Comparison of the effects of desloratadine and levocetirizine on histamine-induced wheal,flare and itch in human skin

Objective: A previous study showed the inhibitory effects of loratadine on histamine-induced wheal, flare and itch in human skin to be very variable between individuals. It was hypothesised that this variability may have been due to differences in the rates of metabolism of loratadine to its active form, desloratadine. This double blind, crossover study examined the effects of desloratadine in 12 healthy volunteers. Levocetirizine was used as a comparator. Methods: Desloratadine (5 mg), levocetirizine (5 mg) or placebo was taken orally 4 h before an intradermal injection of histamine (20 l, 100 M) or vehicle control into the forearm skin. Flare areas were assessed by scanning laser Doppler imaging before and at 30 s intervals for a period of 9 min. Wheal areas were measured by planimetry at 10 min. Itch was scored every 30 s for 5 min using a visual analogue scale. Results: Following placebo administration, the mean (± SEM) wheal area at 10 min was 79.3 ± 6.9 mm², mean flare area for the first 5 min following challenge 26.6 ± 2.7 cm², and itch score for the same period 48.5 ± 7.6%. The effects of desloratadine were variable between individuals, mean reductions in the wheal and flare areas being 17% (P = 0.033) and 12% (P = 0.036). Desloratadine did not reduce itch significantly. Levocetirizine was more consistent in its effects, mean reductions in wheal, flare and itch being 51%, 67% 78% respectively (all P < 0.001). Conclusions: A single dose of 5 mg levocetirizine produced more consistent and greater inhibitory effects on histamine-induced wheal, flare and itch than did 5 mg desloratadine. The difference is suggested to reflect the basic pharmacokinetics of the two drugs.Received 21 May 2003; returned for revision 29 May 2003; accepted by M. Parnham 5 June 2003     

Tissue Repair and Fibrosis

Background

Because antileukotrienes may inhibit inflammation, it is plausible that montelukast administered for a long time could suppress skin wheal and flare reaction, and thus, it should be discarded prior to the tests. This study assessed the effect of long-lasting treatment with montelukast alone or in combination with antihistamines on wheal and flare in skin pricks tests (SPT) in patients sensitized to perennial allergens.

Methods

We conducted a 32-week, double-blind, placebo-controlled, cross-over and randomized trial that implicated two arms: arm A, 20 patients received levocetirizine, montelukast with or without levocetirizine or placebo; arm B, 20 patients received desloratadine, montelukast with or without desloratadine or placebo. All treatment periods lasted 6 weeks and were separated by 2-week washouts. At baseline and on the last day of each treatment period, SPT were performed in all participants.

Results

Both levocetirizine and desloratadine in monotherapy, or in combination with montelukast, were effective in reducing wheal and flare in SPT. Monotherapy with montelukast did not change the size of the wheal for either histamine or for house dust mites, in either arm of the study, but significantly reduced the size of flare for histamine in arm A. Addition of montelukast to antihistamine did not exceed efficacy of monotherapy with antihistamine in both arms of the study.

Conclusions

Since the size of wheal determines the results of SPT, montelukast, even taken for a long time, does not have to be discarded prior to the tests.     

Relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo using a skin test model of wheal-and-flare suppression.

