Non-invasive instrumental techniques to detect terfenadine and temelastine induced suppression of histamine weals in man.

1. The effectiveness of chronic dosing with temelastine (SK&F 93944) 75 mg twice daily and terfenadine 60 mg twice daily compared with placebo in inhibiting the weal and flare response to intradermal histamine was assessed using non-invasive objective assessment techniques. 2. The mean weal thickness, as measured by the A-scan pulsed ultrasound device, was significantly decreased by both temelastine and terfenadine when compared with placebo. 3. There was a significant reduction in both the areas of the weal and the weal and flare, as measured by a digitizing tablet linked to a microcomputer, following treatment with temelastine and terfenadine compared with placebo and also between temelastine and terfenadine. 4. No significant difference was found in blood flow in the weal or flare as measured by the laser doppler flowmeter among any of the groups tested. 5. The ultrasound and digitizer techniques aid objectivity and precision in the investigation of the effects of drugs on histamine induced weals. 6. Temelastine and terfenadine were found to possess antihistaminic effects on histamine induced weal and flare in the skin.     

Importance of beta 2-adrenoceptor stimulation in the suppression of intradermal antigen challenge by adrenaline.

1. Seven atopic subjects received two injections of antigen and one of saline intradermally in the back on each of 4 separate days. They were pretreated with four different drug combinations: (a) adrenaline 0.3 mg subcutaneously over the deltoid muscle (b) subcutaneous adrenaline preceded by 5 mg of the specific beta 2-adrenoceptor antagonist ICI 118,551 orally (c) 8 mg of salbutamol orally (d) placebo. Tablets were given 2 h before and subcutaneous injections 15 min before the intradermal injections of saline and antigen. 2. The median flare response to intradermal low dose antigen and high dose antigen after pretreatment with adrenaline was 4% and 49% of the response seen following pretreatment with placebo (P less than 0.001). When adrenaline was preceded by ICI-118,551, the corresponding median flare responses were 2% and 44% (P less than 0.001) of the placebo response. The flare response after pretreatment with salbutamol was not significantly different from placebo. 3. Adrenaline suppressed the median weal response to the higher dose of antigen to 52% of the response after pretreatment with placebo (P less than 0.05). This suppression by adrenaline was blocked by pretreatment with ICI 118,551. The median weal response after the highest dose of antigen was suppressed by salbutamol to 66% of the response seen after placebo, although this was not significant even when a further three subjects were studied with either salbutamol or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of astemizole on histamine-induced weal and flare

The effect of astemizole on the weal and flare response to intradermal histamine has been studied in normal volunteers after single dosing, and in patients with urticaria and pruritus after chronic dosing with the drug. Single doses of astemizole (40 mg) in normal volunteers significantly reduced histamine weal and flare at 24 and 48 h (p less than 0.001). Before treatment, there was a significantly greater response to intradermal histamine in patients with urticaria than pruritus (p less than 0.05). Chronic dosing with astemizole produced significant reduction in histamine-induced weal and flare in both patient groups which did not show evidence of tachyphalaxis over the period of the study. The effect of astemizole on histamine-induced weal and flare was accompanied by a significant increase in the rate of weal and flare disappearance in both patients (weal p less than 0.002, flare p less than 0.05) and volunteers (weal p less than 0.02, flare p less than 0.005); but there was no change in the rate of weal formation. The effects of astemizole on weal and flare kinetics may be a function of its high level of H1 antagonist activity.     

A comparison of triprolidine and clemastine on histamine antagonism and performance tests in man: Implications for the mechanism of drug induced drowsiness

