No release of histamine and substance P in capsaicin-induced neurogenic inflammation in intact human skin in vivo: a microdialysis study

Background Studies in rodents ‘skin have indicated substance P to be the main inflammatory mediator involved in neurogenic inflammation, acting partly by release of histamine from skin mast cells. The mediators released in neurogenic inflammation in human skin remain to be determined. Objectives To determine the effects of intradermally injected and topically applied capsaicin on the release of histamine and substance P and skin responses in intact human skin in vivo. Methods Extracellular skin levels of histamine and substance P were measured by microdialysis technique and assayed by enzyme and radio immunoassays. Two kinds of dialysis fibres (210μm, 2 kDa, and 500 μm, 20 kDa) were inserted intradermally into forearm skin for studies of histamine release to topically administered capsaicin and intradermally injected capsaicin and substance P. Results Baseline histamine skin levels were 8.0 ± 0.7 nM. Intradermally injected capsaicin (0.3–30μM, 7.5–750 pmol) caused significantly and dose-related flare and pain reactions, but no significant histamine release or weals. Intradermally injected substance P (1 and 3 μM, 25 and 75 pmol) released significant amounts of histamine (peak levels being 90 and 475 nM), evoked weal-and-flare reactions, but did not cause pain. Capsaicin 2% ointment, applied on the skin for 2.5 h, increased skin blood flow by 300–400% as measured by laser Doppler flowmetry, elicited a longstanding burning sensation, but did not release histamine. Substance P-like immunoreactivity (SP-LI) was below the 1.8 pM detection limit following insertion of 20 kDa dialysis fibre and after intradermal injection of capsaicin 3μM. Intradermal injection of injection of 1 μM of substance P increased SP-LI levels to values greater than 4500 pM, confirming the ability of the dialysis fibre to recover this peptide. Conclusions Capsaicin-induced neurogenic activation does not involve the release of histamine from mast cells or detectable amounts of substance P release from sensory nerves in normal human skin in vivo.     

Non-specific histamine release activity of busereline, LH-releasing hormone

Busereline acetate is an LH-RH agonist that was found to induce local reactions at the injection site or generalized minor skin reactions in some patients. Since these reactions may represent the first reaction of systemic anaphylaxis, we tested the non-specific histamine releasing activity of this drug by intradermal skin tests. It was found that all subjects tested had a positive wheal and flare reaction, the flare being significantly decreased by terfenadine. Benzyl alcohol, the preservative used in commercial preparation of busereline acetate, did not elicit a positive wheal and flare reaction in two patients who had experienced a clinically noticeable reaction. It is concluded that busereline is likely to be a non-specific histamine releasing compound.     

Effects of cromolyn on codeine-induced histamine release in vivo

Cromolyn has been shown to inhibit histamine release from mast cells induced by various stimuli in vitro. However, the local effects of cromolyn on codeine-induced wheal and flare skin reactions are not well understood. Intradermal injection of codeine induced prominent whealing in almost all humans. We studied the effect of local cromolyn injection on codeine-induced skin reactions, histamine release, and ultramicroscopic changes in mast cells in 10 volunteers. The finding in this study showed that injection of a 2% cromolyn solution before or together with the codeine injection does not affect the subsequent skin reactions, histamine release and ultramicroscopic changes of mast cells.     

The effect of cetirizine and loratadine on codeine-induced histamine release in human skin in vivo assessed by cutaneous microdialysis

Objective and Design To determine whether or not cetirizine and loratadine inhibit codeine- induced histamine release in human skin in vivo, we conducted a placebo-controlled double-blind trial in which histamine release was assessed by dermal microdiaysis.Subjects A group of ten normal volunteers were studied, each subject visiting the laboratory on three occasions with intervals of at least 2 weeks between visits.Treatment Cetirizine, loratadine (both 10 mg) or placebo was given orally 4h before provocation of weal and flare responses in the skin by intradermal injection of 25 l of 3 or 10 mg/ml codeine 1 mm from the centre of individual 216 m diameter microdialysis fibres inserted in the dermis.Methods Dialysate was collected at 2 min intervals for 4 min before and 20 min after codeine injection and histamine assayed spectrofluorometrically. Weal and flare responses to codeine were assessed in the opposite arm.Results Histamine concentrations in the microdialysis fibre outflow with 3 and 10 mg/ml codeine were maximal at 2–4 min when 910±156 and 1194±304 nM respectively were found in the placebo group. Cetirizine and loratadine did not modify either the kinetics or total histamine release while significantly (p<0.01) inhibiting weal and flare responses.Conclusions Neither cetirizine nor loratadine inhibited codeine-induced histamine release or modified the time course of its release in human skin in vivo when given in clinically used doses which are sufficient to significantly reduce weal and flare responses.accepted by M. J. Parnham     

