Histamine In Human Skin Research Articles

Effects of botulinum toxin type A on histamine-induced itch and vasomotor responses in human skin

Clinical evidences reveal the anti-pruritic effect of Botulinum toxin type A (BoNT/A). BoNT/A inhibits the release of acetylcholine as well as some other substances, which may be involved in pruritus. The present study investigated the effect of subcutaneous administration of BoNT/A on experimentally induced itch by histamine in human skin. Fourteen healthy male volunteers (26.3±2.6 years) received BoNT/A (5 U, BOTOX ® , Allergan, US) and isotonic saline in the volar surface of either forearm. Histamine-prick tests were performed 4 times at the treatment sites (before, day 1, day 3 and week 1 after treatments). The itch intensity (VAS0-10) and neurogenic inflammation were measured and the effect of treatments over trials was assessed by repeated ANOVA. BOTOX ® significantly reduced the histamine-induced itch intensity ( F 1,39 =30.2, P <0.001) compared to saline. Flare area was smaller in BOTOX ® -treated arm compared to saline ( F 1,39 =15.4, P =0.002). Findings from laser Doppler assessed blood flow ( F 1,26 =177.3, P <0.001) and thermo-images ( F 1,26 =27.6, P <0.001) clearly showed the suppressive effect of BOTOX ® on histamine-induced vasomotor reactions compared to saline. BoNT/A reduced itch intensity and neurogenic inflammation to histamine-prick test in human skin. The findings can be applicable in future treatments of some pruritic conditions.

A comparison of levocetirizine and desloratadine in the histamine-induced wheal and flare response in human skin in vivo

The histamine-induced wheal and flare response was used to compare quantitatively the antihistaminic potency of levocetirizine and desloratadine. In this double-blind, placebo-controlled crossover study, 24 healthy male non-atopic volunteers received weekly single doses of 1.25, 2.5 or 5 mg levocetirizine, 2.5, 5 or 10 mg desloratadine, or placebo. Four hours after dosing, histamine (100 mg/ml) skin prick tests were performed on the volar surface of both forearms. The diameters of the wheals and flares were measured 10 minutes later. Sedation was evaluated using a visual analogue scale and a motricity test. The effects of individual drug doses were compared using Student's t-test for paired data and the overall effects of the two drugs by ANOVA. All doses of levocetirizine significantly (P < 0.0001) inhibited both wheals and flares in a dose-related manner. Only the 10 mg dose of desloratadine achieved significant inhibition of response. ANOVA showed levocetirizine to be significantly (P < 0.0001) more active than desloratadine. Neither drug caused significant sedation or loss of motricity. Levocetirizine is significantly more effective than desloratadine in inhibiting wheal and flare responses to histamine in human skin in vivo, with 1.25 mg levocetirizine being more effective than 10 mg desloratadine.

Investigation into the mechanisms by which nedocromil sodium, frusemide and bumetanide inhibit the histamine‐induced itch and flare response in human skin in vivo

In a previous study, iontophoresis of nedocromil sodium into human skin in vivo was shown to reduce histamine-induced itch and flare. In asthma, the Na+/K+/2Cl- cotransporter inhibitors, frusemide and bumetanide, have been reported to have many similar actions to nedocromil sodium. To compare the effects of these drugs in the histamine-induced itch, flare and weal response in human skin in vivo and elucidate their site of action. Nedocromil sodium, frusemide bumetanide and reversed osmosis water (control), were introduced by iontophoresis into the forearm skin of 10 volunteers in each of two single-blind studies. In study 1, histamine (20 microL of 100 microM) or vehicle was injected into the area of iontophoresis 10 min later. In study 2, histamine or vehicle was injected 5 mm outside the area of iontophoresis so the flare developed over the area of iontophoresis. Itch was scored on a visual analogue scale every 20 s for 5 min, flare areas were assessed using scanning laser Doppler imaging up to 10 min and weal was assessed by planimetry at 10 min. In study 1, nedocromil sodium, frusemide and bumetanide reduced itch scores by 36%, 48% and 34%, respectively, and flare areas by 17%, 26% and 15% respectively (all P<0.05). Weal areas and blood flux in the flare were unaffected. In study 2, itch scores, flare areas and weal areas were not inhibited. Also, blood flux values in areas of drug and water iontophoresis were not different. This study has provided evidence to support the hypothesis that nedocromil sodium, frusemide and bumetanide inhibit sensory nerve activation to reduce the itch and flare responses induced by histamine in human skin in vivo. It is likely that inhibition of a Na+/K+/2Cl- cotransporter in the sensory nerve membrane is a possible mechanism of action.

