Wheal Suppression Research Articles

Cetirizine Pharmacokinetics and Pharmacodynamics in Primary Biliary Cirrhosis

The new H1-receptor antagonist, cetirizine, is eliminated primarily unchanged by renal excretion and is thus potentially useful for relief of pruritus in patients with hepatic dysfunction, in whom many H1-receptor antagonists are contraindicated. The authors studied the elimination of cetirizine in six patients with primary biliary cirrhosis. In contrast to data obtained in healthy adults with normal hepatic function reported in the medical literature, they found that the mean serum elimination half-life value of cetirizine, 13.8 +/- 1.8 hours, was longer, and the mean clearance rate, 0.44 +/- 0.10 mL/min/kg, was lower (P < .05). The mean peak serum cetirizine concentration, 498 +/- 118 ng/mL, was higher, the mean area under the curve, 6438 +/- 1621 ng/mL/hr, was larger, and the mean fraction of the dose excreted as unchanged cetirizine in the urine, .32 +/- .14, was lower (P < .05). The duration of action of cetirizine was prolonged, as evidenced by significant suppression of the histamine-induced wheal and flare for 48 and 72 hours, respectively, after a single dose. Cetirizine elimination was impaired in patients with hepatic dysfunction.

Pharmacology of antihistamines

Unlike the classic antihistamines, the new H1-receptor antagonists do not block cholinergic or central H1 receptors and thus do not produce the side effects, such as sedation, impaired psychomotor performance, and excessive mucosal drying, that are commonly associated with the older agents. Important pharmacokinetic and pharmacodynamic differences that exist among this class of antihistamines translate into varying pharmacologic effectiveness. Terfenadine, loratadine, and cetirizine are all rapidly absorbed in healthy and allergic volunteers (peak plasma levels, 2 to 5 hours); astemizole, however, has an initial distribution phase of 2 to 3 days. Further, astemizole has the longest time to relief of symptoms in this class; histamine wheal inhibition is not apparent until the second day of 10 mg dosing and does not peak for 9 to 12 days. In comparison, terfenadine's antihistaminic action peaks at 3 to 4 hours, loratadine's at 4 to 6 hours, and cetirizine's at 4 to 10 hours. However, whereas the recommended dose of loratadine (10 mg) confers 50% wheal inhibition, 60 mg terfenadine produces an 85% to 90% inhibition. In addition, loratadine and cetrizine have apparent dose-related sedative effects.

A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: Suppressive effects on histamine-induced wheals and flares during 24 hours in normal subjects

We objectively tested the relative antihistaminic effects of cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60 mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo in healthy, male volunteers, mean age 25 +/- 4 years, and mean weight, 73 +/- 9 kg. The wheal areas and flare areas produced by epicutaneous tests with histamine phosphate, 1 mg/ml, before ingestion of the H1-receptor antagonist or placebo, and afterward, at 0.3 and 0.7 hours, then hourly from 1 to 12 hours and at 24 hours, were traced at 10 minutes and measured with an IBM-PC digitizer and stereometric software. In this experimental model, the H1-receptor antagonists differed significantly with regard to time of onset of action, amount of suppression of the histamine-induced wheal and flare, and duration of action. The rank order was, from most effective to least effective, cetirizine, 10 mg; terfenadine, 120 mg; terfenadine, 60 mg; loratadine, 10 mg; astemizole, 10 mg; chlorpheniramine, 4 mg; and placebo.

Diphenhydramine: Pharmacokinetics and Pharmacodynamics in Elderly Adults, Young Adults, and Children

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly

In a double-blind, randomized, crossover study, the H 1-receptor antagonists, terfenadine and chlorpheniramine, were investigated in eight healthy, fasting female subjects, aged 67.8 ± SD 0.8 years, who ingested single doses of terfenadine, 1 mg/kg (mean dose, 69.6 ± 11.2 mg), and chlorpheniramine, 0.12 mg/kg (mean dose, 8.4 ± 1.3 mg). The mean serum-elimination half-life of terfenadine metabolite I was 8.7 ± 3.7 hours. After terfenadine ingestion, significant wheal suppression occurred from 2 to 24 hours compared to predose wheal size, with maximum wheal suppression, 42 ± 13% to 60 ± 16% from 2 to 12 hours. Significant flare suppression occurred from 2 to 24 hours, with maximum flare suppression, 75 ± 15% to 78 ± 13% from 4 to 8 hours. The mean serum-elimination half-life of chlorpheniramine was 22.6 ± 11.0 hours. After chlorpheniramine ingestion, significant wheal suppression occurred from 1 to 10 hours, inclusive, compared to predose wheal size, with maximum wheal suppression, 36 ± 11% to 37 ± 11% from 5 to 6 hours. Significant flare suppression occurred from 1 to 12 hours, with maximum flare suppression of 43 ± 14% to 46 ± 19% at 2, 5, and 6 hours ( p < 0.01). Adverse effects, chiefly sedation, occurred in five of eight patients after receiving terfenadine, and in all eight patients after receiving chlorpheniramine; but, since no placebo control was administered, these adverse effects could not be definitely attributed to H 1-receptor-antagonist ingestion.