BACKGROUND: H1-receptor antagonists differ in their ability to produce peripheral H1-blockade. Suppression of histamine-induced flares and wheals is a useful objective test for measuring these differences. OBJECTIVE: To evaluate the relative potency of fexofenadine HCI 180 mg, loratadine 10 mg, and placebo (PBO) in suppressing histamine-induced flares and wheals and compare the onset, duration, and maximum suppression of histamine achieved with each agent. METHODS: Thirty healthy volunteers were enrolled in this randomized, double-blind, single-dose, crossover study. Flares and wheals induced by skin-prick testing with histamine 1.8 mg/mL were measured before treatment, every 20 minutes during the first hour after dosing, and thereafter hourly between 2 and 12 hours and between 23 and 25 hours postdose. RESULTS: Fexofenadine was significantly more effective than loratadine in suppressing the histamine-induced flare response at hours 2 through 7 and 10 through 12 and produced greater flare suppression than did PBO at hours 2 through 25. Onset of flare suppression occurred 2 hours after dosing with fexofenadine and 4 hours after dosing with loratadine. Likewise, fexofenadine was superior to loratadine in suppressing the wheal response from hours 1 through 12 and was more effective than PBO at hours 1 through 12, 24, and 25. Throughout the 25-hour measurement interval, the magnitude of difference in both wheal and flare suppression consistently favored fexofenadine over loratadine. CONCLUSIONS: In a skin test model of wheal-and-flare suppression, fexofenadine showed rapid distribution into the skin compartment with faster onset of action and greater potency vs loratadine.     

Atopic skin test re-evaluated. V. The wheal-flare ratio of skin reactions to extracts of grass pollen, Dermatophagoides pteronyssinus and to histamine and compound 48/80.

Some formulas are given for the relationship between the sizes of wheals and flares of skin reactions to three allergen extracts and to histamine and compound 48/80. Only compound 48/80 shows a somewhat different wheal/flare relationship.     

Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin

BACKGROUND: This randomized, double-blind, crossover study compared the effects of the R-enantiomer of cetirizine, levocetirizine, with those of loratadine on the wheal, flare, and itch response to histamine in human skin. METHODS: Levocetirizine (5 mg), loratadine (10 mg), or placebo was taken orally 4 h before the intradermal injection of histamine (20 microl, 100 microM) or the control vehicle into the forearm skin of healthy volunteers. Flare areas were assessed by scanning laser Doppler imaging before and at 30-s intervals for a period of 9 min. Wheal areas were measured by planimetry at 10 min. Itch was scored every 30 s with a visual analogue scale. RESULTS: After placebo administration, the mean peak flare area was 23.01+/-1.94 cm(2), the wheal area 248+/-27 mm(2), and the cumulative itch score 28.8+/-4.6% (mean+/-SEM). Levocetirizine reduced the flare, wheal, and itch by 60%, 68%, and 91%, respectively (all P<0.001, Student's t-test for paired data). The effects of loratadine were variable and not statistically significant. CONCLUSION: Levocetirizine (5 mg) is a potent inhibitor of the effects of histamine in human skin with an efficacy that exceeded that of loratadine (10 mg) when single doses of the drugs were administered 4 h before the test.     

A double‐blind, single‐dose, crossover comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine versus placebo: suppression of histamine‐induced wheal and flare response for 24 h in healthy male subjects

BACKGROUND: New H1-antagonists have become available, but there has been no comparison of their potency for inhibiting histamine in the skin. METHODS: Cetirizine 10 mg, ebastine 10 mg, epinastine 20 mg, fexofenadine 60 mg, terfenadine 60 mg, loratadine 10 mg, or placebo was given to 14 healthy male volunteers in a double-blind, crossover randomized manner. Inhibition of the wheal and flare response to epicutaneous histamine phosphate (100 mg/ml) challenge was measured at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h after doses. RESULTS: Epinastine inhibited the wheal and flare after 30 min. Cetirizine commenced acting at 1 h and was superior to other treatments. Ebastine was no better than placebo until 4 h, but was efficacious thereafter until 24 h. Terfenadine induced potent inhibition after 1 h and was superior to its metabolite fexofenadine. Loratadine was the least potent inhibitor. Inhibition of the flare response paralleled the patterns seen for wheals. The rank order for area under the curve (0-24 h) was cetirizine, epinastine, terfenadine, ebastine, fexofenadine, loratadine, and placebo. CONCLUSIONS: The inhibition of histamine effects in the skin may be useful in predicting the clinical utility of newly introduced antihistamines in treating allergic disorders.     

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects

BACKGROUND: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to sixfold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P < 0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P < 0.01) and 65% for PT (P < 0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.     

