Histamine Wheal Research Articles

Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines

Antihistaminic drugs have been used successfully for many years in the treatment of allergic diseases. Second-generation antihistamines have fewer sedating side effects than first-generation agents, and the number of newer drugs available for clinical use is growing. Various methods have been used to assess antihistaminic activity, the most popular of which is the epicutaneous histamine-induced wheal and flare. This test relies on the ability of epicutaneously injected histamine to bring about the wheal and flare, a neurovascular response that involves reflex vasodilation (flare) and local swelling caused by plasma extravasation (wheal). Antihistamines have been compared on the basis of their ability to block the histamine-induced wheal and flare in the skin. Results of these trials have been applied to predict the global antiallergic efficacy of various antihistamines. This review has examined the reliability of suppression of the histamine wheal and flare reaction in the skin to predict an antihistamine's clinical efficacy in two common allergic diseases, seasonal allergic rhinitis and chronic idiopathic urticaria. Although histamine is one mediator in the allergic response in the skin and nasal mucosa, many other agents are important modulators of the allergic response. In addition, the major structural and functional differences that exist between the nasal mucosa and the skin affect the type of local response. These manifest themselves as differences between the responses to antigen and histamine challenge in the skin and the nose. The allergic responses in these tissues are not simply the consequence of one chemical but are the result of a cascade of interactions among various cells and mediators. The clinical manifestations of these complex interactions obviously cannot be fully replicated by injection of one chemical mediator, histamine, into the outer layer of the skin. Studies with antihistamines have shown that certain drugs, such as cetirizine, are more suppressive than others (loratadine, terfenadine) in controlling the histamine-induced wheal and flare reaction in the skin. When the clinical efficacy of these medications is compared in clinical trials in seasonal allergic rhinitis and chronic idiopathic urticaria, all are equally efficacious in controlling symptoms. Although the histamine-induced wheal and flare reaction can serve as a useful clinical pharmacologic test to assess dose-response relations for an antihistamine, its lack of correlation with clinical responses among antihistamines indicates that this model should not be used to predict or compare clinical efficacies of antihistamines in seasonal allergic rhinitis and chronic idiopathic urticaria. (J Allergy Clin Immunol 1997;99:S798-806.)

Estimation of skin prick test reactions with a scanning program

We evaluated a new method of computer-based scanning of skin prick test wheal areas. To test the calibration of the program, we scanned five constructed circles of exactly defined areas between 5 and 255 mm2. One of these circles was scanned in different degrees of contrast (modes), the middle mode being used in the other experiments. We also investigated the inter- and intraoperator variation. Finally, results obtained by measuring diameters of wheals and by the new method of area determination were compared for 82 histamine and 75 egg wheals. The areas found agreed well with the real areas (P < 0.01) (mean 97.4-100.8%), except for the smallest wheal (5mm2) (NS). Areas obtained in the "middle position" closely resembled the real area. The intraoperator coefficient of variation (c.v.) was 1.4% (0.3-4.3), the day-to-day c.v. was 1.9% (0.2-5.3), and the interoperator c.v. was 2.3% (0.7-5.7), with a higher c.v. for small areas. Histamine and egg wheals were significantly larger with the diameter method (126% and 129%, respectively) than with the area method. The difference between the methods was most pronounced for small wheal areas. The c.v. of the scanning method was significantly lower than that of the diameter method. The new program was precise and is recommended for registration of skin test reactions in scientific trials. Although the scanner works well and has high precision, the major problem in skin testing seems still to be the reproducibility of the skin test technique employed.

Measuring atopy in a multi-centre epidemiological study.

Skin prick tests are used as a measure of atopy in epidemiological studies, but results may be influenced by the fieldworker performing the test. In a multi-centre epidemiological study the method of reporting the results should consider the need for comparability of findings from different centres. Data on over 1000 subjects from three English centres of the European Community Respiratory Health Survey were analysed to determine whether allergen wheal should be adjusted for histamine wheal, and what cutoff diameter gave the most comparable results. No consistent relation between allergen wheal diameter and histamine wheal diameter was found for any fieldworker or allergen. A cutoff of > 0 mm for a positive result gave a more consistent relation with the corresponding specific IgE value between fieldworkers than either a cutoff of > or = 3 mm or the use of the mean wheal diameter. While this result is not immediately generalisable to studies using different skin prick test reagents, the method of analysis to determine the appropriate criterion of reporting can be used in other epidemiological studies.

