The effect of H1 and H2 histamine antagonists on symptomatic dermographism

In ten patients suffering from symptomatic dermographism the combined administration of chlorpheniramine + cimetidine produced a greater reduction in the weal and flare response provoked by a standardized scratch than the administration of chlorpheniramine alone. There was a statistically significant improvement in the overall assessment of the patient's skin condition with the combined administration of chlorpheniramine + cimetidine. Chlorpheniramine given alone produced no significant benefit whilst cimetidine alone produced a marked exacerbation in itching in nearly half the patients who initially entered the study and was sufficient to require withdrawal.     

Suppression of alcohol-induced flushing by a combination of H1 and H2 histamine antagonists

Alcohol-induced flushing of the face and neck regions is a well recognized condition, probably genetically determined and due to individual differences in alcohol metabolism. We have shown that the flushing appears only after a threshold level of blood alcohol (20–35 mg per 100 ml) is exceeded. The rate of alcohol absorption and peak blood levels were reduced by a combination of H₁ and H₂ antagonists. This reduction was accompanied by abolition of flushing in sensitive individuals.     

The apparent volumes of distribution of H1 receptor antagonists

ABSTRACT: The apparent volume of distribution (V_D) of a drug estimates its distribution into the body. Referring to the volume of exchangeable water (0.6 L/kg body weight), it indicates if tissue distribution is extensive when V_D is greater than 0.6 L/kg or poor if V_D is less than 0.6 L/kg. Its interest in the selection of an appropriate drug is found after comparing the map of selected targets (mainly receptors) to be reached by the drug, the accessibility of these targets by the drug, and the V_D necessary and sufficient to reach them. This analysis is here applied to H₁ receptor antagonists, a pharmacologic class, where target cells, endothelial cells such as eosinophils, mastocytes, basophils, and smooth fibers have receptors on the external side of cell membranes and thus are more readily accessible from blood than toxic sites located inside cells (heart, brain, liver). Of the H₁ receptor antagonists marketed today, cetirizine has the lowest V_D, 0.4 L/kg, enough to reach selected targets without extensive distribution in organs where it would be useless. These characteristics are related to its chemical amphoteric structure.     

Multiple H1-antihistamine-induced urticaria

H₁‐antihistamines are widely used in the treatment of various allergic diseases. Particularly, a cornerstone of the management of chronic idiopathic urticaria is treatment with H₁‐antihistamines. However, a few cases of H₁‐antihistamine‐induced urticaria have been reported. A 34‐year‐old woman presented with a 4‐month history of recurrent urticaria, which was prominently exacerbated by the administration of H₁‐antihistamines. The patient consented to a provocation test of fexofenadine among drugs including cetirizine and hydroxyzine, which were suspected of inducing severe symptoms in episodes. One hour after challenge with 12 mg fexofenadine (one‐fifth of the therapeutic dose), a urticarial reaction rapidly developed on nearly the entire body with remarkably increased levels of plasma histamine (190 nmol/L) and plasma leukotriene B4 (150 pg/mL). In challenge tests with other antihistamines, generalized urticaria occurred 5 and 1 h after intake of 10 mg loratadine and 10 mg bepotastine, respectively, whereas challenges with chlorpheniramine, mequitazine and azelastine were all negative. Skin prick tests with H₁‐antihistamines used in the challenges were all negative, indicating that the urticarial reactions after challenges with the causative drugs might not be immunoglobulin E‐mediated. Among the causative drugs in our case, cetirizine and hydroxyzine are the piperazine derivatives, whereas fexofenadine, bepotastine, ebastine and loratadine are the piperidine derivatives. The chemical structures of both derivatives are very similar. Therefore, in this case, H₁‐antihistamine‐induced urticaria may have been due to cross‐reactivity between metabolites of these drugs, but not to drugs before metabolization. Hypersensitivity to H₁‐antihistamines should be considered when urticarial lesions worsen after H₁‐antihistamine treatment.     

