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 mig q.i.d.), (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 H1 and H2 antihistamines in the management of some patients with difficult chronic urticaria.     

The effect of H1 and H2 blockade on cutaneous histamine response in man

Histamine-induced cutaneous wheal responses were measured in 10 healthy subjects. The effect of the potent H1 blocker, hydroxyzine HCl, the H2 blocker, cimetidine, and the two drugs in combination was determined. The H1 blocker alone produced a mean wheal suppression of 75% (p less than 0.001). The H1 plus H2 blocker produced 84% suppression. The augmented suppression of H1 plus H2 blocker vs H1 blocker was statistically significant (p less than 0.02). The H2 blocker alone produced suppression that was not statistically significant. The results provide additional evidence that H2 receptors are present in the human cutaneous microcirculation, and add support to the clinical observation of therapeutic efficacy of H1 plus H2 blockers seen in some patients with chronic urticaria.     

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.     

Inhibition of dermographia, histamine, and dextromethorphan skin tests by ketotifen. A possible effect on cutaneous vascular response to mediators

Forty-one subjects with dermographia were studied for a 4-week period. Twenty subjects received ketotifen therapy, the other 21 received chlorpheniramine (H1) for 2 weeks, and then chlorpheniramine plus cimetidine (H1 + H2). Both groups had significant suppression of dermographia and skin wheals caused by dextromethorphan and histamine after 2 weeks. The inhibition by ketotifen of dermographia, histamine wheal, and the dextromethorphan wheal increased from week 2 to week 4. During the first 2 weeks, ketotifen's activity was comparable to chlorpheniramine. Ketotifen's activity increased during the second 2 study weeks to match the additional chlorpheniramine. These results suggest that ketotifen may have additional pharmacologic activities besides H1 antagonism, including possible inhibition of mast cell mediator release. As a consequence, cutaneous vascular hyperresponsiveness may decrease. Ketotifen appears promising as treatment for allergic skin disorders.     

The effect of ranitidine, alone and in combination with clemastine, on allergen-induced cutaneous wheal-and-flare reactions in human skin

The effect of intradermal ranitidine (administered alone and in combination with clemastine) on allergen-mediated wheal-and-flare reactions has been evaluated in a double-blind study on 10 healthy atopic volunteers. Ranitidine alone, administered in doses over a 10(4)-fold concentration range, had no effect on the size either of allergen-induced wheal or flare reactions. Clemastine alone evoked a dose-related inhibition of both wheal and flare. Compared to the inhibition achieved by clemastine alone, the combination of ranitidine with clemastine produced a small but significant increase in inhibition of allergen-induced flare at ranitidine concentrations of 10(-5) mol/L (p less than 0.001) and 10(-6) mol/L (p less than 0.01), and of allergen-induced wheal at ranitidine concentration 10(-5) mol/L (p less than 0.01). Our results provide further evidence for the presence of cutaneous histamine H2 receptors and their participation in the formation of allergen-mediated skin reactions but indicate that the contribution of cutaneous histamine H2-receptor stimulation to the production of immediate wheal-and-flare reactions evoked by allergen is only modest.     

Skin responses to intradermal histamine and leukotrienes C4, D4, and E4 in patients with chronic idiopathic urticaria and in normal subjects

Mast cell inflammatory mediators, such as histamine, and newly formed compounds, such as the leukotrienes, cause wheal and flare when they are injected intradermally into normal subjects and may therefore play a role in the formation of urticaria. The effects of intradermal injections (50 microliters) of six different concentrations of histamine (range, 3.3 x 10(-4) to 3.3 x 10(-9) mol/L) and the leukotrienes C4, D4, and E4 (range, 2 x 10(-4) to 2 x 10(-9) mol/L) have been compared in 10 normal subjects and in 10 patients with chronic idiopathic urticaria. Wheal-and-flare sizes were measured at timed intervals up to 4 hours, and area under the curve for each response over time was calculated. There were no significant differences in leukotriene-induced responses between groups. Maximum sizes of histamine-induced wheal and flare were similar in each group of subjects. There were, however, significant increases in mean areas under the response curve of histamine wheal and flare in the patients with urticaria (wheal, p less than 0.001; flare, p less than 0.001; analysis of variance). These findings demonstrate a prolongation of skin responses to histamine in patients with urticaria and suggest an impaired clearance of histamine (or other vasoactive agents released by histamine) from the skin of these patients.     