Actions of terfenadine and cimetidine on histamine wheal formation.

1. A Latin square design was used to compare the effects of four masked oral drugs, placebo, cimetidine, terfenadine and cimetidine plus terfenadine, at single standard doses against histamine injected at concentrations of 0.3 mM and 0.074 mM subepidermally in eight healthy volunteers studied at weekly intervals. 2. Wheal growth occurred in three phases, an initial delay, a phase of rapid growth where drugs were effective, and a phase of slow growth where there were no significant drug effects. 3. Terfenadine was an effective antihistamine. 4. The data were consistent with a terfenadine effect continued into the next treatment block. 5. Under these conditions cimetidine apparently reduced the effects of terfenadine during the rapid wheal growth phase both simultaneously and after a week's interval from terfenadine dosing.

Reliability of skin prick tests during terfenadine treatment in adults with pollen rhinitis

The variation in skin prick test (SPT) results was evaluated clinically during terfenadine treatment in 39 adult patients with pollen rhinitis. A change in the perceived state of the patient as regards sensitization to a specific pollen allergen or atopic constitution was judged to be clinically important. A randomized, double-blind, crossover design was used, comprising 2 weeks on terfenadine 120 mg once a day and 2 weeks on placebo. SPT for two pollen allergens and histamine (10 mg/ml) were evaluated at the start of the study and at the end of each period. When SPT was used as a discovery test and liberal definitions were applied, predictive values for a positive test were 100%. 1-Sensitivity ranged between 10 and 54% with substantially lower values when a histamine wheal reaction was noted. The inhibitory effect of terfenadine was detectable 2 weeks after withdrawal as a reduction in the median of the mean diameter for the histamine-induced wheal response of 1 mm (0-1.5). The data implied that a positive SPT is reliable when liberal definitions are adopted for sensitization and atopy; a negative SPT is presumably reliable when the measurement artifact is considered and the wheal reaction to histamine is detectable.

Influence of skin prick test criteria on estimation of prevalence and incidence of allergic sensitization in children

In a prospective cohort study on atopy in childhood, three skin prick tests (SPT) were performed in 1135 primary schoolchildren over a 2-year period. We studied the development of average sizes of allergen wheals in reactive children and of average sizes of histamine wheals in all children, and we investigated the influence of choice of SPT criterion on the prevalence and incidence of sensitization. A year-to-year increase of average allergen wheal sizes as well as of average histamine wheal sizes was observed. These increases seemed to be related to the natural growth of the children. Furthermore, an observer bias effect of the person who did the pricking on average wheal sizes was found. There were considerable differences in estimations of prevalences and incidences depending on the definition of SPT criterion. Estimations using a criterion based solely on the allergen wheal size were affected by variation of allergen wheal sizes caused by growth and observer effects. The ratio criterion was not influenced by observer effects, nor did it seem to be affected by aging effects. In conclusion, our data suggest that the ratio criterion, which relates the size of the allergen wheal to the size of the histamine wheal, is the most appropriate SPT criterion because it is not affected by growth of allergen wheals in childhood and it appears to compensate for possible observer bias.

Echographic Evaluation with Image Analysis of Histamine-lnduced Wheats

10 healthy, non-atopic women, aged 20-30, underwent histamine prick tests, performed in duplicate on the volar surface of the forearm with progressively increasing histamine concentration, from elbow to wrist on the left arm and from wrist to elbow on the right. Histamine wheal assessments were performed with the following methods at 5, 10, 15 and 20 min from challenge: planimetry for wheal area determination, A-scanning for skin thickness evaluation and echographic image analysis for assessing skin edema corresponding to the hypoechogenic area in the dermis. Wheal extension, skin thickness and edema of the dermis increase in time according to the histamine concentration. However, in response to the same concentration, regional variations consisting in greater wheal extension and dermis hypoechogenic areas were observed on proximal than on distal sites. Conversely, statistically significant differences were found between tests carried out on the right arm compared to those on the left regarding skin thickness. These variations have to be considered when interpreting data derived from pharmacological studies on the inhibition of histamine-induced reactions.

Initiation of the effects of acrivastine and cetirizine on histamine/induced wheals and itch in human skin.