Cetirizine: A pharmacokinetic and pharmacodynamic evaluation in children with seasonal allergic rhinitis

In a double-blind, randomized, parallel-group 5-week study, cetirizine, 5 mg or 10 mg daily, was ingested by 10 and nine children, respectively. Cetirizine was rapidly absorbed with mean peak cetirizine concentrations of 427.6 ± SD, 144.2 ng/ml. 1.4 ± 1.1 hours after the 5 mg dose, and 978.4 ± 340.6 ng/ml, 0.8 ± 0.4 hours after the 10 mg dose. The dose-independent serum-elimination half-life of cetirizine was 7.1 ± 1.6 hours after cetirizine, 5 mg, and 69 ± 1.6 hours after cetirizine, 10 mg. Urinary excretion of unchanged cetirizine during 24 hours after the initial dose of cetirizine, 5 mg, was 40 ± 15%, and after cetirizine, 10 mg, it was 39 ± 14%. The mean histamine-induced wheal-and-flare areas were significantly suppressed from 1 to 24 hours after the first dose of cetirizine, 5 mg, and from 1 2 to 24 hours after the first dose of cetirizine, 10 mg, compared to the mean predose wheal-and-flare areas ( p < 0.01). During daily dosing with cetirizine, 5 mg or 10 mg at bedtime for 35 days, serum cetirizine concentrations and suppression of histamine-induced wheals and flares were monitored every 7 days, 12 hours after the cetirizine dose. The mean serum cetirizine concentrations remained relatively stable during this time, and the mean wheal-and-flare areas remained significantly suppressed ( p < 0.01) compared to baseline wheal-and-flare areas measured before the first dose of cetirizine. The symptoms and signs of allergic rhinitis were suppressed throughout the study by cetirizine, 5 mg and 10 mg. No sedation, dry mouth, or other adverse effects were reported at any time. Cetirizine is a potent, new H 1-receptor antagonist without central nervous system or anticholinergic activity. No evidence of subsensitivity to cetirizine was found during 5 weeks of treatment.

Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly

The pharmacokinetics and pharmacodynamics of the antipruritic H1-receptor antagonist hydroxyzine hydrochloride were studied in nine healthy, fasting subjects (mean age 69.5 +/- 3.7 years) who ingested a single dose of hydroxyzine syrup, 0.7 mg/kg (mean dose 49.0 +/- 6.7 mg). Blood samples were collected hourly for 6 hours, every 2 hours from 6 to 12 hours, at 24 hours, and then every 24 hours for 144 hours. At these times an intradermal injection of 0.01 ml of a 0.1 mg/ml histamine phosphate solution was performed, and wheal and flare areas were computed. The serum elimination t1/2 of hydroxyzine was 29.3 +/- 10.1 hours; the volume of distribution was 22.5 +/- 6.3 L/kg; the clearance rate was 9.6 +/- 3.2 ml/min/kg, and the AUC was 1383.1 +/- 1039.0 ng.hr/ml. The mean serum elimination t1/2 of cetirizine, the active metabolite of hydroxyzine generated in vivo, was 24.8 +/- 7.7 hours, not significantly different from that of the parent compound (p = 0.05). After a single dose of hydroxyzine the mean wheal and flare areas were significantly suppressed from 1 to 144 hours, compared with the mean predose wheal and flare sizes (p less than 0.01). Maximum wheal suppression, compared with all other wheals measured during the study, occurred from 4 to 10 hours, inclusive, and maximum flare suppression occurred from 2 to 72 hours, inclusive (p less than 0.01). Hydroxyzine has a long t1/2 and a large volume of distribution in the elderly. The suppressive effect on the wheal and flare after a single dose of hydroxyzine is also extremely prolonged, suggesting the possibility of enhanced H1-receptor activity in old age.