Cutaneous responses to human C3 anaphylatoxin in man

Intracutaneous injection of the low molecular weight fragment (C3a) of the third component of human complement caused pruritus, wheal and axon-reflex erythema in human skin. The response was maximal at 5–10 min after injection and dose-dependent between 15 and 600 ng. On a molar basis, C3a was more effective than histamine. The response to C3 anaphylatoxin required the release of 10 to 15 moles of histamine per mole of C3a. Biopsies of skin revealed mast cell degranulation and free metachromatic granules in sites injected with 320 or 2000 ng C3a. Margination and extravascular emigration of neutrophilic granulocytes was observed about cutaneous vessels within 10 min following injection of 2 μg of the polypeptide.

The wheal and erythema were diminished by prior injection of antihistamine agents; axon-reflex erythema was selectively abolished by local anaesthesia. After brief incubation of C3a with the serum exopeptidase, anaphylatoxin inactivator, the wheal and flare were decreased by greater than 95% and granulocyte accumulation was prevented.

     

Methacholine induces wheal-and-flare reactions in human skin but does not release histamine in vivo as assessed by the skin microdialysis technique

A number of investigations have indicated that cholinergic agonists release histamine from isolated mast cells and suggested that cholinergic stimulation releases histamine in vivo. The purpose of this study was to investigate whether the cutaneous wheal-and-flare reaction induced by methacholine challenge in human skin involves histamine release as measured by the skin microdialysis technique. Five hollow dialysis fibers were inserted intradermally in forearm skin in eight healthy subjects. Each fiber was perfused with Kreb's-Ringer bicarbonate at a rate of 3 μl/min. Dialysates were collected in 2-min fractions before skin challenge and for 20 min after intradermal injection of methacholine 10–^-3 -10^-1 M, the vehicle, and a positive control, codeine phosphate 0.3 mg/ml. Histamine was assayed spectrofluorometrically. Methacholine caused a statistically significant dose-related wheal-and-flare reaction, the flare reaction to methacholine 10^-1 M being comparable with that seen with codeine 0.3 mg/ml. No significant histamine release was observed with methacholine, cumulative histamine release of 16 ± 8nM by methacholine 10^-1 M being similar to vehicle responses of 15 ± 9 nM. Histamine release by codeine was 2524 ± 435 nM. In conclusion, methacholine-induced wheal-and-flare reactions in human skin appeared not to involve histamine release from skin mast cells.     

The release of leukotriene B4 from human skin in response to substance P: evidence for the functional heterogeneity of human skin mast cells among individuals

Substance P is located in cutaneous nerve fibres and induces wheal and flare responses, accompanied by granulocyte infiltration, upon intradermal injection. Studies with animal skin and rat peritoneal mast cells have suggested that substance P induces the release of histamine and leukotriene B4 (LTB4), a potent chemoattractant for granulocytes, from skin mast cells. However, the release of LTB4 has not been detected from mast cells enzymatically isolated from human skin. In order to investigate the mechanism of granulocyte infiltration induced by substance P in human skin, we studied the release of LTB4 and histamine in response to substance P, and the effect of dexamethasone using human skin obtained from 22 nonallergic individuals. Histamine was released from all skin tissue samples in a dose-dependent manner. However, the amount of LTB4 release, both constitutive and inducible, was variable among skin preparations. Substance P induced a large release of LTB4 from the skin of eight donors (twice to six times that of the spontaneous release), but no or only negligible release from the skin of 14 donors. The amount of constitutive release of LTB4 correlated with the amount of tissue histamine. Dexamethasone selectively abolished the inducible release of LTB4, without an effect on histamine release and the constitutive release of LTB4. These results suggest that substance P induces the release of LTB4 in a certain population of human individuals by a glucocorticosteroid-dependent mechanism, and plays an important role in neurogenic inflammation with granulocyte infiltration.     

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 naturally occurring opioid peptide from cow's milk, beta-casomorphine-7, is a direct histamine releaser in man.

beta-Casomorphine-7, a naturally occurring product of cow's milk with opiate-like activity, was studied for possible direct histamine liberation activities in humans. It was found to cause concentration-dependent in vitro histamine release from peripheral leukocytes of healthy adult volunteers. Intradermal injection of beta-casomorphine-7 induced a wheal and flare reaction in the skin similar to histamine or codeine. Oral pretreatment with the H1 antagonist terfenadine significantly inhibited the skin responses to beta-casomorphine-7. The intradermal injection of an opiate receptor antagonist, naloxone, inhibited in vitro histamine release and skin reactions only in a 100-fold excess over beta-casomorphine-7. These findings suggest that beta-casomorphine-7 can be regarded as a noncytotoxic, direct histamine releaser in humans. The clinical relevance of these findings deserves further studies.     