The initiation of the antihistamine effect of a single dose of acrivastine (8 mg) or cetirizine (10 mg) on wheals and itch induced by histamine dihydrochloride (10 mg/ml) in the prick test was studied in a randomized cross-over design employing 20 healthy medical students. The prick test was performed before ingestion of the drug and after 15, 20, 25, 30, 60 and 90 min and 2, 3 and 4 h. Local symptoms (itching) were recorded on a visual analogue scale. The inhibitory effect of acrivastine on the histamine wheal was first noticed 20 min (p < 0.01) after ingestion of the drug and that of cetirizine after 60 min (p < 0.001). The maximum effect of cetirizine, at 4 h, was greater than that of acrivastine, at 3 h (p < 0.001). The suppression of itching was first noticed 25 min after ingestion with both drugs.

Interpretation of skin tests to house dust mite and relationship to other allergy parameters in patients with asthma and chronic obstructive pulmonary disease

Background: The relationships between allergic symptoms after exposure to house dust, allergy parameters (skin test to house dust mite [HDM], total IgE, HDM-specific IgE, and blood eosinophil counts), and several confounding variables (age, sex, smoking habits, and airway hyperresponsiveness) were evaluated in 235 patients with asthma and chronic obstructive pulmonary disease (COPD). Results: Skin tests had higher diagnostic value (sensitivity plus specificity) for symptomatic allergy than specific IgE (1.45 versus 1.36) or total IgE (1.16). The other allergy parameters gave no additional information on symptoms once the skin test was known. Expressing the skin test relative to the histamine control proved slightly better than uncorrected wheal size, but this probably has limited clinical value. The best cutoff level for a positive skin test was 0.7 when the histamine wheal size was accounted for by division, −6 mm when subtraction was used, and 7 mm for absolute wheal size. These cutoff levels proved equally applicable in various subgroups of patients with asthma and COPD. Only the skin test and female sex were independent predictors of allergic symptoms. Conclusion: We conclude that skin tests to HDM are better predictors for clinical allergy than total or specific IgE levels and eosinophil count, and that they are applicable in most patients with asthma and with COPD.

Skin responses to intradermal histamine and leukotrienes C 4, D 4, and E 4 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.

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.

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.

Actions of locally administered adrenoceptor agonists on histamine-induced cutaneous responses in atopic eczema.

Summary An in vivo method for the assessment of adrenergic reactivity has been employed to examine alpha-adrenergic and beta-adrenergic responses in atopic eczema. In a randomised, double-blind study, intradermal administration of noradrenaline (predominantly an alpha-1-adrenoceptor agonist) or salbutamol (predominantly a beta-2-adrenoceptor agonist) significantly inhibited the histamine wheal response (P <0.001) in atopic and control subjects. However, the responses to alpha-adrenergic or beta-adrenergic effects were similar in both groups, a finding which does not support the concept that atopy is due to impaired beta-adrenergic reactivity accompanied by enhanced alpha-adrenergic reactivity. The ability of patients with atopic eczema to respond normally to the anti-inflammatory effect of a beta-2-adrenoceptor agonist is of therapeutic interest.

Antihistaminic effect of terfenadine: A new piperidine‐type antihistamine

AbstractThe antihistaminic effect of terfenadine was studied in the isolated guinea pig ileum, histamine skin wheals in guinea pigs and monkeys, and i.v. histamine‐induced death in guinea pigs. In the guinea pig ileum, terfenadine, 1 × 10−7 M, shifted the histamine dose‐response curve to the right in a parallel fashion without affecting the dose‐response curve of acetylcholine and barium chloride. However, as the dose of terfenadine was increased (3.16 × 10−7 and 1 × 10−6 M) the histamine dose‐response curves were displaced to the right with a depression of the maximum response and a reduction of the slope. Thus an unsurmountable type of antagonism was observed. Acetylcholine was also antagonized in a similar fashion by these two concentrations. In contrast, terfenadine appeared to displace the barium chloride dose‐response curve to the right in a parallel fashion. At 0.4 and 0.8 mg/kg p.o., terfenadine shifted the histamine skin wheal dose‐response curves to the right in a parallel fashion, but at 1.6 to 6.4 mg/kg, terfenadine antagonized the histamine wheal dose‐response curves with a depression of the maximum and the slope of the curve. These results were also similar to those of cyproheptadine but were different from those of chlorpheniramine, which produced parallel shifts. In monkeys, terfenadine produced a substantially greater effect on the histamine wheal than did chlorpheniramine (both administered at 30 mg/kg p.o.). Terfenadine also completely protected against i.v. histamine‐induced death in guinea pigs. Terfenadine produced no atropine‐like effect against pilocarpine‐induced salivation in rabbits, no demonstrable histamine H2 antagonism, no antiserotonin activity, no α or β antagonism, and no untoward cardiovascular effects. Most significantly, terfenadine had no overt central nervous system (CNS) effects in mice, rats, guinea pigs, or monkeys; whereas chlorpheniramine produced tremors and convulsions in mice and monkeys when tested at much lower doses than those used for terfenadine. It is concluded that terfenadine is an effective and specific antihistaminic compound with the potential advantage of a lack of CNS sedative effects.