Significance of H1 and H2 receptors in the human nose: rationale for topical use of combined antihistamine preparations

The aim of this experiment was to study the importance of histamine H1 and H2 receptors in the human nose. We therefore provoked 25 healthy human subjects with histamine after local pretreatment with the H1 receptor antagonist, chlorpheniramine maleate, the H2 receptor antagonist, ranitidine hydrochloride, and a combination of these two antihistamines. The histamine-induced increase in nasal airway resistance was 52% inhibited by combined use of the two antihistamine sprays (p less than 0.05), 22% by chlorpheniramine alone (p less than 0.05), and 29% by ranitidine. The two sprays together were significantly better than the H1 antagonists alone (p less than 0.05). These results suggest an equal importance of H1 and H2 receptors in nasal blood vessels, and an additive effect of H1 and H2 antihistamines. Although chlorpheniramine effectively blocked tickling and the reflex-mediated symptoms, sneezing and hypersecretion, ranitidine had no effect, which suggests an H1 and not an H2 effect on sensory nerve endings in the airway epithelium.     

Functional depression of H2 histamine receptors in sheep with experimental allergic asthma

We tested the hypothesis that airway hyperresponsiveness to histamine in the allergic sheep is related to functional depression of H2 histamine receptors. Thirteen of 32 sheep responded with bronchoconstriction to inhaled Ascaris suum antigen (allergic sheep), and the remainder served as controls (nonallergic sheep). In the allergic sheep, 50 and 100 breaths of 5% histamine solution increased mean pulmonary resistance (RL) to 235% and 438% of baselines, respectively. The corresponding values in nonallergic sheep were 200% and 211%, indicating a greater response to the higher dose of histamine in allergic sheep. Selective H1-receptor stimulation with 50 breaths of histamine (pretreatment with the H2-receptor antagonist metiamide) failed to enhance the effect of histamine in allergic sheep (mean RL increased to 239% of baseline) whereas it enhanced the histamine response in nonallergic sheep (RL increased to 438% of baseline). Selective H2-receptor stimulation (pretreatment with the H1-receptor antagonist chlorpheniramine) caused histamine to decrease RL by 31% in the nonallergic sheep group; it blocked but did not reverse the histamine effect in the allergic sheep. Similar observations were made in a different group of animals when selective H1- or selective H2-receptor stimulation was produced by 100 breaths of histamine. The cutaneous wheal response to intradermal histamine dilutions of 0.0001. 0.001, 0.01, and 1 mg/ml was similar in both groups. In nonallergic sheep, both chlorpheniramine and metiamide blunted the cutaneous wheal response. In allergic animals, only chlorpheniramine blunted the cutaneous wheal response, whereas metiamide was without effect. We conclude that airway hyperresponsiveness to histamine in allergic sheep is related to a functional depression of H2 receptors and that such a defect is observed both in the airways as well as in the skin.     

The development of subsensitivity to chlorpheniramine

To assess the development of subsensitivity to antihistamines, titrated prick skin test (PSTs) were performed to seven fivefold dilutions of histamine and either morphine or antigen at specific intervals during therapy. Ten subjects received chlorpheniramine, 24 mg per day, and placebo in a double-blind crossover study. Total wheal area was measured at baseline and after 1, 3, 7, 21, and 24 days. The dose of chlorpheniramine (or placebo) was doubled from days 22 to 24 to assess the response to dosage increase. Serum levels of chlorpheniramine were measured at days 3 and 21 in six patients. Maximal skin test suppression was observed on days 3 or 7. On day 21 there was significantly less (p less than 0.01) suppression of all PSTs than on days 3 or 7. Mean serum chlorpheniramine was 48.7 ng/ml on day 3 and 36.1 ng/ml on day 21 (not significant). There was no significant correlation between changes in serum chlorpheniramine levels and changes in PST suppression. Doubling the dose of chlorpheniramine did not achieve the maximal suppression observed at days 3 or 7. We conclude that subsensitivity to antihistamines develops between 7 and 21 days of therapy and cannot be completely overcome by doubling the dose. The decreased effect does not appear to be due to induced metabolism but may be related to increased H1 receptor number.     