Intradermal injections of bradykinin or histamine cause a flare-like vasodilatation in monkey. Evidence from laser Doppler studies

The spreading cutaneous vasodilatation (flare) that follows a cutaneous injury is readily visible in humans but cannot be visualized in monkey. To determine if monkeys exhibit this neurally mediated reaction, cutaneous blood flow changes after intradermal injections of bradykinin and of histamine were monitored in the hairy skin of pentobarbital anesthetized monkeys. Using a laser Doppler device, recordings of cutaneous blood flow were made at distances of 15 and 25 mm from the injection of 50 microliters of saline, bradykinin (10(-3) M) and histamine (10(-3) M). These sites were beyond the radius of the wheal caused by bradykinin (6.3 mm) or histamine (6.8 mm). At both recording sites, both drugs caused an increase in blood flow that was significantly larger than that caused by the injection of the same volume of saline. These results provide evidence that although a flare is not visible in monkey skin, a flare-like vasodilatation does occur over an area of at least 50 mm diameter.     

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.     

The neurogenic vasodilator response to endothelin-1: a study in human skin in vivo

We have investigated the mediators and mechanisms underlying the vasodilator effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its isomers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to quantify the release of mediators within the dermal response and scanning laser Doppler imaging to measure changes in blood flux. The effects of local anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET receptor blockade on the ET-induced vascular response were also investigated. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by a long-lasting flare which was accompanied by a short-lived burning pruritus. The concentration of nitric oxide (NO) in dialysate collected within the pallor response to 5 microM ET-1 (1.43 +/- 0.64 microM, n = 5) was not significantly different from baseline levels collected prior to injection (0.86 +/- 0.38 microM) whilst that in the flare increased to reach a peak value of 2.28 +/- 0.61 microM at between 4 and 10 min after intradermal injection (P < 0.004). Pretreatment with local anaesthetic slowed the development of the flare and significantly reduced its size by up to 52% at 20 min after injection (P < 0.05) but had no significant effect on the central pallor. L-NAME, delivered by dialysis also caused a significant reduction in the ET-1-induced flare (P < 0.005). Bosentan, the non-selective ET(A)/ET(B) antagonist, when given by dialysis at the site of injection, reduced the area of both the ET-1-induced pallor and surrounding flare by 41 and 26%, respectively. No significant increase in tissue histamine was measured within either the pallor or flare response to ET-1, -2 or -3. Together these data confirm that the vasodilator response to endothelin-1 in human skin is neurogenic in origin and that it is in part mediated by the local release of nitric oxide. There appears to be little evidence for the involvement of mast cell-derived histamine in the initiation or modulation of ET-induced vasodilatation, in vivo.     

Bronchial allergen challenge in subjects with low levels of allergic sensitization to indoor allergens

BACKGROUND: Low skin reactivity to common inhalant allergens is frequently found in asymptomatic individuals as well as in patients with respiratory complaints. However, most studies on bronchial allergen challenge concern patients with high levels of allergic sensitization. The present study was directed to bronchial reactions after allergen challenge in subjects with low skin reactivity to Dermatophagoides pteronyssinus or cat dander. METHODS: Titrated intracutaneous skin tests, skin prick tests, specific IgE assays, histamine release on washed leukocytes, and bronchial histamine and allergen-challenge tests were performed in 20 subjects with an intracutaneous skin test threshold for cat dander (Felis domesticus) or D. pteronyssinus above 0.1 BU/ml (mean wheal diameter in skin prick test with 10000 BU/ml: 4.4mm). Ten of the 20 patients had specific IgE below the detection limit in at least one of the three IgE assays which were done. Fifteen patients had a specific IgE level below 2 kU/I in all three tests. As a positive control group, the same parameters were studied in seven moderately sensitized patients with an intracutaneous skin test threshold below 0.1 BU/ml (mean wheal diameter with 10000 BU/ml: 7.2mm). RESULTS: The 20 subjects with low levels of allergic sensitization had an early decrease in FEV1 of 8.6% (P<0.01) and a mean late decrease of 6.3% (P<0.05). There was a trend for decrease in PC20 histamine 24h after allergen challenge (-0.4 doubling doses, P=0.09). CONCLUSIONS: In this group of subjects with low levels of allergic sensitization, a statistically significant early and late decrease in FEV1 was found. However, the decrease in lung function was small and unnoticed by most patients. The increase in nonspecific bronchial hyperresponsiveness after bronchial allergen challenge did not reach statistical significance in the study group. The results indicate that allergen exposure in patients with low levels of allergic sensitization may lead to airways changes in the absence of acute symptoms.     

