histaminic H1 binding sites in rat brain preparations. All of the antihistamines were able to interact with the sigma site, as well as the other two sites. In addition, tripelennamine was found to elicit sigma-like behaviors when administered to rats. This affinity for the sigma site suggests that the compounds may elicit some of their undesirable CNS side effects via this interaction.

Animals↗

PubMed1989

Effects of antihistamines on centrifugal rotation-induced analgesia and conditioned flavor aversions.

Centrifugal rotation induces short lasting analgesia, as shown in tail flick tests conducted immediately afterwards, and apparently induces visceral upset that can support aversions for flavors ingested immediately beforehand, as indicated in later preference tests. Two experiments were performed with antihistamines to determine whether the analgesic and visceral effects of rotation were attributable to separate neurochemical systems. In each experiment four groups of rats were defined by factorial combination of UCS (rotation at 150 rpm vs. no rotation) and Drug (antihistamine vs. saline). In Experiment 1 the H1 blocker chlorpheniramine (20 mg/kg, IP) was found to be ineffective against analgesia and to block conditioned flavor aversions (CFAs). In Experiment 2 the H2 blocker cimetidine (100 mg/kg, IP) was found to have a nearly significant attenuating effect on analgesia and to have no effect on CFAs. The data support the idea that analgesia and visceral upset are attributable to separate mechanisms, both of which are activated by the same manipulations.

Analgesia↗

PubMed1985

Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole.

Antihistamines are being increasingly administered in combination with various other agents, with adverse drug reactions the frequent result. The present study consisted of two experiments. Experiment 1 examined the toxicological response of rats to nicotine tartrate (0.0, 2.0, 4.0, and 8.0 mg/kg) in combination with either of two H1-histamine receptor antagonists, the ethylene diamine tripelennamine HCl (0.0, 16.0, 32.0, and 64.0 mg/kg) or the aminoethyl ether diphenhydramine HCl (0.0, 32.0, 64.0, and 96.0 mg/kg). Adult female rats received intraperitoneal injections when housed 12 per cage and toxicological response (number dead per group) was assessed 24 hours post-treatment. The results showed that over the dose ranges employed, and when given alone, nicotine was completely non-lethal, tripelennamine was virtually non-lethal and diphenhydramine was toxic only at the highest dose (5 of 12, at 96.0 mg/kg). However, when nicotine and the antihistamines were delivered in combinations, the toxicological response was markedly altered. Tripelennamine in combination with nicotine yielded supra-additive interaction, with the degree of potentiation being a simple linear function of nicotine within each dose of tripelennamine. The interaction between nicotine and diphenhydramine was more complicated, with certain dose combinations yielding supra-additivity, yet with others yielding antagonism. It was suggested that seizure-precipitated cardiopulmonary collapse was the immediate cause of death, plausibly mediated by central mechanisms. As such, Experiment 2 examined the influence of adding the proconvulsant pentylenetetrazole (PTZ) (0.0, 10.0, and 20.0 mg/kg) to nicotine (0.0, 2.0, 4.0, and 8.0 mg/kg)-tripelennamine (0.0 and 32.0 mg/kg) combination treatments. Effects were assessed both at 1.0 and 24.0 hours post-injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Antihistaminic drugs increase feeding, while histidine suppresses feeding in rats.

The present studies tested the hypothesis that histamine blockade stimulates appetite, while increases in histamine levels suppress appetite. Results show that the classical antihistamines cyproheptadine and promethazine both produced significant and long-lasting increases in food intake. Pronounced appetite stimulation was also seen following the administration of doxepin, the most potent antihistamine among the antidepressants. In contrast, administration of the histamine precursor histidine produced a profound suppression in food intake. The results thus suggest that an inverse relationship may exist between histamine and food intake.

Animal Feed↗

PubMed1975

Suppression of histamine-induced pruritus by three antihistaminic drugs.

A double-blind crossover study of inhibition of histamine-induced pruritus by three commonly prescribed antihistamines was conducted on 28 normal subjects. Drugs used included diphenhydramine HCl (Benadryl), cyproheptadine (Periactin), hydroxyzine HCl (Atarax), and a lactose placebo in identical capsules. Intradermal histamine dose-response thresholds of pruritus were obtained before and after pretreatment with the three antihistamines and placebo in each subject. Analysis of data revealed a fivefold increase above baseline of the histamine dose required to produce pruritus following both cyproheptadine and placebo. This compared to a tenfold increase following diphenhydramine and a 750-fold increase following hydroxyzine HCl. The most common side effect was drowsiness, which occurred with all three drugs.