Evaluation of combined H1- and H2-receptor blocking agents in the treatment of seasonal allergic rhinitis

During an 8 wk period (September 23 to July 30) 23 patients with histories of late-summer allergic rhinitis received, on a random basis, alternating 2 wk courses of either chlorpheniramine (anti-H1), 12 to 48 mg/day, plus placebo, or anti-H1 in the same dose plus cimetidine (anti-H2), 300 mg t.i.d. Symptom (SX) and medication (MED) scores were recorded twice daily. After the season the immediate (ICR) and late (LCR) reactions to allergens and histamine were measured in six of these patients while on: (1) no drugs, (2) anti-H1 plus placebo, or (3) anti-H1 plus anti-H2 in the doses employed during the season. Mean weekly SX scores were significantly lower on anti-H1 plus anti-H2 compared with anti-H1 plus placebo during the sixth week of the study (p less than 0.001). MED scores were lower on the anti-H1 and anti-H2 combination than on anti-H1 alone during weeks four and five (p less than 0.02). In the six patients studied after the season, the ICRs were consistently smaller with the anti-H1 and anti-H2 combination, but the differences were only significant for the histamine-induced wheal (p less than 0.01). In this study of allergic rhinitis there appeared to be a small but statistically significant additive effect of anti-H2 to the clinical response to anti-H1. No additional side effects were noted.     

Mediator release in local heat urticaria: protection with combined H1 and H2 antagonists

Two patients with local heat urticaria were examined for evidence of histamine release and for changes in mast cell morphology after local heat challenge. Both patients demonstrated significant release of histamine into the draining venous blood in the challenged arm. Biopsy specimens revealed mucosal edema after 30 min, followed by a mononuclear, perivascular infiltrate by 6 hr, and increasing in intensity by 24 hr. Degranulated mast cells were observed by electron microscopy. Heat challenge was repeated after treatment with hydroxyzine, cimetidine, or a combination of both drugs. Neither hydroxyzine nor cimetidine alone affected the clinical response to challenge, but both drugs together completely abolished the clinical response. In addition, the combination of both drugs taken regularly completely prevented symptoms. This observation suggests that histamine is one of the major mediators of this disorder and that both H1 and H2 receptors are operative.     

Effects of infused histamine on asthmatic and normal subjects: comparison of skin test responses

The effect of histamine infused intravenously at sequentially increasing concentrations (0.05, 0.1, 0.25, 0.5, and 1 μ/kg/min) on the wheat responses to intradermal histamine and compound 48/80 in eight normal and five asthmatic subjects and to allergen skin tests in five asthmatic subjects was measured. These measurements were repeated following pretreatment with the H-1 antagonist hydroxyzine or the H-2 antagonist cimetidine, either alone or in combination. Histamine infused in progressively increasing concentrations had no effect on histamine, compound 48/80, or allergen skin tests either before or after H-1 or H-2 antihistamine treatment. No significant differene was found in the concentration of histamine or compound 48/80 required to elicit a 10-mm wheat in normal or asthmatic patients. Pretreatment with the H-2 antagonist alone had no effect on histamine or compound 48/80 skin tests in either group. However, the H-1 antagonist significantly reduced the wheat response to histamine (p < 0.05 normal; p < 0.025 asthmatics) and compound 48/80 (p < 0.05 normal; p < 0.025 asthmatics) in both groups. The combination of H-1 and H-2 histamine antagonists was not significantly different from the H-1 antagonist alone. Antigen skin testing was suppressed 82% by the hydroxyzine alone; no significant suppression was induced by cimetidine alone, and the combination of hydroxyzine plus cimetidine was only slightly more effective than hydroxyzine alone. The results indicate that blockade of histamine H-2 receptors with cimetidine has little or no additive effect on H-1 antagonist-suppressed skin test responses to histamine, compound , or antigen. Furthermore, the capacity of histamine to suppress histamine release in vitro from basophils was not demonstrated in vivo assessing skin mast cell responses. This observation combined with earlier studies on the human lung mast cell, which also failed to demonstrate that histamine had an inhibitory action, suggests that the human mast cell may not respond to histamine like the basophil and that this discrepancy may represent a fundamental difference in the cell types.     