Cetirizine inhibits bradykinin-induced cutaneous wheal and flare in atopic and healthy subjects

BACKGROUND: Kinins are vasoactive mediators involved in allergic reactions. When applied on the skin or in the nose, bradykinin (BK) elicits inflammation that is poorly affected by previous H1-blockade. The aim of this study was to compare the possible effect of cetirizine (an H1-antagonist) on wheal and flare responses to BK, histamine, and compound 48/80 in atopic and healthy subjects. METHODS: In a randomized, double-blind, crossover study, eight atopic and eight healthy subjects received cetirizine (10 mg/day) or placebo for 3 days before cutaneous tests. Intradermal tests (IDT) and prick tests (PT) were performed with BK (20 nmol/ml for IDT and 20 micromol/ml for PT), histamine (100 microg/ml IDT and 100 mg/ml PT), and compound 48/80 (100 microg/ml IDT and 100 mg/ml PT) as positive controls and saline as negative control. The skin responses were monitored by measurement of wheal and flare areas. RESULTS: BK, histamine, and 48/80 induced wheal and flare reactions in all placebo-treated subjects. Histamine elicited larger wheal and flare reactions than BK and 48/80. IDT with BK induced four- to six-fold larger wheal and flare reaction than PT. No differences in BK-induced wheal and flare were observed between atopic and healthy subjects. In atopic subjects, cetirizine induced a significant reduction of flare reactions after the BK test (80% for IDT, and 94% for PT [P<0.01]). Moreover, cetirizine reduced significantly BK-induced wheals by 70% for IDT (P<0.01) and 65% for PT (P<0.01). A similar inhibiting effect of cetirizine was also observed in healthy subjects. CONCLUSIONS: These findings showed that the wheal and flare reactions induced by BK challenge were markedly inhibited by previous intake of cetirizine. The mechanism by which this effect is mediated cannot be established at present.     

Comparative activity of cetirizine and desloratadine on histamine-induced wheal-and-flare responses during 24 hours.

BACKGROUND: Cetirizine and desloratadine are antihistamines active in the treatment of symptoms associated with seasonal allergic rhinitis and chronic urticaria. OBJECTIVE: To compare the antihistamine activity of desloratadine, the active metabolite of loratadine, with that of cetirizine in the skin wheal-and-flare responses during 24 hours. METHODS: This was a double-blind, randomized, placebo-controlled, single oral dose, crossover study. Skin reaction to histamine (100 mg/mL), administered by prick tests, was measured by the wheal and flare surface areas for 24 hours (before treatment and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours). Eighteen healthy volunteers (mean age, 33.9 years; 13 women) participated in this study. The areas under the curves of the wheal-and-flare responses as a function of time (primary efficacy variables) were compared using analysis of variance. RESULTS: A highly significant overall treatment effect (P < .001) was detected for wheal and flare inhibition, with the activity of cetirizine and desloratadine significantly superior to that of placebo (P < .001). In addition, the activity of cetirizine was significantly superior to that of desloratadine (P < .001). With desloratadine, only 3 of the 18 subjects achieved a wheal inhibition of at least 70%, occurring between 2 and 4 hours, whereas all subjects using cetirizine reached a wheal inhibition of at least 70% between 0.5 and 3 hours (median time, 1.7 hours). The difference between the 2 active drugs was highly significant (P < .001). The median duration of wheal inhibition of at least 70% was zero with placebo and desloratadine and was 21.9 hours with cetirizine (P < .001). No serious adverse events were reported, and no subject withdrew from the study due to an adverse event. CONCLUSION: Cetirizine was associated with significantly greater suppression of skin reactivity to histamine compared with desloratadine during 24 hours after a single dose, with a consistent duration of action for cetirizine, as previously reported.     