Novel insights into the molecular mechanism of the cardiac actions of histamine H1 receptor antagonists

ABSTRACT: When compared to older first‐generation antihistamines, second‐generation antihistamines are characterized by improved selectivity for histamine receptors, absence of sedation, and, possibly, antiallergic properties distinct from their antihistaminic activity. Such a pharmacologic profile, arising from specific pharmacodynamic and pharmacokinetic properties, bears an obvious clinical advantage for the therapy of allergic diseases; thus second‐generation antihistamines have become the treatment of choice for chronic urticaria and allergic rhinitis. Despite such a therapeutic advantage, adverse cardiovascular effects associated with the use of some congeners belonging to the class of second‐generation antihistamines (particularly terfenadine and astemizole) have been reported, and a major concern about the therapeutic selection of antihistamines now is represented by their potentially severe arrhythmogenic properties. This article reviews the recent advances in the understanding of the pathogenesis and etiology of the cardiotoxic actions of some second‐generation antihistamines, underlining their molecular actions at the level of K⁺ channels controlling the cardiac action potential. In particular, emphasis is given to the interaction of second‐generation antihistamines with the K⁺ channels encoded by the human ether‐a‐gogo‐related gene (HERG), which is crucially involved in the repolarization process of the cardiac action potential. This review will also focus on the recent concerns over the potential cardiac adverse effects of first‐generation H₁ receptor blockers. The present exploration of the molecular basis of the adverse cardiac effects of antihistamines shows how important contributions in deciphering such complex phenomenon have emerged from disciplines and techniques not traditionally related to immunology, such as molecular genetics and cellular electrophysiology; it seems possible to anticipate that the exchange of results from such different disciplines in the future will provide patients and physicians with medications with improved therapeutic efficacy and safety for the clinical management of allergic diseases.     

H2 Blockers in Chronic Urticaria

Two hundred unselected patients with chronic idiopathic urticaria were treated with adequate doses of conventional antihistamines given at frequent intervals; 98.5% were completely freed of disease while on therapy. In three cases, the lesions subsided but did not clear completely. The addition of 800 mg of cimetidine in divided doses cleared the lesions in two cases, and in the third case the dose of H1 blocker was increased, which resulted in complete clearance of wheals and symptoms. Addition of H2 blockers play a role, but only in a very small percentage of patients with chronic idiopathic urticaria who do not completely respond to adequate doses of H1 blockers.     

The effect of H1 and H2 receptor antagonists on the dermographic response

The effect on dermographic wealing of an H1 and H2 receptor antagonist was studied separately and in combination. a double-blind protocol was used and dermographism was measured as the diameter of weal response to a measured force. Both H1 and H2 antagonists had a small but non-significant effect, but the combination of H1 plus H2 antagonist had an approximately additive effect which was significant. Although this indicates a role for H2 receptors in dermographism it does not establish the degree of involvement, nor whether H2 antagonists necessarily have any advantage over a potent H1 blocker alone in the treatment of dermographism.     

Histamine H2-receptor antagonists inhibit enzymic histamine degradation in human skin

The histamine H₂-receptor antagonists burimamide and cimetidine cause inhibition of human skin histamine-N-methyl transferase (HMT) in the dose range 10^-3–10^-4 M. Amodiaquin, a recognized inhibitor of animal HMT, also produced dose-related inhibition of human HMT. These findings may explain the observation that H₂-receptor antagonists enhance certain types of inflammatory response in skin.     

Human epidermal acetylcholinesterase (AchE) is regulated by hydrogen peroxide (H2O2)

Extraneuronally, acetylcholine (Ach) is synthesized, stored and secreted in the tegumental cells covering the inner and outer surfaces of the body. It acts via nicotinic (nAchR) and muscarinic (mAchR) receptors in a paracrine and autocrine fashion influencing various keratinocyte functions. Using in vitro studies, we present evidence that effects of cholinergic agonists and antagonists on cutaneous biology are dependent upon specific Ach‐R, localised in the different compartments of the skin. Using immunohistochemistry on frozen section of normal skin we could previously demonstrate a differential distribution of alpha 3*, alpha 7, alpha 9 and beta 1 nAchR and m1, m3–5 mAchR in human epidermis. Here we show the functional significance of AchR blockage using organotypical keratinocytes cultures. Cholinergic agonists and antagonists were added on the day of the lift to the air‐liquid interface. After 5 days, blockage of all AchR using mecamylamine and atropine resulted in complete inhibition of terminal differentiation. Mecamylamine and atropine alone had only a retarding effect suggesting an additive mechanism of nAchR and mAchR blockage. Specific inhibition of α9 homooligomers with strychnine produced the strongest effects leaving behind only a keratinocytes monolayer. Stimulation of AchR with either nicotine or muscarine in short term organotypic cultures did not produce dramatic changes of epidermal morphology. We conclude that alpha 9 AchR that are located in the basal and lower suprabasal layers of the epidermis, are crucially involved in terminal differentiation of keratinocytes. The functional significance of other nAchR expressed in the epidermis remains unclear, due to the lack of specific agonists and antagonists.     