Experimental models of skin inflammation.

The skin is the most accessible organ of the body in which to view the inflammatory process and its pharmacological modulation. However, there are relatively few studies in which the response of the dermal vasculature to inflammatory stimuli has been assessed quantitatively or the chemical mediators of the response measured directly. The mechanisms underlying these responses remain unclear despite the fact that altered microvascular function plays an important part in a number of clinical conditions. This paper describes recent studies in which an experimental model of inflammation in the skin has been used to investigate the pharmacological mechanisms underlying microvascular responses. As allergen-induced cutaneous weal and flare responses are mediated mainly by histamine, we first set out to characterize the vascular responses using the intradermal injection of histamine as a first step, experimental model of allergic skin disease. To quantify the inflammatory responses and to explore the mediator mechanisms underlying them we have combined the techniques of scanning laser Doppler imaging of blood flux and dermal microdialysis to make simultaneous measurements of changes in skin blood flow and the release of mediators within the weal and flare response to intradermal injection of histamine in human skin, in vivo.

The Effect of Prostaglandin D2 on the Response of Human Skin to Histamine

The interaction of prostaglandin D2 (PGD2) and histamine in human skin was studied by intradermal injection of the compounds alone or in combination in healthy volunteers. Responses were recorded by measurement of areas of wheal and erythema, and changes in cutaneous blood flow quantified using a laser Doppler flow meter. The effect of a near-threshold dose of PGD2 on histamine dose-response relationships and on the response to a single low dose of histamine were examined. Histamine caused dose-related increases in blood flow and in areas of wheal and erythema in human skin. Prostaglandin D2 caused dose-related increases in blood flow and erythema area, but not wheal area, in the dose range used. When the compounds were injected together, PGD2 did not potentiate the increase in blood flow and areas of wheal and erythema due to histamine. The modest augmentation of histamine response in the presence of PGD2 could be attributed to summation alone. The role of PGD2 in cutaneous disorders such as the physical urticarias, in which its release has been demonstrated, is therefore uncertain. In the amounts measured in the urticarias, it is unlikely alone to cause a significant cutaneous response; nor does it appear to act by potentiation of the response to histamine.

Separate effects of topical indomethacin on the itch response and on the flare reaction induced by histamine in human skin

The effects of topical indomethacin on histamine responses and histamine release were studied in 15 healthy volunteers. Three hours before testing, the indomethacin solution was applied under occlusion on one arm and the corresponding vehicle on the other. Solutions of histamine and the histamine releasing compound 48/80 were injected intradermally in both arms. Indomethacin treatment inhibited the flare reactions induced by histamine and compound 48/80 to about 50%, whereas no influence was seen on the itch responses. Our results indicate that indomethacin has no effect on the release of histamine, but it selectively suppresses the histamine-induced flare reaction leaving the itch duration unaffected.

Increased Concentrations of Arachidonic Acid, Prostaglandins E2, D2, and 6-oxo-F1α, and Histamine in Human Skin Following UVA Irradiation

The buttock skin of clinically normal human subjects was subjected to approximately 2.5 minimal erythema doses of ultraviolet A irradiation. Deep red erythema developed during irradiation, faded slightly within the next few hours, increased to maximum intensity between 9-15 h, and decreased gradually thereafter although still persisting strongly at 48 h. Suction blister exudates were obtained at 0, 5, 9, 15, 24, and 48 h after irradiation as well as suction blister exudates from a contralateral control site and assayed for arachidonic acid, prostaglandins D2 and E2, and the prostacyclin breakdown product 6-oxo-prostaglandin F1 alpha by gas chromatography-mass spectrometry, and for histamine by radioenzyme assay. Increased concentrations of arachidonic acid and prostaglandins D2, E2, and 6-oxo-prostaglandin F1 alpha were found maximally between 5-9 h after irradiation, preceding the phase of maximal erythema. Elevations of histamine concentration occurred 9-15 h after irradiation, preceding and coinciding with the phase of maximal erythema. At 24 h, still at the height of the erythemal response, all values had returned to near control levels. Hence increased concentrations of arachidonic acid and its products from the cyclooxygenase pathway, and of histamine, accompany the early stages up to 24 h. A causal role in production of the erythema seems likely for these substances although other mediators are almost certainly involved.