Levocetirizine: pharmacokinetics and pharmacodynamics in children age 6 to 11 years

BACKGROUND: The pharmacokinetics and pharmacodynamics of medications may differ between children and adults, necessitating different dose regimens for different age groups. Levocetirizine, the active enantiomer of cetirizine, is used in the treatment of allergic rhinitis and chronic urticaria in Europe. Its pharmacokinetics and pharmacodynamics have not yet been studied prospectively in school-age children. OBJECTIVES: This study was performed to investigate levocetirizine pharmacokinetic disposition and pharmacodynamics in relation to skin reactivity to histamine in children aged 6 to 11 years. METHODS: Blood samples were obtained at predose baseline and at defined intervals up to and including 28 hours after a 5-mg levocetirizine dose. Concurrently, epicutaneous tests with histamine phosphate, 1 mg/mL, were performed. Wheals and flares were traced at 10 minutes, and the areas were measured with a computerized digitizing system. RESULTS: In children aged 8.6 +/- 0.4 years (+/- SEM), the peak levocetirizine concentration was 450 +/- 37 ng/mL, and the time at which peak concentrations occurred was 1.2 +/- 0.2 hours. The terminal elimination half-life was 5.7 +/- 0.2 hours, the oral clearance was 0.82 +/- 0.05 mL/min/kg, and the volume of distribution was 0.4 +/- 0.02 L/kg. Compared with predose areas, the wheals and flares produced by histamine phosphate were significantly decreased from 1 to 28 hours, inclusive (P < .05). Mean maximum inhibition of wheals and flares occurred from 2 to 10 hours (97% +/- 1%) and from 2 to 24 hours (93% +/- 1%), respectively. CONCLUSIONS: Levocetirizine had an onset of action within 1 hour and provided significant peripheral antihistaminic activity for 28 hours after a single dose. Once-daily dosing may be optimal in children aged 6 to 11 years, as it is in adults.     

Reproducibility of Histamine Skin Prick Test

The reproducibility of skin prick test using histamine dihydrochloride 1, 5, and 10 mg/ml was tested by three nurses in five non-atopics in a double-blind trial. The variations day-to-day, within-day, between and for the same tester were calculated. Seventy-five percent of wheal reactions obtained by histamine 1 mg/ml were less than 15 mm2. With histamine 5 mg/ml there were only a few wheals less than 15 mm2 and none at all with histamine 10 mg/ml. The mean coefficient of variation of wheals greater than 15 mm2 was between 20-30%, in contrast to figures between 30-60% with wheals less than 15 mm2. No significant day-to-day or within-day variation was shown concerning histamine wheal areas. It is suggested that histamine dihydrochloride 10 mg/ml should replace histamine dihydrochloride 1 mg/ml as the positive reference in routine skin prick tests and biological standardization.     

Effect of Topical Indomethacin on Allergen-Induced Dual Skin Reactions

Twelve asthmatics with dual bronchial and skin reactions after allergen challenge received topical treatment with a 5%-indomethacin cream half an hour before and up to 7h after intradermal allergen and histamine injections. The erythema during the first 20 min of the wheal and flare reaction (WFR) was not affected, neither were the diameters of wheals and flares. 40 to 60 min after injection we observed a marked reduction of the erythema in histamine-and allergen-tested skin areas of 10 Patients. This effect lasted up to the 5th h alter injection of high allergen doses. During the hilly developed late cutaneous reactions (LCR) no effect 0f indomethacin on the erythema was observed, the edema of LCR was only insignificantly reduced. These results suggest that the erythema in LCR between the 1st and 4th is caused, at least in part, by local formation of prostaglandins.     

