Dose-response relationship between objective measures of histamine-induced weals and dose of terfenadine.

Terfenadine is a safe non-sedative H1-receptor antagonist. This study aimed to quantify the relative reduction in weal and flare area, thickness and erythema at 4, 8, 12 and 24 h following a single but variable oral dose of terfenadine compared with pre-treatment measurements, in order to compare the dose-effect relationship and time course of the different dosages. In a double-blind randomized cross-over study, 12 healthy volunteers were given 60, 120 or 240 mg of terfenadine or placebo. Twenty micrograms of histamine acid phosphate was then injected intradermally at 4, 8, 12 and 24 h. The weal and flare areas were measured by planimetry, the thickness of the weal by an A-scan pulsed ultrasound device and the redness of both the weal and flare by an erythema-meter. A definite dose-response relationship was demonstrated between the weal and flare areas and the three active treatments. For the weal area, there was a significant difference between 60 mg and 240 mg of terfenadine at 4 h (p less than 0.01), at 8 and 12 h (p less than 0.05). For the flare area there was a similar significant difference at 4 h (p less than 0.01) and at 8 h (p less than 0.05). A dose-response relationship was demonstrated between weal erythema and 120 mg or 240 mg and 60 mg of terfenadine (p less than 0.05). There was a correlation between the plasma levels of the major metabolite and the initial dose of terfenadine, demonstrating their expected proportionality. This metabolite was also demonstrated in tissue fluid.     

Onset and duration of action of topical antihistamine: a study of histamine skin test response

Background   Most patients who require skin prick testing cannot deal with their pruritus without taking antihistamines (AH). Orally administered AH has a quick onset of action, but it will suppress skin test responses (STR) from several days to weeks. In this study, we aimed to determine the onset and duration of action of single topical AH application by observing histamine-STR suppression over time.
Methods   A two-step, randomized, intraindividual parallel-comparative, double-blind, placebo-controlled trial was conducted on the volar side of the forearm. Step 1 was aimed to determine the onset, while step 2 determined the duration of action. The topical AH tested was a single application of 5% doxepin hydrochloride cream, while 10 mg/ml histamine dihydrochloride was used to test the skin responses.
Results   Our 10 subjects' mean age was 35.8 ± 3.179 years. Histamine wheal response was suppressed starting on minute 90 and the wheal width were back to ≥ 7 mm² on minute 270. Significant histamine reactivity difference between genders ( P  = 0.201) and atopic status ( P  = 1.000), which could be a source of bias in histamine STR, was not found among our subjects.
Conclusion   Single application of topical AH has an onset of action in 90 min and duration of action < 180 min. Because of its short duration of action, topical AH can be used in a patient who needs AH but is scheduled to undergo skin prick testing after a few hours, without influencing the patient's STR.     

A quantitative study of the effect of terfenadine on cutaneous erythema induced by UVB and UVC radiation

Terfenadine, given in sufficient dose to cause maximum H1 receptor blockade, had no effect on the intensity of UVB or UVC erythema measured with a reflectance instrument at 4, 8, and 24 h after irradiation. Histamine, acting on the H1 receptor, is not a significant mediator of UVB or UVC erythema.     

The role of trauma in the spreading weals of hereditary angio-oedema

Twenty patients with hereditary angio-oedema (HAO) were regularly observed. Trauma often initiates the swellings of HAO which, once formed, may continue to spread. In the prodromal rash too, a narrow band of weals spreads out from a central point, which often corresponds to a site of trauma e.g. a pin prick. The relationship of these observations to the role of trauma in the initiation and spread of weals in other forms of urticaria is discussed.     