H2 Antihistamines (Cimetidine) and Allergic-Inflammatory Reactions

Experiments in the skin and synovialis have thrown new light on the allergic-inflammatory reactions. The inflammatory effect of histamine is thus due to stimulation of two different types of receptors in the vessels, i.e. histaminergic H1 and H2 receptors. Both types of receptors are of importance for the immediate cutaneous response to allergens and histamine. Treatment with a combination of H1 antagonists (classical antihistamines) and the H2 antagonist cimetidine will thus cause a much stronger inhibition of the urticarial reactions than treatment with the H1 and H2 antagonist alone. It is therefore probable that a combination therapy could have an advantage over the traditional treatment with classical antihistamines in urticaria and other histamine-mediated skin diseases. Histamine might also be of importance for the swelling of the joints in inflammatory diseases such as rheumatoid arthritis, and clinical trials with H1 and H2 antagonists are in progress.     

Modulation of histamine type II receptors on CD8+ T cells by interleukin-2 and cimetidine.

CD8+ T cells are known to play a major role in regulating immune functions under normal and disease conditions. In this study a radioligand binding assay was used to quantitate histamine type II (H2) receptors on activated T cells. The objective was to examine the expression of H2 receptors on T cells during activation with interleukin-2 (IL-2) and treatment with cimetidine. Activated suppressor T cells induced by concanavalin A+IL-2 showed a significant (p less than 0.01) increase in H2 receptors compared to the control nonactivated T cells. The T cells expressing the H2 receptors were identified as CD8+ cells; those among them that had an enhanced level of H2 receptors were identified as CD25+. Treatment of activated suppressor cells with the H2 receptor antagonist cimetidine at a concentration of 10(-5) M significantly reduced the number of H2 receptors. Suppressor cells induced by Con A+IL-2 were able to suppress both IgG and IgM production that was reversible with cimetidine. Incubation of lymphocytes with 50 U/ml IL-2 alone in 3-day culture significantly (p less than 0.005) enhanced H2 receptor expression. These studies demonstrate that activated suppressor T cells that are CD8+CD25+ have enhanced levels of H2 receptors and can be modulated by cimetidine.     

Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients

From a pool of 624 patients with idiopathic chronic urticaria and angioedema, 90 patients had evidence of associated thyroid autoimmunity (TA). Since the number expected by chance alone is 37, given that less than 6% of normal subjects have TA, the association is significant (p less than 0.01; chi-square test). Age and sex distribution was typical of patients with TA. Clinically, most patients suffered relentless and severe urticaria and/or angioedema. With the exception of thyroid function and thyroid antibody tests, other laboratory tests were not rewarding. In most cases, treatment with 1 thyroxine did not improve urticaria or angioedema, but a few patients demonstrated a dramatic response. Awareness of the association resulted in the identification of previously undiagnosed thyroid disease. The authors hypothesize that a subset of idiopathic chronic urticaria and angioedema may be an autoimmune disease.     

The Regulatory Effect of Histamine on the in Vitro Synthesis of IgE

The effect of histamine and its H1 and H2 antagonists, chlorpheniramine and cimetidine, on the in vitro, PWM-induced, synthesis of IgG and IgE was studied. Histamine had no effect, and cimetidine had a slight inhibitory action. In contrast, chlorpheniramine induced marked suppression of both IgE and IgG synthesis. This effect could not be attributed to drug-induced cytotoxicity. These results suggest that the modulatory effect of histamine on antibody production involves predominantly H1 receptors.     

