Non-H1-receptor effects of antihistamines

Visit any international allergy meeting and you will soon learn that there are a plethora of very potent and effective histamine H₁-receptor antagonists, or antihistamines as they are more often called. Thus, in order to make any particular antihistamine stand out therapeutically or commercially from the others, additional properties, e.g. anti-inflammatory properties, are often claimed. But are these claims valid and, if so, are the 'additional properties' clinically relevant? This document will review the evidence behind some of the 'additional properties' of antihistamines and lay the basis for discussion of their relevance.     

Differential effects of new-generation H1-receptor antagonists in pruritic dermatoses

In search of an improved treatment of pruritic dermatoses, we have studied azelastine, a novel H₁-receptor antagonist, during a 2-week treatment period, using a double-blind, placebo-controlled design. The potent H₁-antagonist cetirizine was used for comparison. Symptoms were recorded daily by the patients on a diary card, using a 4-point scale. The same parameters and adverse events were evaluated at weekly intervals, and global improvement was evaluated at the end of treatment. In all 230 evaluable patients with moderate to severe itching, azelastine caused an overall significant improvement in comparison to placebo (F=0.02), with significance also for pruritus (P=0.01 after 1 week and P=0.02 after 2 weeks). Both drugs reduced itching more effectively in urticaria than in atopic eczema. Azelastine was superior to cetirizine in reducing pruritus, whereas cetirizine caused a more marked reduction of whealing. Both drugs rarely caused fatigue and dry mouth, but taste perversion occurred only in azelastine-treated patients (9.7%) and headaches only with cetirizine (10.4%). Therefore, the two H, blockers exert differential effects on pruritus verses whealing and a distinctive adverse events pattern. TTie data also underline the low efficacy of antihistamines in atopic eczema, compared to urticaria.     

Effects of H1-receptor antagonists on nasal obstruction in atopic patients

The aim of this study is to investigate whether H₁-receptor antagonists, besides their effect on nasal itching and sneezing, also have a measurable effect on nasal obstruction caused by allergen challenge. The antihistamine used was astemizole (10 mg) versus placebo, in a double-blind, cross-over, randomized study of two groups. Between the two sessions there was a wash-out period of at least 4 weeks. Seven patients of both sexes, with proven allergy to grass pollen, underwent a specific long-term provocation with grass pollen in the Vienna challenge chamber. Using a physiological method of challenge and a sensitive method for evaluating nasal function, we were able to prove H₁-receptor antagonist influence on nasal airway obstruction. The main parameters obtained arc nasal flow and nasal resistance at 75, 150 and 300 Pa, evaluated by active anterior rhinomanometry. We also investigated subjective symptom scores (0–3) of nasal, eye. and lung symptoms. It can be shown that the nasal flow under astemizole treatment is statistically significantly higher than the nasal flow under placebo treatment ( P = 0.034). This is in accordance with the findings in subjective nasal itching and sneezing.     

Influence of H1-receptor antagonists on adhesion molecules and cellular traffic

Bagnasco M, Canonica GW. Influence of H₁-receptor antagonists on adhesion molecules and cellular traffic.     

Comparison of the central nervous system effects produce by six H1-receptor antagonists

Background A comprehensive comparative study of the central nervous system (CNS) properties of newer H₁-receptor antagonists is needed. Objective Our objective was to investigate the central nervous system eifects of u single manufacturer's recommended dose of six H₁-receptor antagonists, using appropriate controls. Methods Fifteen healthy subjects received astemizole 10mg, cetirizine 10mg, ketotifen 2mg, loratadine 10 mg, terfenadine 60mg, diphenhydramine 50mg or placebo. Before and 2-1.5 h after dosing, cognitive function was assessed using the P300-event-related potential, somnolence was assessed using a subjective score, and histamine skin tests were performed. Results In rank order from least to greatest effect on the P300 latency, the medications were: terfenadine, placebo, cetirizine, ketotifen, loratadine, astemizole and diphenhydramine. Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo. Subjective somnolence was significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine. All the H₁-receptor antagonists suppressed the histamine-induced weal significantly compared with baseline. Conclusions The H₁-receptor antagonists tested affected cognitive functioning and somnolence to different extents, although all produced satisfactory peripheral H₁-blockade.     