Comparative Studies on Tree Pollen Allergens

The aqueous extract of alder (&lt;i&gt;Alnus incana&lt;/i&gt;) pollen was found to consist of a protein mixture amounting to 3% of the dry pollen weight. Separation by gel permeation chromatography on an AcA-54 column resulted in 6 fractions designated chronologically to their relative elution volumes (AI 1 to AI 6). The immunological reactivity of these fractions was demonstrated in both IgE and IgG test systems. Being both immunochemically and quantitatively dominant fraction AI 4 was selected for further purification by a semipreparative isoelectric focusing column. A well-resolved and apparently homogeneous component with a pI value of 4.78 was eluted from the IEF column. The homogeneity of this fraction was demonstrated by one sharp band in thin layer IEF, one single band in HVE, one distinct sharp peak in HPLC and a symmetrical precipitate in CIE. The molecular weight was estimated to 22,500 daltons. Fraction pI 4.78 was shown to be a major allergen of alder pollen, it elicited a 1.17 histamine wheal reaction in skin prick test at a concentration of 1 mg·ml&lt;sup&gt;––&lt;/sup&gt;&lt;sup&gt;1&lt;/sup&gt; and showed a significantly high RAST inhibition in all of the reaginic sera used. Fraction pI 4.78 was found to be an adequate model allergen of alder pollen well suited for further immunochemical characterization.

Inhibitory activity of terfenadine on histamine-induced skin wheals in man.

The inhibitory effect of orally administered terfenadine on the area of histamine-induced skin wheals was studied by single dose and multiple dose trials in 12 normal male volunteers. Single doses of 20, 60 and 200 mg of terfenadine produced dose-dependent decreases in histamine wheal area that reached a maximum by the fourth hour after dosing. The 60 and 200 mg doses blocked almost 90% of histamine whealing, and significant reduction of the wheal area persisted for 8 h. During the multiple dose trial histamine whealing was markedly inhibited after the fifth and sixth dose of terfenadine 20, 40 or 60 mg every 8 h and of 60 mg every 12 h. On the last three dosage schedules inhibition persisted for at least 12 h after the final dose. Inhibition of histamine-induced skin whealing appears to be a quantitative index of the time course of histamine H1-receptor antagonist action.

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).

Histamine Wheal Formation and Schizophrenia

Chronic schizophrenic patients were found to exhibit an insensitivity to intradermally injected histamine. They differed in this regard from schizophrenics ill with a first episode and from patients suffering from organic brain syndromes. The finding does not seem to be related to age or duration of institutionalization; there is a suggestion that the degree of insensitivity may be correlated to the degree of functional disability.

Hypnotic suggestion and the histamine wheal

Recent articles by several British investigators report that the responses to skin test reactions in immediate and delayed hypersensitivity can be inhibited by direct suggestion under hypnosis. With the use of a standardized hypnotic technique, groups of normal, allergic, and urticarial subjects were given skin tests with histamine and ragweed, in an attempt to alter the whealing response. However, under the conditions of this experiment no significant change was observed.

Some Observations on Peripheral Blood Flow During Administration of Ethylene Diamine Tetraacetic Acid (EDTA)

Ethylene diamine tetraacetic acid (EDTA) is a chelating agent which has been used in the treatment of a number of seemingly unrelated conditions, all pertaining to the removal of a heavy metal from the body (1-6). Chelating agents have the ability to combine with metallic ions rendering the metal no longer available for its usual reactions. The chelate thus formed is d unchanged in the urine (6, 7). A has no reported effect on the peripheral flow or skin. However, it was administered travenously to three cases of scleroderma by ukavina, et al (8) with considerable subjective and objective improvement in the skin and sseous findings. During the course of therapy two of these cases it was noted that the extremities seemed warmer. However, peripheral vascular studies such as skin temperature measurements, histamine wheal and oscillometry, demonstrated that no statistically significant changes occurred between the before and after comparisons.