Effects of H1 antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging

Histamine plays an important part in the cutaneous weal and flare response which underlies many allergic skin conditions. It has a direct effect on the local vasculature to promote vasodilatation and increase microvascular permeability and may also initiate the more widely spread neurogenic flare. Quantification of these responses and studies of the mediator mechanisms underlying them have been limited by the lack of appropriate techniques to investigate them. To address this we have used two relatively new techniques, scanning laser Doppler imaging (LDI) and dermal microdialysis to measure changes in skin blood flow and the release of histamine within the weal and flare, following intradermal injection of histamine or bradykinin. These measurements have been made both in the absence and presence of the H₁ receptor blockers cetirizine and loratadine. Scanning LDI of the inflammatory response revealed marked differences in both the development and steady state responses to the intradermal injection of histamine (1–3 μmol/L) and bradykinin (1 μmol/L). The development of the flare and the weal response to both histamine and bradykinin was significantly reduced by cetirizine but not by loratadine. The histamine-induced flare area fell by 57 ± 4% (mean ± SEM, n = 10, P < 0.001) after cetirizine and the area of the weal fell by 73 ± 11% (P < 0.009). Bradykinin-induced inflammatory responses were similarly reduced by cetirizine, the weal by 60 ± 16% (P < 0.02) and the flare by 61 ± 4% (P < 0.005). Measurement of histamine concentration in skin using microdialysis, in six subjects, confirmed that histamine levels rose in the dialysate collected from the weal to 310 ± 16 nmol/L following injection of histamine. Histamine levels also rose following bradykinin injection in some subjects (mean 147 ± 46 nmol/L, range 18–336). Little increase in histamine concentration was seen in the dialysate from the flare following injection of either histamine or bradykinin. The histamine concentration in dialysate from unprovoked skin was 4.19 ± 0.75 nmol/L. These data reveal differences in the dermal responses to different mediators when assessed using scanning LDI. They confirm that histamine is released within the weal but not the flare response to the intradermal injection of both histamine and bradykinin and that its effects on the local vasculature to cause the oedematous weal and the axon reflex-mediated flare are significantly attenuated by the H₁ antagonist cetirizine and to a lesser extent by the H₁ antagonist loratadine.     

Effects of H1- and H2-antihistamines on platelet-activating factor and bradykinin-induced inflammatory responses in human skin

Previous studies show that oral antihistamines affect the Weal and flare response to intradermal injections of the inflammatory mediators platelet-activating factor (PAF) and bradykinin (BK). The aim of this study was to compare the effects of terfenadine (an H₂-antagonist) and cimetidine (an H₂-antagonist) on weal and Hare responses to PAF and BK in healthy non-atopic human volunteers. The effects of doxepin on PAF responses were investigated, as there is evidence that doxepin may have direct anti-PAF ejects in addition to its known antihisiaminic actions.     

In vivo formation of prostaglandin E1 and prostaglandin E2in atopic dermatitis

Immunological and biochemical alterations in atopic dermatitis have been attributed to a deficient conversion of omega-6 fatty acids (i.e. linoleic acid, gamma-linolenic acid, and dihomo-gamma-linolenic acid) to prostaglandin (PG)E₁. In patients with atopic dermatitis, however, the formation of PGE₁ has not been evaluated so far. We therefore measured plasma concentrations of 15-keto-13.14-dihydro-PGE₁ which reflects endogenous PGE₁ release, by gas chromatography-mass spectrometry in 31 patients with atopic dermatitis (aged 18-41 years, median 26 years) and in 31 healthy, age and sex-matched control subjects. In order to exclude a metabolic shift from PGE₁ to PGE₂, we also measured the plasma levels of 15-keto-13, 14-dihydro-PGE₂. There was no difference between patients and control subjects with respect to plasma concentrations of 15-keto-13, 14-dihydro. PGE₁ (3.9-49.6, median 10.3pg/ml vs. 3.2-80.4, median 8.3pg/ml, P = 0.22), 15-keto-13,14-dihydro-PGE₂ (11.6-201.0 median 24.8pg/ml vs. 8.6-201.0.median 19.6 pg/ml, P = 0.10), and the ratio of 15-keto-13,14-dihydro-PGE₁ to 15-keto-13.14-dihydro-PGE₂ (0.17-1.39, median 0.41 vs.0.2-0.17, median 0.45, P = 0.29). These results indicate that the endogenous formation of both PGE₁ and PGE₂ is normal in our patients. The results do not confirm the pivotal role that other authors have attributed to a deficient PGE₁ formation in the pathogenesis of atopic dermatitis.     