Urinary levels of RANTES and M-CSF are predictors of lupus nephritis flare

Objective: To explore a new predictor of renal flares after successful inductive treatment for diffuse proliferative glomerulonephritis(DPGN) in patients with lupus nephritis. Methods: A cohort of patents with SLE DPGN who were treated initially with prednisone and cyclophosphamide were studied. Those who responded to inductive treatment were followed up for the occurrence of renal flares. Urinary levels of RANTES, MCP-1 and M-CSF were measured by ELISA. Other clinical and laboratory data were collected. The predictors and outcome of renal flare were analyzed. Results: Seventy-three qualified patients with SLE DPGN were investigated. After a mean follow-up of 24.5 ± 6.4 months, 22 patients experienced renal flares. The median time to relapse was 14.1 ± 4.1 months. The patients experiencing renal flare showed higher urinary RANTES, MCP-1 and M-CSF. However, independent predictors of renal flares were increased urinary RANTES and M-CSF. Eight patents developed doubling of the serum creatinine (CRX2) level. The occurrence of renal flares was the only predictor of CRX2. Conclusions: Persistently increased urinary levels of RANTES and M-CSF after initial remission are predictors of renal flare in patients with SLE DPGN. Our results indicate monitoring urinary pro-inflammatory factors may direct us in managing those patients. Received 6 September 2006; returned for revision 30 November 2006; returned for final revision 23 February 2007; accepted by G. Wallace 19 March 2007     

Comparison of the efficacy of levocetirizine 5 mg and desloratadine 5 mg in chronic idiopathic urticaria patients

Background: Nonsedating H₁‐antihistamines are recommended for the treatment of urticaria by the recent EAACI/GA²LEN/EDF guidelines. The aim of this study was to compare the efficacy, after 4 weeks of treatment, with levocetirizine 5 mg and desloratadine 5 mg, both once daily in the morning, in symptomatic chronic idiopathic urticaria (CIU) patients. Methods: This multi‐center, randomized, double‐blind study involved 886 patients (438 on levocetirizine and 448 on desloratadine). The primary objective was to compare their efficacy on the mean pruritus severity score after 1 week of treatment. Mean pruritus severity score over 4 weeks and pruritus duration score, number and size of wheals, mean CIU composite score (sum of the scores for pruritus severity and numbers of wheals), quality of life, and the patient’s and investigator’s global satisfaction with treatment, were secondary efficacy measures. Results: Levocetirizine led to a significantly greater decrease in pruritus severity than desloratadine over the first treatment week; mean pruritus severity scores of 1.02 and 1.18 for levocetirizine and desloratadine, respectively (P < 0.001). The result was similar for the entire 4‐week treatment period (P = 0.004). In addition, levocetirizine decreased pruritus duration and the mean CIU composite scores to a significantly greater extent than desloratadine during the first week (P = 0.002 and 0.005, respectively) and over the entire study (P = 0.009 and P < 0.05, respectively). Similarly, levocetirizine increased the patients’ global satisfaction after one and 4 weeks (P = 0.012 and 0.021, respectively), compared with desloratadine. Safety and tolerability were similar in both groups. Conclusions: Levocetirizine 5 mg was significantly more efficacious than desloratadine 5 mg in the treatment of CIU symptoms.     