Histaminergic pharmacology of primate lower esophageal sphincter.

We have studied the lower esophageal sphincter (LES) response to exogenous histamine and to H1- and H2-blocking agents in the awake baboon. Increasing intravenous bolus doses of histamine produce an increase in LES pressure with a maximum response at a dose of 12 microgram/kg. H1-receptor blockade with chlorpheniramine over a wide dose range did not alter basal LES pressure but did abolish the response of the LES to exogenous histamine. H2-receptor blockade with cimetidine at doses markedly inhibiting gastric acid secretion (2 mg/kg.h) did not alter basal LES pressure or the response of the LES to exogenous histamine. In addition, cimetidine did not alter the response of the LES to pentagastrin and bethanechol. Although histamine and histamine receptors are important in gastric secretion, they appear to have no identifiable role in the maintenance of basal LES smooth muscle tone in the baboon. These results demonstrate the presence of a stimulatory H1 receptor on baboon LES smooth muscle, but provide no evidence for the presence of an H2-inhibitory receptor. As opposed to the parietal cell, the LES response to pentagastrin and bethanechol does not require a H2 receptor.     

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly

In a double-blind, randomized, crossover study, the H1-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 less than 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 H1-receptor-antagonist ingestion.     

H1- and H2-receptor antagonists prevent histamine release in allergic patients after the administration of midazolam-ketamine. A randomized controlled study

OBJECTIVE: The prophylactic effects of H1- and H2-receptor antagonist against histamine release and clinical symptoms (e.g. skin reactions, hemodynamic changes) were examined in 80 allergic patients after the administration of midazolam-ketamine. SUBJECT: We examined 80 allergic patients undergoing oral surgery. METHODS: A prospective randomized controlled study was performed in four groups of 20 patients who received either hydroxyzine (H1-receptor antagonist), chlorpheniramine (H1-receptor antagonist), a combination of chlorpheniramine and famotidine (H1- and H2-receptor antagonist) or a placebo (control) as premedications. Venous blood samples were obtained before introduction as a control and 0.5, 1, 3, 5 min after the administration of midazolam-ketamine in order to measure the plasma histamine level. In addition, any observed hemodynamic changes were simultaneously recorded. The plasma histamine level was measured using the HPLC (high performance liquid chromatography) post-label system. RESULTS: The patients who were treated with both chlorpheniramine and famotidine demonstrated a high level of basal plasma histamine compared to the patients who were treated by hydroxyzine alone (p < 0.05), and they also showed less histamine release and anaphylactoid reactions during midazolam-ketamine anesthesia. Allergic patients demonstrated a high percentage of eosinophils, with an average of 4.79 +/- 3.78%. CONCLUSION: The administration of midazolam-ketamine in allergic patients demonstrated no significant problems. The combined premedication with chlorpheniramine and famotidine was thus found to have the most prophylactic effect against histamine release after the administration of midazolam-ketamine in allergic patients in spite of a high level of basal plasma histamine.     

Plasma level of histamine in aspirin-sensitive urticaria

Twelve patients with a history of aspirin-induced urticaria and/or angioedema were studied before and after the provocation of symptoms with aspirin. The resting plasma histamine levels in these patients (0.95 +/- 0.25 ng/mL) were significantly higher than in 30 control subjects (0.21 +/- 0.02 ng/mL) (P less than .0005) and nine patients with non-aspirin-sensitive urticaria (0.27 +/- 0.06 ng/mL) (P less than .01). The plasma histamine levels fell significantly at the time of adverse reactions to aspirin (P less than .01). The high resting histamine levels, like the high venous prostaglandin F2 alpha levels that we have previously reported in the same group of patients and the high plasma histamine levels we have found in aspirin-sensitive asthmatics suggest an abnormality of mediator release in aspirin-sensitive patients.