Release of prostaglandin D2 and histamine in a case of localized heat urticaria, and effect of treatments

A case of localized heat urticaria in a 70-year-old woman is reported. Increased plasma levels of prostaglandin D2 and blood histamine after heat challenge indicate a role for mast cell degranulation in the pathophysiology of the syndrome. Treatment with astemizole increased the temperature threshold to wealing, but not to itch or erythema. The patient was partially desensitized by repeated exposure to heat and this was further improved by indomethacin. After treatment there was no increase in plasma prostaglandin D2 on challenge. No evidence was found for the activation of the alternative complement pathway.     

The intradermal effects of the H3 receptor agonist R α methylhistamine in human skin

We have investigated the possible existence of the H₃ histamine receptor in human skin with the highly selective ligands R α methylhistamine (RAMHA) (H₃ agonist) and thioperamide (H₃ antagonist). We compared the intradermal effects of RAMHA with histamine, and studied their potential modulation by the H₁ antagonist terfenadine, and H₂ antagonist cimetidine. The effects of RAMHA and thioperamide on codeine phosphate-, substance P- and histamine-induced weal and flare responses were also studied. RAMHA produced dose-related weal and flare responses that were approximately 10- and fivefold less, respectively, than responses to histamine. Flare responses to RAMHA were significantly inhibited by oral terfenadine ( P  < 0.05). Weal and flare responses to histamine after oral cimetidine showed much intersubject variation, and cimetidine did not significantly alter either RAMHA- or histamine-induced weal and flare responses. Codeine phosphate-, substance P- and histamine-induced responses were not significantly affected by concurrent administration of RAMHA. Thioperamide was not found to influence codeine phosphate-, substance P-, RAMHA- or histamine-induced effects. RAMHA induces vascular (weal and flare) responses in human skin, and these responses are partially inhibited by terfenadine. There is a trend for RAMHA to have an additive effect to the weal induced by substance P and histamine, although our results largely do not reach statistical significance. Thioperamide does not affect the vascular responses to RAMHA, codeine phosphate, histamine or substance P. We cannot conclude that the effects of RAMHA are induced by H₃ receptors on cutaneous endothelial or mast cells.     

Localized heat urticaria associated with a decrease in serum complement factor B (C3 proactivator)

A case of localized heat urticaria is reported in a 51-year-old woman who within a few minutes of contact with warm water developed erythema and swelling sharply localized to the heated area. After a hot bath urticarial lesions appeared over large areas of her body, accompanied by a feeling of weakness, but no other systemic symptoms. After challenge with heat by immersing her left arm in water heated to 42°C, a rapid decrease of her serum complement level of factor B was demonstrated, suggesting that activation of an alternative complement pathway plays a role in this form of urticaria. Biopsies for immunofluorescent study of complement and immunoglobulins were negative at 30 and 180 min after heat challenge. The dermal fibres and endothelial cells of dermal vessels were capable, in vitro, of complement binding before and after exposure to heat.     

In vitro activity of the lipopeptide derivative (Pal-lys-lys-NH2), alone and in combination with antifungal agents, against clinical isolates of dermatophytes

Background  An increasing number of antimycotics have become available for the treatment of dermatophytoses; however, there are reports suggesting recalcitrance to therapy or resistance of a dermatophyte against conventional treatment. Lipopeptides represent novel therapeutic drugs with a new mode of action.
Objectives  The aim of this study was to investigate the in vitro effects of the lipopeptide Pal-Lys-Lys-NH₂ (PAL) alone and in combination with standard antifungal agents, such as fluconazole (FLU), itraconazole (ITRA) and terbinafine (TER) against 24 clinical isolates of dermatophytes belonging to four species.
Methods  A broth microdilution method following the Clinical and Laboratory Standards Institute recommendations (M38-A) was used for testing drugs alone and in combination.
Results  PAL minimum inhibitory concentrations (MICs) ranged from ≤ 0·25 to > 16 μg mL⁻¹ and they were similar to those of FLU and higher than those of either ITRA or TER. Synergy, defined as a fractional inhibitory concentration (FIC) index of ≤ 0·50, was observed in 67%, 52% and 15% of PAL/ITRA, PAL/TER and PAL/FLU interactions, respectively. None of these combinations yielded antagonistic interactions (FIC index > 4). When synergy was not achieved, there was still a decrease in the MIC of one or both drugs used in the combination.
Conclusions  Our study demonstrates that PAL has potential activity against dermatophytes. In addition, the in vitro activity of PAL can be enhanced upon combination with standard drugs. This lipopeptide applied in the form of lacquer, spray or ointment, could represent an interesting new therapy, particularly when combined with conventional treatment in recalcitrant or resistant dermatophyte infections.     