Lack of subsensitivity to terfenadine during long-term terfenadine treatment

Eleven healthy male volunteers ingested térfenadine, 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 < 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 < 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 < 0.05) and maximal flare suppression occurring from 3 to 9 hours ( p < 0.01). On day 28 in the subgroup, the mean wheal area was significantly larger 12 hours after the dose than before the dose or at any other time ( p < 0.01), but the mean flare areas did not differ significantly at any time ( p = 0.01). On day 56 in the subgroup, the mean wheal areas did not differ significantly from before the dose to 12 hours after the dose, nor did the mean flare areas differ significantly at any time ( p = 0.01). The mean serum concentration of terfenadine metabolite 112 hours after the evening dose did , not differ significantly on days 7, 14,21, 28, 35, 42, 49,adn 56 ( p = 0.01). Unscheduled serum terfenadine metabolite I concentrations measured 12 hours after the dose provided additional confirmation of compliance. In the subgroup, the mean serum elimination half-life value and the mean area under the serum concentration versus time curve of terfenadine metabolite I did not differ significantly on day 0, day 28, or day 56 ( p = 0.01). We conclude that subsensitivity to the antihistaminic effect of terfenadine did not develop during 56 days in compliant subjects, as evidenced by continued suppression of the histamine-induced wheals and flares. Also, the pharmacokinetics of terfenadine metabolite 1 remained unchanged after 56 days of terfenadine treatment.

The pharmacokinetics and pharmacodynamics of terfenadine in children

The pharmacokinetics and pharmacodynamics of terfenadine were studied in 13 children with allergic rhinitis, mean age 7.45 +/- 0.54 SEM years. Serum concentrations of the active carboxylic acid metabolite of terfenadine (terfenadine metabolite I) were measured before and hourly for 8 hours after administration of a single dose of terfenadine suspension. The mean maximum serum concentration of terfenadine metabolite I, 242 +/- 28 ng/ml, occurred at 2.3 +/- 0.2 hours; the mean serum half-life value was 2.0 +/- 0.1 hours. Wheals and flares after epicutaneous tests with histamine phosphate, 1.0 mg/ml and 0.2 mg/ml, were significantly suppressed from 1 to 8 hours after the terfenadine dose compared to predose values. Maximum wheal suppression occurred at from 3 to 6 hours. Itching was completely suppressed for 8 hours. No serious adverse effects occurred. Terfenadine in children appears to be well absorbed, and its carboxylic acid metabolite has a short serum elimination half-life. The duration of its suppressive effect on the histamine-induced wheal and flare greatly exceeds that expected from consideration of serum terfenadine metabolite I concentrations.

The pharmacokinetics and antihistaminic of the H 1 receptor antagonist hydroxyzine

We studied the pharmacokinetics and the suppression of histamine-induced wheals, flares, and pruritus in the skin after administration of the histamine H 1 antagonist hydroxyzine to seven healthy adults. After a single oral dose of hydroxyzine, 0.7 mg/kg (mean dose 39.0 ± 5.4 mg), the mean maximum serum hydroxyzine concentration of 72.5 ± 11.1 ng/ml occurred at a mean time of 2.1 ± 0.4 hr. The mean elimination half-life calculated from the terminal linear portion of the serum hydroxyzine concentration vs. time curve was 20.0 ± 4.1 hr. The mean clearance rate was 9.78 ± 3.25 ml/min/kg and the mean volume of distribution was 16.0 ± 3.0 L/kg. The single dose of hydroxyzine suppressed pruritus at the wheal and flare sites from 1 to 36 hr. Maximal suppression of the wheals was 80% and maximal suppression of the flare was 92%. Significant suppression of the wheals and flares persisted for 36 and 60 hr. respectively. Pharmacodynamic analysis of the wheal and flare suppression data and the mean serum hydroxyzine concentrations supports the prolonged terminal serum half-life value for the drug.

Pharmacokinetics and efficacy of chlorpheniramine in children

Chlorpheniramine is widely used, but there is very little information about its pharmacokinetics and efficacy in children. In 11 patients with allergic rhinitis, ages 6 to 16 yr, we found a mean serum chlorpheniramine half-life of 13.1 ± 6.3 hr, a mean volume of distribution of 7.0 ± 2.8 L/kg, and a mean clearance rate of 7.2 ± 3.2 ml/min/kg. Suppression of symptoms and signs of allergic rhinitis and suppression of the histamine-induced wheal and flare responses occurred when mean serum chlorpheniramine concentrations ranged from 2.3 to 12.1 and 4.1 to 10.0 ng/ml, respectively. This, combined with the large volume of distribution for the drug, suggests that tissue binding is an important aspect of chlorpheniramine pharmacokinetics.