Summary The effects of triprolidine hydrochloride 1.25, 2.5 and 5 mg, clemastine 1 and 2 mg and lactose dummy administered orally, in a balanced order, at weekly intervals to 12 healthy volunteers, on the flare and weal responses to intradermal histamine injection, and also on both subjective effects and objective psychomotor tests were examined. The histamine response was significantly larger at 09.00 h falling through the day but increasing by late afternoon. Triprolidine produced a dose-related antagonism of both flare and weal response maximal at 3 h and wearing off after the lower doses at 8 h. Clemastine by contrast produced poor antagonism of histamine at 3 h but a marked effect at 5.5 and 8 h. Auditory vigilance was significantly (p<0.05) impaired by all doses of triprolidine 1 to 2 h after administration, but no change followed clemastine at this time. When tested 6 to 7 h after administration significant impairment followed both doses of clemastine but only the 5 mg dose of triprolidine. Both drugs prolonged reaction time in a dose-related manner at 2.5 and 5.0 h but the effects had worn off at 7 h. Digit symbol substitution was impaired by the top doses of both antihistamines but short term memory was unaffected. Subjective effects measured using analogue lines reflected the effects in the vigilance test, in that drowsiness and mental impairment were noted early after triprolidine, while clemastine produced maximal effects at 5 h. Subjects were ranked in order of magnitude of inhibition of both flare and weal, and impairment of vigilance, prolongation of reaction time and subjective drowsiness score. There was no indication of a significant correlation, using Spearman's test, between antagonism of histamine and effects on the central nervous system.     

Cimetidine's effect on dermal H1-receptor antagonist tolerance.

The effect of the H2-receptor antagonist cimetidine upon H1-receptor antagonist tolerant histamine induced weal and flare responses was studied in nine healthy male subjects taking clemastine 1 mg orally twice a day. After 21 days clemastine therapy, the weal response became tolerant to clemastine but the flare response did not. Cimetidine, 400 mg, did not produce a significantly greater decrease in the area of the H1-receptor antagonist tolerant weal response than in the non-tolerant weal response. The results suggest that histamine mediated skin reactions may develop a tolerance to H1-receptor antagonist therapy that cannot be overcome by the addition of the H2-receptor antagonist cimetidine.     

Effect of captopril on skin blood flow following intradermal bradykinin measured by laser Doppler flowmetry

Summary The effect of captopril on skin response to intradermal injection of bradykinin was investigated by laser Doppler flowmetry (LDF) and weal and flare measurements in this randomised, double-blind, placebo-controlled, cross-over balanced study. Intradermal injections of 1 and 2.5 µg of bradykinin and normal saline were made into the forearm skin of six healthy volunteers between 1 and 2 h (t1) and between 3 and 4 h (t2) after either 25 mg captopril or placebo. Skin blood flow outside the induced weal was monitored continuously by LDF for 15 min and the mean LDF values over the last 15 s were used for analysis. Weal and flare sizes were measured at 15 min.On the placebo days, the mean LDF output, weal volume and flare area increased with incremental bradykinin dose. Pre-treatment with captopril significantly increased LDF output following intradermal bradykinin at t1 but not at t2. At both t1 and t2, captopril significantly increased weal volume. There was no significant difference between treatments in flare areas. Skin response following intradermal normal saline, measured by the above parameters, was not affected by captopril.This study showed that captopril potentiated the effects of intradermal bradykinin both with respect to blood flow changes and weal formation. The non-invasive technique of LDF can be used to detect the skin blood flow changes induced by intradermal bradykinin and the potentiation of this effect by captopril. It appears to be a useful and more objective method of quantifying local cutaneous blood flow changes than measurement of flare area.     

A double-blind placebo controlled dose response study of noberastine on histamine induced weal and flare

Summary The antihistaminic effects of 7 days treatment with each of three doses of noberastine (10, 20 and 30 mg) were compared to placebo in 12 healthy male volunteers. The antihistaminic activity was assessed from the inhibition of weal and flare formation after intradermal histamine injections. For both weal and flare there was a highly significant effect of treatment with each of the three doses of noberastine, compared to placebo. The 30 mg daily dose produced the maximum inhibition of weal and flare. The daily mean values for the assessment of sedation by visual analogue scales at 09.00 h, 15.00 h and 21.00 h showed no significant treatment, or order, effect for any of the three doses of noberastine compared to placebo. The mean steady-state plasma concentrations of noberastine were significantly higher with increasing daily doses of noberastine (trough concentrations: 1.0, 1.6 and 2.2 ng·ml^–1; peak concentrations: 3.5, 13.4 and 20.9 ng·ml^–1 for 10, 20 and 30 mg daily dose, respectively). The percentage weal inhibition correlated (r=0.77) with steady-state noberastine plasma trough levels. The percentage flare inhibition showed a weaker correlation (r=0.35) with steady-state noberastine plasma trough levels.     