A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers

BACKGROUND: Cetirizine is a highly efficacious and long-acting second-generation H1-receptor antagonist for the treatment of allergic diseases, such as allergic rhinitis and chronic idiopathic urticaria, in adults and children. Pharmacologic studies have demonstrated that cetirizine, a racemate mixture composed of equal amounts of two enantiomers, does not undergo hepatic metabolism to any significant level. The enantiomers are excreted mainly unchanged, predominantly in the urine and to a lesser extent in the faeces. METHODS: The pharmacologic activity and potency of the two enantiomers of cetirizine in the management of allergic skin conditions were investigated by studying the effect of treatment with 5.0 mg cetirizine; 2.5 mg levocetirizine, the (R)-enantiomer; and 2.5 mg ucb 28557, the (S)-enantiomer, on histamine-induced wheal and flare response in 18 healthy volunteers. Each treatment was administered as a single oral dose in randomized, double-blind, and crossover manner, and the efficacy of treatment was assessed over a period of 32 h, as per cent inhibition of the histamine-induced wheal and flare areas before treatment. Blood and urine samples were collected in a time-dependent manner and analyzed for the total amounts of each study drug, to elucidate their pharmacokinetic profiles. RESULTS: Both cetirizine and levocetirizine caused a marked inhibition of histamine-induced wheal and flare, whereas ucb 28557 was inactive in this model. Inhibition of the wheal response observed for cetirizine and levocetirizine was apparent by 1 h after dosage and lasted for mean durations of 24.4 and 28.4 h, respectively. In addition, the response for cetirizine and levocetirizine became maximal by 6 h after treatment, rising to 79.5% and 83.8%. Similarly, cetirizine and levocetirizine also markedly inhibited the histamine-induced flare response. This effect was evident for both drugs by 1 h after dosage and lasted over a mean period of 28.4 and 26.0 h, respectively, for cetirizine and levocetirizine. The inhibitory effect of these compounds on histamine-induced flare response was also maximal by approximately 6 h after dosage, peaking at 88.5%) and 83.6%, respectively. Statistical evaluation showed that cetirizine and levocetirizine were equivalent for maximum inhibition of histamine-induced wheal and flare. However, levocetirizine was found to be superior to cetirizine when area under the curve was compared. In contrast, ucb 28557 was not found to inhibit histamine-induced wheal and flare responses at any time during the study period. Plasma concentrations of levocetirizine were found to be approximately double those of ucb 28557 at 4 and 8 h after dosing, and 50-60% of the drugs were excreted unchanged in urine over a period of 32 h. CONCLUSIONS: The finding that, in this model, levocetirizine 2.5 mg has comparable antihistaminic activity to cetirizine 5 mg, whereas its other enantiomer ucb 28557 has no pharmacodynamic effect, suggests that the antihistaminic properties of cetirizine observed in the management of allergic skin conditions are likely to be attributable to levocetirizine.     

Wheal and flare responses to muscl relaxants in humans

Chemically and pharmacologically unrelated molecules release histamine in humans to produce both cutaneous and systemic responses. It has been suggested that molecular changes in the new benzylisoquinoline-derived muscle relaxant, atracurium, make it less likely to cause histamine release. We therefore injected volunteers intradermally with equimolar concentrations of various muscle relaxants, morphine, papaverine (a benzylisoquinoline), and histamine, to evaluate the relative ability of these drugs to cause wheal and flare responses, and mast-cell degranulation. There were no significant differences in wheal and flare responses among the three benzylisoquinoline-derived muscle relaxants,d-tubocurarine, metocurine, and atracurium. The cutaneous effects of morphine were significantly greater than those of the benzylisoquinoline muscle relaxants, suggesting both direct vascular changes and histamine release. Papaverine injection was followed by a significant wheal but no flare. Skin biopsies from vecuronium- and papaverine-induced wheals revealed normal intact mast-cell granules, suggesting a direct cutaneous vascular response rather than histamine release. Skin biopsies after morphine and atracurium injections revealed mast-cell degranulation. All evaluated benzylisoquinoline muscle relaxants are equipotent histamine releasers at equimolar concentrations. A hydrogenated, benzylisoquinoline-nitrogen-containing ring, present in atracurium but not in papaverine, appears to be the molecular conformation responsible for mast-cell degranulation by atracurium.     

Lack of subsensitivity to terfenadine during long-term terfenadine treatment

Eleven healthy male volunteers ingested terfenadine, 60 mg, every 12 hours for 56 days. Compliance was monitored strictly throughout the study. Before the first terfenadine dose on day 0, and 12 hours after the evening terfenadine dose every seventh day and on randomly selected "unscheduled" days, wheal-and-flare areas were measured after intradermal injections of 0.01 ml of histamine phosphate (1.0 mg/ml and 0.1 mg/ml). On days 0, 28, and 56, six volunteers had skin tests hourly for 12 hours after the morning terfenadine dose. On all study days, serum terfenadine metabolite I concentrations were measured each time histamine skin tests were performed. On days 7, 14, 21, 28, 35, 42, 49, and 56, the mean areas of the histamine-induced wheals did not differ significantly from each other but were significantly decreased compared to the mean wheal area on day 0 (p less than 0.01). On these days, the mean areas of the histamine-induced flares also did not differ significantly from each other but remained significantly suppressed compared to the mean flare areas on day 0 (p less than 0.01). Wheal-and-flare suppression was noted in all unscheduled histamine skin tests performed 12 hours after the evening terfenadine dose. In the subgroup of volunteers who had hourly tests, on day 0, the mean wheal-and-flare areas were significantly suppressed from 2 to 12 hours after the dose, with maximal wheal suppression occurring at 5 hours (p less than 0.05) and maximal flare suppression occurring from 3 to 9 hours (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of beta adrenergic stimulation and blockade on cutaneous reactivity to histamine.