Direct effects of second-generation H1-receptor antagonists on the activation of human basophils

The present study was performed to investigate the putative suppressive effects of H₁-receptor antagonists (HRA) of the second generation (astemizole (AS), cetirizine (CT), loratadine (LO), oxatomide (OX) and terfenadine (TF)) on the mediator release from human basophils activated by two classical stimuli. Anti-IgE-mediated histamine release was inhibited in a dose-dependent fashion by TF (maximum inhibitory value: 33.8±7.6%, 100 M,n=7), whereas the other HRA exhibited weaker activity. The anti-IgE-induced LTC₄ production was strongly suppressed by TF, LO and OX (92.4±6.3%, 90.8±6.0% and 88.5±5.6%, 100 M,n=4–5), while As was less active (56.4±4.1%, 100 M,n=5). Histamine release induced by incubation with grass pollen antigen (0.01%) was inhibited by TF (40.7±4.1%, 50 M,n=4), but the other HRA showed only low activity. The present findings suggest that some HRA might exhibit direct inhibitory effects on activation of IgE-receptor bearing cells.     

A comparison of the pharmacodynamics of H1-receptor antagonists as assessed by the induced wheal-and-flare model

Juhlin L. A comparison of the pharmacodynamics of H₁-receptor antagonists as assessed by the induced wheal-and-flare model.     

ATP modulates intracellular Ca2+ and firing rate through a P2Y1 purinoceptor in cane toad pacemaker cells

Bipolar sensory neurons within the vomeronasal organ (VNO) are thought to mediate the detection of pheromones in vertebrates. In the mouse, VNO neurons respond to pheromones with a rise in intracellular Ca²⁺ that accompanies a depolarization of the cell. Transduction of the pheromone appears to occur through the activation of a phosphatidylinositol signalling pathway, but the ion channels that respond to this signalling pathway have not been identified. In this report patch-clamp recording from hamster vomeronasal sensory neurons was used to identify second-messenger-gated channels that might play a role in transduction. The results demonstrate that VNO neurons show abundant expression of a Ca^2+-activated non-selective (CaNS) cation channel. The CaNS channel does not discriminate between Na⁺ and K⁺ and has a slope conductance of 22 pS. Half-activation of the channel occurs at a Ca²⁺ concentration of 0.5 m m (at -80 mV). The probability of opening ( P _o) of the channel is further augmented at positive potentials, and shows an e-fold voltage dependence per 37 mV. The channel exhibits rapid rundown following patch excision with P _o decreasing from near 1.0 to near 0. The adenine nucleotides ATP and cAMP block the channel with an apparent affinity of 3 and 42 μ m , respectively (-80 mV). Both the activation of the channel by Ca²⁺ and the block of the channel by adenine nucleotides show a mild voltage dependence, which can be accounted for by the voltage dependence of P _o. The properties of this channel make it a candidate to either directly mediate vomeronasal sensory transduction, or to amplify the primary sensory response.     

Slow excitatory synaptic transmission mediated by P2Y1 receptors in the guinea-pig enteric nervous system

Electrophysiological recording was used to study a type of slow excitatory postsynaptic potential (slow EPSP) that was mediated by release of ATP and its action at P2Y₁ receptors on morphologically identified neurones in the submucosal plexus of guinea-pig small intestine. MRS2179, a selective P2Y₁ purinergic receptor antagonist, blocked both the slow EPSP and mimicry of the EPSP by exogenously applied ATP. Increased conductance accounted for the depolarization phase of the EPSP, which occurred exclusively in neurones with S-type electrophysiological behaviour and uniaxonal morphology. The purinergic excitatory input to the submucosal neurones came from neighbouring neurones in the same plexus, from neurones in the myenteric plexus and from sympathetic postganglionic neurones. ATP-mediated EPSPs occurred coincident with fast nicotinic synaptic potentials evoked by the myenteric projections and with noradrenergic IPSPs evoked by sympathetic fibres that innervated the same neurones. The P2Y₁ receptor on the neurones was identified as a metabotropic receptor linked to activation of phospholipase C, synthesis of inositol 1,4,5-trisphosphate and mobilization of Ca²⁺ from intracellular stores.