The effect of terfenadine on dermographic wealing

A double-blind comparison of terfenadine with placebo showed a reduction in potency of measured dermographic force-response of 67%, which is similar to that for inhibition of histamine weals by terfenadine. This and the parallel displacement of the force-response curves indicates that histamine is the main cause of dermographic wealing. Dermographic threshold and itch change together and appear to be the main determinant of the patients' subjective response. Dermographism relapsed towards its pre-treatment state during the 3 days after treatment was stopped. There was a small decrease in effect after administration of 60 mg b.d. for 47-84 days and a further small increase in response when the dose was increased to 120 mg t.d.s., but neither change was significant. None of the patients had a sedative response to the drug and terfenadine should prove useful in the treatment of wealing disorders.     

The effect of hypnotically induced analgesia on flare reaction of the cutaneous histamine prick test

Summary The effect of psychological pain reduction on the cutaneous inflammatory process was investigated by studying the effect of hypnotically induced analgesia on the flare reaction of cutaneous histamine prick tests. Ten highly hypnotically susceptible volunteers had their cutaneous reactivity against histamine prick tests on both arms measured before hypnosis. Their pain-related brain potentials were measured on the basis of eight argon laser stimulations. These measurements were repeated in the hypnotic condition, where subjects were given repeated suggestions of analgesia in one arm. Final measurements were performed in the post-hypnotic condition. Subjectively felt pain was measured on a visual analogue scale. Results showed a mean reduction in subjectively felt pain of 71.7% compared to the baseline condition. A significant (P<0.01) mean reduction of the evoked potentials was found in the hypnotic analgesic condition compared to both the pre-hypnotic (49.9%) and the post-hypnotic condition (36.9%). A significant difference was measured in the histamine flare area between the pre-hypnotic and the hypnotic analgesic condition (P=0.01–0.02) and between the hypnotic analgesic and the post-hypnotic condition when compared with the control arm. The mean ratio of flare area between the analgesic arm and the control arm was 1.04 (SD, 0.16) in the pre-hypnotic condition, 0.78 (SD, 0.22) in the hypnotic analgesic condition, and 1.37 (SD, 0.49) in the post-hypnotic condition. The results support the hypothesis that higher cortical processes can be involved in the interaction of inflammatory and pain processes.     

The effect of histamine receptor antagonists on immunosuppression induced by the cis-isomer of urocanic acid

Urocanic acid (UCA) is found in the stratum corneum predominantly as the trans-isomer; on ultraviolet B (UVB) irradiation, isomerization to the cis-isomer occurs. Cis-UCA has been shown to mimic the consequences of UVB irradiation in generating transient suppression of contact and delayed hypersensitivity (DH) responses. In an attempt to elucidate the mechanisms of action of UCA, the effects of 2 histamine receptor antagonists, cimetidine and terfenadine, were examined. One day after skin painting murine ears with cis-UCA, the number of ATPase- cells was reduced from 1068 to 408 mm-2. However, if cimetidine or terfenadine was applied at the same time as cis-UCA, the number of ATPase- cells was reduced only slightly from the control value, to 1028 and 892 respectively. Cis-UCA given subcutaneously or epidermally 5 h before infection of mice with herpes simplex virus suppressed the DH response on subsequent challenge with the virus. If cimetidine or terfenadine was added at the same time as cis-UCA, little suppression of the DH response to the virus occurred. Thus 2 effects of cis-UCA, on the number of ATPase+ epidermal cells and on DH response, were reduced or abrogated by histamine receptor antagonists, which may indicate that cis-UCA acts through histamine-like receptors in the skin.     

The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor

This study revealed that the absence of histamine in histidine decarboxylase gene-knockout (HDC(-/-)) mice resulted in delayed cutaneous wound healing and that exogenously administered histamine compensated this process. With the overproduction of histamine in HDC gene-transgenic mice, the healing was accelerated compared to the HDC(+/+) mice. These results indicate that histamine positively accelerated the cutaneous wound healing. Macrophage recruitment and angiogenesis at the wound edge were specifically impaired in HDC(-/-) mice, and histamine-treated wounds in HDC(-/-) mice demonstrated increased macrophage recruitment and angiogenesis. The amount of basic fibroblast growth factor (bFGF) in protein level at the wound edge was higher in HDC(+/+) mice, especially on the 3rd and 5th day of wound healing compared to those in HDC(-/-) mice. Topically administered SU5402, a specific antagonist to fibroblast growth factor receptor-1 tyrosine kinase, to the wound surface suppressed the wound healing in HDC(+/+) mice but not in HDC(-/-) mice. Moreover, SU5402 reduced macrophage recruitment and angiogenesis in HDC(+/+) mice. From these observations, it was concluded that the accelerated wound-healing activity of histamine was mediated by the activity of bFGF, which leads to angiogenesis, and macrophage recruitment in the wound-healing process.     