Effects of substance P, neurokinin A and calcitonin gene-related peptide in human skin and their involvement in sensory nerve-mediated responses

The effects evoked by intradermal injections of substance P (SP), neurokinin A (NKA) or calcitonin gene-related peptide (CGRP) were studied in 51 non-atopic subjects. SP and NKA produced flare and weal, and CGRP produced an indurated erythema. The reactions to SP were strong, the flare being maximal 3-5 min after injection and the weal after 10-15 min. NKA evoked a much weaker flare and a slightly weaker weal than did SP. CGRP produced a prominent long-lasting, indurated erythema with pseudopodia surrounded by a pallor edge. The mode of action of the three peptides was studied by pretreatment of the skin with the histamine-releasing compound 48/80, the H1-antagonist mepyramine or the local anesthetic xylocaine. The results suggest that mast-cell histamine and an intact sensory nerve supply are essential for the flare response to both SP and NKA. The weal response to SP was somewhat reduced by pretreatment with either 48/80 or xylocaine. The weal response to NKA, however, did not seem to depend upon either mast cells or sensory nerve fibres. The erythema evoked by CGRP was not suppressed by pretreatment with xylocaine, compound 48/80 or mepyramine, suggesting a direct action of CGRP on the blood vessels. The interaction between SP and CGRP was studied in subjects receiving a low dose of CGRP and increasing doses of SP or a low dose of SP and increasing doses of CGRP. CGRP did not potentiate the SP-evoked flare and weal and SP did not seem to enhance the response to CGRP.     

Histamine weal formation and absorption in man.

1 The weal and flare response to intradermal histamine was measured over a range of doses in forearm skin of man. 2 The use of calipers to measure weal thickness was validated by measurement of observer and method errors. Repeated measurements at intervals of 5 min or more compressed the weals by 6% per reading. 3 Flare response reached a maximum at 5 min compared with 20 min for weal thickness and the sensitivity of the flare response was greater than the weal response at lower doses of histamine. 4 Sensitivity, lambda was comparable for the measurement of flare, weal diameter and thickness or volume. The advantage of weal thickness was in the measurement of weal formation and resorption. 5 The time course of histamine weal formation and disappearance was measured and found to have a T1/2 of 5.4 min and 87 min, respectively. 6 The T1/2 of disappearance of comparable 09% w/v NaCl solution and serum weals were 18 and 28 min respectively. 7 It is suggested that persistence of histamine weals is due to a vasoactive agent other than histamine.     

A comparison of the effects of captopril and enalapril on skin responses to intradermal bradykinin and skin blood flow in the human forearm.

1. The effects of captopril and enalapril on skin responses to intradermal injections of bradykinin and skin blood flow in the forearm were investigated in this randomised, double-blind, placebo-controlled, cross-over study. 2. Intradermal injections of 0, 1, 2.5 and 5 micrograms of bradykinin in 0.9% sodium chloride were made into the forearm of twelve healthy volunteers before and at 2, 6 and 24 h after single oral doses of 25 mg captopril, 10 mg enalapril or placebo. Forearm skin blood flow was measured by the technique of laser Doppler flowmetry (LDF) before the injections were made and the skin responses evaluated at 15 min after injections of bradykinin by measurement of cutaneous blood flow outside the induced weal, erythema area and weal volume. 3. The bradykinin-induced cutaneous responses measured by LDF, erythema area and weal volume increased with incremental bradykinin dose. Compared with placebo, captopril significantly augmented the cutaneous vasodilator effects of bradykinin, measured by LDF and erythema area, at 2 h and the weal responses at 2 and 6 h. Enalapril enhanced the vasodilator responses to bradykinin at 2 and 6 h and the weal responses at 2, 6 and 24 h. Neither captopril nor enalapril significantly affected forearm skin blood flow. 4. This study showed that captopril and enalapril potentiated the effects of intradermal bradykinin both with respect to blood flow changes and weal formation in keeping with effective kininase II inhibition and the time course of these changes are consistent with enalapril being a longer acting drug than captopril. Captopril and enalapril exerted no influence on forearm skin blood flow measured by LDF.     

Comparative wheal and flare study of mizolastine vs terfenadine, cetirizine, loratadine and placebo in healthy volunteers.