The effect of a new non-sedative H1-receptor antagonist (LN2974) on the itching and scratching of patients with atopic eczema

Ten adult male patients with long-standing atopic eczema took part in a double-blind randomized cross-over trial of compound LN2974. This is a new potent selective H₁-receptor antagonist, unrelated to other antihistamines and devoid of H₂-reccptor antagonist activity. It has little or no sedative action. No significant suppression of scratching, as measured by limb movement meters, or of itching, recorded on visual analogue scales, could be demonstrated.     

1α,25(OH)2 vitamin D3 increases intracellular calcium in human keratinocytes

Vitamin D3 metabolites have been found to improve psoriasis but their mechanism of action is not clear. Keratinocyte proliferation and differentiation are known to be dependent on calcium concentrations in vitro. The aim of this study was to examine whether 1 alpha,25(OH)2 vitamin D3 had any direct effect on intracellular free calcium concentrations in cultured keratinocytes. A response to 1 alpha,25(OH)2 vitamin D3 was seen in 88% of monolayers of normal human keratinocytes attached to glass coverslips. An increase in intracellular free calcium was seen in 80% of the reactive cultures, with over half the responses occurring within 30 s of exposure to 1 alpha,25(OH)2 vitamin D3 and the remainder occurring within minutes. Responses could be seen at physiological concentrations of 1 alpha,25(OH)2 vitamin D3 and were not blocked by the protein synthesis inhibitor cycloheximide. The response to 1 alpha,25(OH)2 vitamin D3 took the form of rapid transient increases in intracellular free calcium in 29 out of 59 coverslips. The basal intracellular free calcium was calculated to be 245 +/- 47 nM rising to a maximum of 834 +/- 267 nM (mean +/- SEM; n = 20) following exposure to 1 alpha,25(OH)2 vitamin D3. We conclude that 1 alpha,25(OH)2 vitamin D3 acts directly on keratinocytes to increase intracellular free calcium and that this may be relevant to its mechanism of action in psoriasis.     

Decreased expression of α2β1 integrin in scleroderma fibroblasts

Abstract Systemic scleroderma (SSc) is a complex connective tissue disorder of unknown etiology. In early stages of the disease, libroblasts are activated to produce large amounts of collagen with subsequent fibrosis. Collagen metabolism of fibroblasts is modulated by their contact with the extracellular matrix (ECM), which involves distinct receptors on the cell surface, mainly belonging to the integrins. We investigated the expression of collagen receptor α₂β₁, in SSc and normal fibroblasts, since this receptor has been shown to be utilized by fibroblasts for adhesion to and reorganization of collagen I. 9 strains of scleroderma fibroblasts grown as monolayer cultures were first analyzed with respect to their collagen I expression. 6 of these strains were similar to controls (“low” producers) and 3 strains showed up to 2–3 × higher levels of collagen I mRNA expression (“high” producers). Northern hybridization using a cDNA probe specific for the α₂ integrin subunit revealed a decrease of the corresponding mRNA in SSc fibroblasts as compared to controls (75% versus 100%). “High” collagen producing cell strains displayed the lowest values for α₂ integrin mRNA. The decrease of α₂ integrin subunit expression at the mRNA level in selected fibroblasts was further substantiated by radioimmunoprecipitation using specific mAbs directed against α₂ integrin subunit. No significant changes in β₁ integrin expression could be observed-neither at mRNA nor at the protein level. Our data indicate a correlation between excessive synthesis of collagen and low levels of α₂ integrin subunit expression in SSc fibroblasts. Further experiments should clarify whether this observation is a phenomenon specific for scleroderma or whether it reflects an “activated” state of fibroblasts.