The effect of salmeterol and salbutamol on mediator release and skin responses in immediate and late phase allergic cutaneous reactions

BACKGROUND: Salmeterol is a long-acting beta2-agonist which in animal studies has been shown to possess anti-inflammatory effects on early (EAR) and late (LPR) phase allergic responses. PURPOSE: To evaluate the anti-inflammatory effects of intradermally injected salmeterol and salbutamol on clinical and biochemical EAR and LPR in human skin. METHODS: Measurement of wheal and flare reactions to allergen, codeine, and histamine, and LPR (induration) to allergen. Assessment of histamine and prostaglandin D2 (PGD2) release by microdialysis technique in EAR, and measurement of mediators in LPR by suction blister technique. RESULTS: Both beta2-agonists inhibited allergen-induced histamine release and wheal and flare reactions with maximum inhibition of 40-50% at 10(-6) M, a concentration which reduced PGD2 synthesis by approximately 55%. Histamine release by codeine and skin reactions to codeine and histamine were not or only marginally reduced. Salmeterol and salbutamol (10(-6) M) inhibited clinical LPR at 6 h by 71% and 48%, Except for the clinical LPR, no statistical differences were found between the two drugs on any parameters. None of the drugs inhibited levels of histamine, tryptase, myeloperoxidase, or eosinophil cationic protein in LPR. CONCLUSIONS: Salmeterol and salbutamol inhibited allergen-induced skin responses, and reduced mediator release in EAR but not LPR. In general, the anti-inflammatory effects of salmeterol did not differ from those induced by salbutamol.     

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.)     

Local histamine release after immunological and non-immunological mast cell degranulationin vivo

Plasma histamine concentration in the circulation has been proposed as an index of mast cell degranulation occurringin vivo but there are problems with this approach in practice. Local elevations in plasma histamine occur in blood draining the site of antigen challenge in forearm skin. We have compared changes in plasma histamine concentration with time following intradermal injection of antigen, codeine or histamine to produce matched wheal and flare responses in 4 atopic subjects. Less histamine appears to be released after non-immunological challenge.     

Skin reactions to histamine of healthy subjects after hypnotically induced emotions of sadness, anger, and happiness

BACKGROUND: The severity of symptoms in asthma and other hypersensitivity-related disorders has been associated with changes in mood but little is known about the mechanisms possibly mediating such a relationship. The purpose of this study was to examine the influence of mood on skin reactivity to histamine by comparing the effects of hypnotically induced emotions on flare and wheal reactions to cutaneous histamine prick tests. METHODS: Fifteen highly hypnotically susceptible volunteers had their cutaneous reactivity to histamine measured before hypnosis at 1, 2, 3, 4, 5, 10, and 15 min after the histamine prick. These measurements were repeated under three hypnotically induced emotions of sadness, anger, and happiness presented in a counterbalanced order. Skin reactions were measured as change in histamine flare and wheal area in mm2 per minute. RESULTS: The increase in flare reaction in the time interval from 1 to 3 min during happiness and anger was significantly smaller than flare reactions during sadness (P<0.05). No effect of emotion was found for wheal reactions. Hypnotic susceptibility scores were associated with increased flare reactions at baseline (r=0.56; P<0.05) and during the condition of happiness (r=0.56; P<0.05). CONCLUSION: Our results agree with previous studies showing mood to be a predictor of cutaneous immediate-type hypersensitivity and histamine skin reactions. The results are also in concordance with earlier findings of an association between hypnotic susceptibility and increased reactivity to an allergen.     

Wheal-and-flare reactions induced by allergen and histamine: evaluation of blood flow with laser Doppler flowmetry

Dermal blood flow was evaluated after skin prick test with histamine and allergen in six patients with seasonal allergic rhinitis. Blood flow was registered continuously for 60 minutes after the test procedure with laser doppler flowmetry, which allows noninvasive measurements. Blood flow was measured close to the skin test in the wheal obtained, and at a greater distance from the prick in the flare reaction. Tests were performed with preloaded skin test needles with histamine and the appropriate allergen freeze-dried on the point of the lancet, as well as with the appropriate negative control. The prick test procedure, by itself, induced a transient increase in blood flow that was normalized again after 9 minutes for the closest measurement. Histamine induced a rapid increase in blood flow in both the flare and wheal reaction that was normalized after about 45 minutes. The increase was significantly higher in the flare compared to the wheal for the time points from 6 1/2 to 13 minutes. Allergen induced a similar increase in blood flow. However, the increase was not noticeable until 2 1/2 minutes after the allergen application and was not completely abolished within 60 minutes. Furthermore, the difference between the flare and wheal reaction, with the higher values for the flare reaction, was present for a longer period of time than for the equivalent histamine measurements. In conclusion, laser doppler flowmetry appears useful for continuous evaluation of vascular changes induced at skin prick tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of butterbur on the histamine and allergen cutaneous response.