1. Mizolastine, a new benzimidazole derivative with potent selective, non-sedative H1-histamine antagonist activity was compared with terfenadine, cetirizine and loratadine using the histamine-induced wheal and flare model in healthy volunteers. 2. Study design was a five way double-blind crossover design using a single dose of mizolastine 10 mg, terfenadine 120 mg, cetirizine 10 mg, loratadine 10 mg and placebo. 3. Histamine tests were performed on 10 occasions up to +24 h after dosing using an intradermal injection of histamine 2 micrograms with concommittant contralateral injection of a saline control. 4. Mizolastine, terfenadine, cetirizine and loratadine significantly (P < 0.001 vs placebo) inhibited the wheal and flare formation starting 1 to 2 h after dosing up to 24 h after dosing. 5. Mizolastine was significantly more active than loratadine on the wheal (P < 0.01) and flare (P < 0.05) inhibition from 3 up to 6 and 8 h respectively, as active as terfenadine on both parameters and as active as cetirizine on wheal inhibition while less active (P < 0.01) than cetirizine on flare inhibition at 2 and 12 h post-dosing.     

Sensory neuropeptide effects in human skin.

1 Neuropeptides released from sensory nerves may account for cutaneous flare and wheal following local trauma. In 28 normal subjects we have studied the effects of four sensory neuropeptides given by intradermal injection on the forearm or back. 2 All peptides caused a flare distant from the site of injection, presumably due to an axon reflex. Substance P (SP) was the most potent (geometric mean dose causing 50% of maximum flare, 4.2 pmol). Neurokinin A (NKA) was the next most potent with neurokinin B (NKB) and calcitonin gene-related peptide (CGRP) the least. The distant flare response to SP, NKA and NKB was maximal at 5 min and disappeared within 2 h. 3 CGRP caused a local erythema over the site of injection at doses above 0.5 pmol which at higher doses lasted for up to 12 h. 4 SP, NKA and NKB caused wheals at doses above 5 pmol with SP and NKB being the most potent. CGRP (up to 250 pmol) did not consistently cause wheal formation. There was no significant effect of coinjection of CGRP upon the response to SP although there was a tendency for an enhancement of the wheal response. 5 The H1-histamine antagonist terfenadine (60 mg orally) significantly inhibited the wheal and distant flare response to histamine (5 nmol) and NKA, but not that caused by NKB. The distant flare of CGRP was also reduced but the local erythema was unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)     

The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare

AIM: To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (L-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments. METHODS: Twenty healthy volunteers (18-50 years) received L-CTZ 5mg, CTZ 10 mg, LOR 10 mg, PRM 30 mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100 mg/ml histamine solution at baseline and at 1, 2, 3 ,4, 6, 8, 10 and 122 hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit. RESULTS: The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p < 0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p < 0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p < 0.005) and significantly higher ratings of subjective sedation on day 1 (p < 0.05). L-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, L-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4. CONCLUSIONS: In a study where the psychometric assessments were shown to be sensitive to impairment, L-CTZ 5 mg was found following both initial and repeated doses, but also to be demonstrably free from disruptive and sedative effects on objective measures of psychomotor and cognitive function. Similarly, CTZ showed evidence of pronounced antihistaminic activity and significantly reduced weal and flare scores after both acute and repeated doses, again without evidence of cognitive or psychomotor impairment. LOR also was non-sedative but the antihistaminic reaction was demonstrably weak.     

The effects of cicletanine, a new antihypertensive compound, on the flare and weal response to histamine

This was an open experimental pilot study in five volunteers to identify any useful effect of cicletanine in the prevention or relief of the flare and weal response to histamine injection on the forearm. Areas of the flare and weal responses to three different concentrations of intradermal histamine injection were determined. Choice reaction time was measured to assess CNS performance. Heart rate, blood pressure and visual near-point were measured as indices of autonomic response. Oral cicletanine (200 mg) reduced the flare and weal response below pretreatment values for at least 8 h (p less than 0.05). There were no apparent changes in heart rate or visual near-point, nor any sedative effects. Diastolic blood pressure was significantly elevated 6 and 8 h after cicletanine (p less than 0.05) but systolic blood pressure was not affected. These results show that cicletanine is a potent non-sedative antihistamine compound.     