A controlled trial of therapy in chronic urticaria

Nineteen patients with chronic idiopathic urticaria (duration 2 to 192 mo) referred to our clinic as therapeutic failures were treated sequentially with five regimens. These were administered orally in a double-blind random sequence and included hydroxyzine pamoate (25 mg q.i.d.) plus one of the following: (1) placebo, (2) terbutaline (2.5 mg q.i.d.), (3) cyproheptadine (4 mg q.i.d.), (4) chlorpheniramine (4 mg q.i.d.), and (5) cimetidine (300 mg q.i.d.). Therapeutic response was assessed by patient's subjective choice, symptom diary scores, and suppression of wheal response to intradermal injections of histamine and compound 48/80. At least 35% improvement was noted in all patients with an average optimal response of 70%. The hydroxyzine-cimetidine combination was favored by 11 of 19 (58%) patients, in addition to producing the lowest symptom scores and the greatest histamine-48/80 wheal suppression. These results support the efficacy of combination H 1 and H 2 antihistamines in the management of some patients with difficult chronic urticaria.

The effect of H 1 and H 2 blockade on cutaneous histamine response in man

Histamine-induced cutaneous wheal responses were measured in 10 healthy subjects. The effect of the potent H 1 blocker, hydroxyzine HCl, the H 2 blocker, cimetidine, and the two drugs in combination was determined. The H 1 blocker alone produced a mean wheal suppression of 75% (p < 0.001). The H 1 plus H 2 blocker produced 84% suppression. The augmented suppression of H 1 plus H 2 blocker vs H 1 blocker was statistically significant (p < 0.02). The H 2 blocker alone produced suppression that was not statistically significant. The results provide additional evidence that H 2 receptors are present in the human cutaneous microcirculation, and add support to the clinical observation of therapeutic efficacy of H 1 plus H 2 blockers seen in some patients with chronic urticaria.

Effect of theophylline on allergen skin tests

The effect of theophylline on allergen-induced wheal and flare responses of 15 adults with atopy was studied in a double-blind, crossover study. After intradermal skin tests to determine baseline wheal and flare responses, subjects were assigned randomly to consecutive seven-day courses of theophylline 16 mg/kg/day (as Aminophylline USP) then of placebo, or the reverse. Subjects were tested with mixed weeds and mixed grasses allergens and with histamine diphosphate, codeine phosphate and a buffered saline control. Skin tests were repeated two hours after the last dose of theophylline or placebo in each treatment course, and serum theophylline concentrations were measured. The surface areas of the wheal and flare responses were measured by planimetry. No statistically significant difference (p greater than 0.05) was found between theophylline and placebo in the suppression of the allergen-induced wheal and flare response. Serum concentrations of theophylline were within the accepted therapeutic range. In therapeutic steady-state serum concentrations, theophylline does not significantly suppress allergen-induced wheal and flare response of atopic patients, and withdrawal of the drug before skin testing is unnecessary.

Degree and duration of skin test suppression and side effects with antihistamines: A double blind controlled study with five antihistamines

The ability of antihistamines to suppress the wheal response of an intradermal skin test is well recognized, but the degree and duration of this suppression have not previously been adequately studied. This double blind study employed five commonly used antihistamines in recommended therapeutic doses. Wheal suppression was recorded immediately after completing a 3 day course of the respective drug and was followed for up to 7 days or until the wheal regained control levels. Mean suppression ranged from 30.7 per cent to 62.7 per cent and required from 1.89 to 4.31 days to re-establish control levels. Incidence and degree of side effects from each antihistamine are also discussed.

Arthritis and psoriasis: the effects of antipsoriatic agents in the adjuvant-induced arthritic rat.

SummaryIn summary, we have shown that two topically useful antipsoriatic agents, anthralin and anthralin triacetate, both exert potent anti-inflammatory effects on oral administration. Anthralin further shows antiarthritic activity, inhibiting the cellular mediated immune processes as evidenced by suppression of both secondary lesions and skin wheal in the rat model. These data are preliminary in nature and further studies are in progress to elaborate on the biological profile of these two agents.