BACKGROUND: Butterbur or Petasites hybridus is an herbal remedy that exhibits antihistamine and antileukotriene activity and has been shown to attenuate the response to adenosine monophosphate challenge in patients with allergic rhinitis and asthma. However, no data are available regarding its effects on the histamine and allergen cutaneous response. OBJECTIVE: To evaluate the effects of butterbur compared with fexofenadine and montelukast on the histamine and allergen wheal and flare cutaneous responses. METHODS: Atopic patients were randomized into a double-blind, double-dummy, crossover study to receive for 1 week butterbur, 50 mg twice daily (8 AM and 10 PM); fexofenadine, 180 mg once daily (10 PM), and placebo once daily (8 AM); montelukast, 10 mg once daily (10 PM), and placebo once daily (8 AM); or placebo twice daily (8 AM and 10 PM). Patients attended the department at 10 AM and had measurements of the cutaneous wheal and flare responses to histamine, allergen, and saline control at 10-minute intervals for 60 minutes. RESULTS: Twenty patients completed the study. The mean +/- SE histamine wheal and flare responses, respectively, were significantly attenuated (P < .05) by fexofenadine (9.4 +/- 1.8 mm2 and 13.5 +/- 3.2 mm2) compared with placebo (15.5 +/- 3.3 mm2 and 179.8 +/- 74.3 mm2) but not by butterbur (16.4 +/- 2.1 mm2 and 297.7 +/- 121.2 mm2) or montelukast (19 +/- 1.9 mm2 and 240.2 +/- 66.6 mm2). The allergen wheal and flare responses, respectively, were also significantly attenuated (P < .05) by fexofenadine (31.1 +/- 6.3 mm2 and 256.9 +/- 86.5 mm2) compared with placebo (65.4 +/- 15.2 mm2 and 1,014.5 +/- 250.0 mm2) but not by butterbur (50.4 +/- 9.2 mm2 and 1,110.3 +/- 256.1 mm2) or montelukast (58.8 +/- 9.1 mm2 and 1,463.6 +/- 295.6 mm2). CONCLUSIONS: Butterbur did not produce any significant effects on the histamine and allergen cutaneous response compared with placebo, whereas mediator antagonism with fexofenadine but not montelukast produced significant attenuation. This finding would suggest that butterbur may not be effective in allergic skin disease.     

Measurement of interstitial cetirizine concentrations in human skin: correlation of drug levels with inhibition of histamine‐induced skin responses

BACKGROUND: The purpose of the present study was to measure the concentrations of cetirizine in the extracellular water compartment in intact human skin and assess simultaneously inhibition of histamine-induced wheal and flare reactions. METHODS: Skin cetirizine levels were collected by the microdialysis technique and analyzed by high-pressure liquid chromatography with mass spectrometry detection. Skin levels in 20 subjects were compared to plasma levels for 4 h after a single oral dose of 10 or 20 mg of cetirizine. Skin prick tests were performed with histamine 100 mg/ml. RESULTS: Plasma cetirizine levels increased within 30 min to reach peak values of 315+/-10 and 786+/-45 ng/ml 90-120 min after administration of 10 and 20 mg of cetirizine. This was followed by a slow decline. In the skin, dialysate cetirizine levels (non-protein-bound fraction only) peaked at 1.6+/-0.1 and 2.4+/-0.3 ng/ml at 120-180 min. In vivo recovery of cetirizine was 14.4+/-4.3%. It was estimated that the non-protein-bound concentration of cetirizine in the skin was 50-70% of corresponding plasma values. Both 10- and 20-mg doses of cetirizine inhibited wheal and flare reactions over 240 min. The time vs concentration profile of cetirizine in skin dialysate paralleled the inhibition of skin reactions, but no significant correlations were found between individual cetirizine levels in skin or plasma with wheal and flare reactions. CONCLUSIONS: Cetirizine concentrations in the skin could be monitored by the microdialysis technique. The results indicate no simple linear correlation between cetirizine skin levels and inhibition of skin reactions.