The Acute and Sub-chronic Effects of Levocetirizine,Cetirizine, Loratadine,Promethazine and Placebo on Cognitive Function,Psychomotor Performance,and Weal and Flare

Summary

Aim: To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (l-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments.

Methods: Twenty healthy volunteers (18–50 years) received l-CTZ 5?mg, CTZ 10?mg, LOR 10?mg, PRM 30?mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100mg/ml histamine solution at baseline and at 1, 2, 3,4, 6,8,10 and 12?hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit.

Results: The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p?<?0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p?<?0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p?<?0.005) and significantly higher ratings of subjective sedation on day 1 (p?<?0.05). l-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, l-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4.

Conclusions: In a study where the psychometric assessments were shown to be sensitive to impairment, l-CTZ 5?mg was found not only to be a potent inhibitor of the histamine-induced weal and flare reaction,     

The role of histamine in the acute inflammatory responses to intradermal platelet activating factor.

1. The role of histamine in PAF-induced acute inflammatory responses (flare and weal) in the skin has been evaluated in a series of three separate studies. 2. Terfenadine, a potent H1-selective histamine antagonist virtually abolished the flare response and significantly inhibited the weal response. 3. Histamine depletion in the skin using compound 48/80 resulted in similar effects on the flare and weal response. Two consecutive daily injections of compound 48/80 were found to deplete comprehensively skin sites of histamine and the ability of skin to respond to PAF was completely restored within 2 weeks of compound 48/80 treatment. 4. Intradermally injected PAF was associated with acute rises in plasma histamine in blood drawn from a draining vein with peak concentrations occurring within 5 min of injection. 5. No difference in PAF-induced flare and weal response was found between atopic and non-atopic subjects and this was reflected in the peak plasma histamine results. A significantly higher baseline plasma histamine was found in the atopic group, however, when compared with the non atopic group. 6. It is concluded that histamine has an important role in the acute inflammatory responses to intradermally injected PAF, although there does appear to be a significant direct vascular component in the PAF-induced weal response.     

The effect of sulindac on dermal responses to bradykinin in normal subjects given an angiotensin converting enzyme inhibitor.

The ability of sulindac to modify the weal response to four doses of intradermal bradykinin in subjects given enalapril was tested in a double-blind cross-over study in normal volunteers. The dose-dependent increase in skin thickness after bradykinin was significantly reduced by prior administration of sulindac. Certain of the actions and adverse effects of angiotensin converting enzyme inhibitors may be due to the interaction of prostaglandins and bradykinin.     

Enhanced weal and flare response to histamine in chronic idiopathic urticaria.

Weal and flare histamine dose-responses were measured in 30 normal subjects and 15 patients with chronic idiopathic urticaria. The log dose-response curves were shifted to the left corresponding to an increase in histamine potency of 2.5 for weal and 3.1 for flare. An enhanced response to histamine may be important in chronic idiopathic urticaria and comparison of potency of antihistamines in different subjects may be unreliable where initial weal response is abnormal.     

Azelastine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential

Azelastine is an antiallergic agent which demonstrates histamine H1-receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis - comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis. Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4 mg dose. Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day. Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.     

Adenosine triphosphate-evoked vascular changes in human skin: Mechanism of action

Adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine, adenine and inosine were injected intradermally into the backs of human volunteers. ATP, ADP and AMP evoked weal and flare responses in the skin in a dose dependent manner. The rank order of potency was ATP>ADP>AMP; other metabolites were apparently inactive. The potency of ATP was approximately 0.002 times that of histamine. In the forearm, cross tachyphylaxis was demonstrated between ATP and histamine weals; also the flare due to injected ATP spead beyond a band which was applied to prevent diffusion, indicating that the flare is neurogenic. Injections of ATP and high doses of ADP produced a sensation of persistent pain, unlike histamine which produced transient pain or itch on some occasions, and saline which was without effect. The possible involvement of histamine, mast cells and prostaglandins in the response was examined. The inhibitory actions of systemic pretreatment with diphenhydramine suggests that the erythema and wealing responses to ATP are at least partly due to ATP-evoked histamine release. Indomelhacin, doxantrazole and cimetidine did not alter the ATP reaction.