Pharmacologic modulation of the whealing response to histamine in human skin: Identification of doxepin as a potent in vivo inhibitor

Tricyclic antidepressants are known to exert potent in vitro H 1 antihistaminic effects. Doxepin, a heterocyclic variant of amitriptyline, is a particularly effective H 1 -antihistamine in vitro. In this study we examined the ability of doxepin to inhibit histamine-induced whealing reactions in human skin. Percutaneous introduction of histamine into skin on the volar surface of the forearm provoked a whealing response that was linearly related to the concentration of histamine from 0.0002M to 1.0M histamine. An average increase in wheal diameter of 2.39 mm (95% confidence interval of 2.19 to 2.60) was observed for each 10-fold increase in the histamine concentration above threshold. Day-to-day shifts in slopes of dose-response curves in 41 subjects were minimal. Day-to-day changes in the concentrations of histamine required to provoke whealing responses equivalent to responses on the first day of testing averaged 1.8-fold (±0.6 SE). Single doses of 5, 10, or 25 mg of doxepin increased the concentrations of histamine required to provoke responses equivalent to control reactions 5.2 (±0.9 SE), 18.4 (±3.3 SE) and 82.2-fold (±37.7 SE), respectively, when reactions were measured 4 hr after drug administration. A randomized double-blind, placebo-controlled study of the effects of five doses of 5 mg of doxepin administered at 12-hr intervals confirmed the effectiveness of doxepin. The blinded study also demonstrated that the amount of histamine required to provoke a response equivalent to the control response increased from 2.5-fold (±0.8 SE) after one dose to 17.2-fold (±4.7 SE) after three doses and to 22.2-fold (±5.9 SE) after five doses. These experiments demonstrate that doxepin is a potent antihistamine in man and suggest that this agent, related antidepressants, or compounds derived from tricyclic antidepressant structures may be useful in the clinical regulation of histamine-mediated reactions.

Mast Cell in Disease and its Pharmacologic Regulation

The factors regulating the magnitude of histamine-mediated reactions in the skin need to be elucidated if we are to devise a rational therapy for urticaria. Attempts to prevent biosynthesis of histamine in vivo have proved unrewarding. Depletion of histamine stores in skin by repeated provocation of release until a state of tolerance has been reached has proved a useful procedure in patients with cold urticaria, but because of its inconvenience it requires a high degree of motivation. Attempts to moderate histamine secretion by mast cells, for example, by drugs that increase cyclic AMP, including isoproterenol and theophylline, have not met with success. Doxantrazole, a systemically administered compound with actions resembling the better known disodium cromoglycate, has been effective in suppressing histamine release evoked by cold in patients with cold urticaria, but there has been a puzzling discrepancy between clinical response and reduction in histamine release. Rate of enzymic histamine degradation may be an important factor in determining the magnitude of histamine-mediated reactions in skin. Degradation of histamine in human skin takes place by N-methylation, catalyzed by N-methyl transferase. Blockade of histamine degradation in the guinea pig leads to amplification of the histamine-mediated passive cutaneous anaphylaxis reaction in this species. Histamine-mediated skin reactions can be modulated by blockade of vascular histamine receptors. Recently the presence of 2 sub-classes of histamine receptors, H 1 and H 2 , on human skin blood vessels, has been established. Combined treatment by classical H 1 antihistamines and H 2 antihistamines offers a possibility of more effective antihistamine treatment.

Pruritogenic activity of prostaglandin E2

The itch and erythematous responses induced by intradermal injection of histamine and PGE2 were studied in human skin. Both compounds produced a sensation of itch. The histamine-elicited flare reached a maximum in 3 min and had disappeared after 1 hours. PGE2 induced a similar flare reaction initially, but it was gradually replaced by a smaller, dusky and well delimited erythema. The itch and the flare-like erythema induced by either histamine or PGE2 were alleviated when the subjects were pretreated with the antihistaminic drug chlorcyclizine, thus indicating that at least part of the PGE2 response may be mediated via histamine release. However, when given combined in a mixture, histamine and PGE2 elicited itch of longer duration and flare of larger area than could be accounted for by simple additive histamine effects. Thus, PGE2 seems to potentiate the itch and flare responses induced by histamine in human skin.

Resistance to histamine in human skin after electroconvulsive treatment.

Resistance to histamine in human skin after electroconvulsive treatment.