Adolescent↗

PubMed1981

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients.

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.

Asthma↗

PubMed1982

The pharmacokinetics and antihistaminic effects of brompheniramine.

We studied the pharmacokinetics and antihistaminic effect of brompheniramine in seven normal adults. The mean peak serum brompheniramine concentration of 11.6 +/- 3.0 ng/ml occurred at a mean time of 3.1 +/- 1.1 hr. The mean serum half-life value was 24.9 +/- 9.3 hr, the mean clearance rate was 6.0 +/- 2.3 ml/min/kg, and the mean volume of distribution was 11.7 +/- 3.1 L/kg. The mean wheal size was significantly suppressed (p less than or equal to 0.1) at 3, 6, and 9 hr after the brompheniramine dose when mean concentrations ranged from 10.2 +/- 2.9 to 7.0 +/- 2.2 ng/ml. Significant suppression (p less than or equal to 0.05) of mean flare size was found from 3 to 48 hr after the brompheniramine dose, when mean concentrations ranged from 10.2 +/- 2.9 to 2.5 +/- 0.6 nl/ml. The mean pruritus score was significantly suppressed at 9 and 12 hr (p less than or equal to 0.1) and at 24 hr (p less than or equal to 0.05). Brompheniramine had a long half-life and large volume of distribution in normal adults. It also had a prolonged antihistaminic effect in the skin as evidenced by suppression of the wheal and flare response to histamine and by suppression of pruritus.

Adolescent↗

PubMed1985

Newer antihistaminic agents.

Two new antihistamines with properties different from those of currently available drugs are nearing licensure. Named terfenidine and astemizole, they are almost exclusively H1-antagonists, lacking anticholinergic and sympathetic activity. They fail to penetrate the central nervous system and lack sedative effects. They are long-acting and require less frequent doses. Thus they allow sustained antihistaminic action without the usual side effects.

Astemizole↗

PubMed1988

Hay fever treatment with combined antihistamine and cyclooxygenase-inhibiting drugs.

Twenty-eight ragweed-allergic patients with hay fever participated in a clinical trial that examined the pattern of symptom relief resulting from addition of a cyclooxygenase-inhibiting drug to standard antihistamine therapy. In the first week antihistamine use by the subjects was standardized, and subjects were oriented to use of the hay fever symptom diary. They were then allocated, according to symptom severity, to two treatment groups. One group received 120 mg of terfenadine and 300 mg of flurbiprofen (a cyclooxygenase-inhibiting drug) per day. Members of the other group received terfenadine and a placebo that looked like flurbiprofen. This treatment lasted 1 week. Subjects recorded severity of congestion, drainage, running, nose blowing, itching, and sneezing four times each day. The flurbiprofen-treated patients experienced less severe symptoms, demonstrating maximum benefit 3 to 5 days into the drug trial with some loss of effect thereafter. Secretion-related symptoms appeared to benefit most. Combined blockade of histamine and cyclooxygenase products appears to offer improved symptom control in ragweed hay fever.

Adult↗

PubMed1989

Antihistamines in asthma.

Substantial evidence indicates that airway hyperresponsiveness in asthma is associated with the inflammatory response directed toward the airway epithelium and submucosa. Endogenously released spasmogenic mediators interacting with smooth muscle have a greater effect on hyperresponsive than on normal airways. Histamine, a bronchoactive and vasoactive mediator, is released in patients with naturally occurring or allergen-induced asthma. It is clear that mast cells are activated as part of the asthmatic response, and they have now been implicated as effector cells of mediator secretion based on the results of provocative tests. The advent of more potent histamine antagonists selective for H1 receptors has led to a reappraisal of antihistamine therapy in asthma. Drugs such as terfenadine and azelastine inhibit early bronchoconstriction and to some extent the late-phase asthmatic response as well. The efficacy of other new antihistamines (e.g., ketotifen and cetirizine) may extend beyond H1-receptor blockade to inhibit some of the chronic (and perhaps more important) cellular events in asthma.

Asthma↗