It has been previously demonstrated that iontophoresis of beta adrenergic agents will alter the size of immediate hypersensitivity skin tests. It was unclear whether this alteration was due to an effect on the dermal mast cell (inhibition of histamine release) or on the cutaneous vasculature (inhibition of capillary permeability). For this reason isoproterenol, propranolol, diphenhydramine as a positive control, and saline as a negative control were iontophoresed onto the forearm of 10 atopic and 10 nonatopic adult subjects. In order to bypass histamine release from mast cells the patients were then challenged directly with histamine by the "prick" technique. The size of the resultant wheals was noted. The data obtained allowed the following conclusions: (1) The atopic group responded to histamine with greater wheal size than the nonatopic group. (2) Iontophoresis of diphyenhydramine effectively reduced the magnitude of the histamine wheal in both groups. (3) Isoproterenol decreased the wheal size in both groups. (4) Propranolol increased the wheal size in only the nonatopic group. (5) The successful modulation of the histamine-induced wheal and flare indicated that these drugs, regardless of their effect on the dermal mast cell, exert a measurable effect on the target organ (vasculature).     

Suppressive effects of histamine skin reactivity by a nonsedating antihistamine-mequitazine.

The suppressive activity of mequitazine (MQZ) on histamine skin reactivity was evaluated in 29 healthy subjects (age 22-25 years) in a single-blind study. Fifteen subjects received MQZ, at a dosage of 5 mg BID, for 7 days while 14 served as controls. A prick skin test with saline or histamine hydrochloride (1 mg/ml and 10 mg/ml) was performed in duplicate, on both forearms, starting from the baseline day and continuing for 4 days after medication had been discontinued (total of 11 days). The skin-test subject and the reader was unaware of the randomization process. Mean diameters of wheal and flare as well as the skin index scores (after Voorhost) were used in the analysis. Maximal flare suppression (as compared to the baseline values) was observed on day 6 (97% suppression for 1 mg/ml and 54% suppression for 10 mg/ml, p less than 0.01). Suppression of wheal size was significant (19% for 1 mg/ml and 28% for 10 mg/ml) but was not clinically relevant. Suppression of skin index scores was maximal on day 6 (71% for 1 mg/ml and 43% for 10 mg/ml, p less than 0.01). After MQZ had been discontinued, all measurements gradually returned to baseline values and were not different therefrom within 3 days. However, final measurements of wheal and flare were smaller than baseline values (60-94% of baselines). We conclude that MQZ, at the manufacturers's recommended dose of 5 mg BID, significantly suppressed flare size of histamine skin tests and recommend that MQZ be discontinued for at least 3 days prior to performing allergy skin tests.     

Compared peripheral H1 inhibiting effects of cetirizine 2 HCl and loratadine

Histamine-induced wheals and flares were measured in seven healthy volunteers zero, four, and eight hours after oral intake of cetirizine, 2.5, 5, and 10 mg; loratadine, 10, 20, and 40 mg; and placebo. Cetirizine (2.5, 5, and 10 mg) and loratadine (20 and 40 mg) significantly inhibited the histamine-induced wheals at all experimental times and with all histamine concentrations. This was not always the case with loratadine, 10 mg. Cetirizine, 2.5 mg, was as potent in inhibiting the histamine skin reactivity as loratadine, 10 mg.