Influence of ultraviolet light on itch and flare reactions in human skin induced by histamine and the histamine liberator compound 48/80

The itch and flare responses induced by intradermal injection of histamine and the histamine liberator compound 48/80 were studied in healthy volunteers before and after exposure to UVB, UVA or PUVA administered 2-3 times weekly for 4 weeks. All three modalities were found to inhibit the responses induced by compound 48/80. The degree of tanning was most pronounced after PUVA and weakest after UVB, without any correlation between tanning and inhibition of itch. In contrast, when induced by histamine, the responses were not inhibited to the same extent, pronounced and significant inhibition being observed only for itching in subjects exposed to UVB. It is concluded that UVB, UVA and PUVA all might be of benefit in treating pruritic states if histamine release is involved and that UVB might have an additional effect by inducing hyposensitivity to itching stimuli.     

Impaired histamine metabolism in the arthus reaction induced in guinea-pig skin

Summary The activities of two histamine-metabolizing enzymes, histamine-N-methyltransferase (HMT) and diamine oxidase (DAO), were examined in various types of experimentally induced cutaneous inflammations in guinea pigs. In intact guinea-pig skin, the specific activities of HMT and DAO were 24.8±1.7 pmol/min per milligram of protein or 0.930±0.097 pmol/min per milligram of the wet weight of skin specimen, and 6.0±0.7 pmol/min per milligram of protein or 0.189±0.011 pmol/min per milligram of the wet weight, respectively. Both enzyme activities were markedly reduced in skin lesions of the Arthus reaction (P<0.005), while those in dinitro-chlorobenzene allergic dermatitis, croton-oil dermatitis, and the intact areas in Arthus-reaction-induced aminals were almost within the normal limits. The activity of HMT decreased linearly with time from the onset of the Arthus reaction, reaching about 20% of the control activity at 48 h; the activity of DAO decreased even from the early stages of the reaction, and this decrease continued throughout first 48 h of the reaction. These results suggest that impaired histamine metabolism in the skin lesions of the reaction plays a distinct role in the formation and development of the Arthus reaction.     

A quantitative comparison of the effect of local analgesics on argon laser induced cutaneous pain and on histamine induced wheal, flare and itch

A quantitative comparison was made of the effect of infiltration of local analgesics and topical analgesic cream (EMLA) on laser-induced pain and histamine-induced wheal, flare and itch. Wheal and flare were quantified by planimetry and analgesia was quantified by the pricking pain threshold to argon laser stimulation. The intensity of histamine-induced itch was scored on a 4-point scale. Local analgesics had no effect on the wheal area. The flare reaction was abolished by infiltrating lignocaine, and gradually inhibited by increased application times of EMLA. Itch was abolished after local lignocaine infiltration, but not significantly reduced after EMLA cream applied for less than 120 min, although the skin was anaesthetized to laser-induced pain. The reduction of flare area correlated to the level of analgesia, which may therefore reflect the cutaneous responsiveness to neurogenic inflammation. It is suggested that itch and pricking pain are mediated by different populations of nerve fibres, as itch can be evoked even when the sensation of pricking pain is abolished. Surgery, skin prick tests and other traumatic procedures should therefore be performed under local anaesthesia to reduce neurogenic inflammation.     

Effect of antianaphylactic agents on substance-P induced histamine release from rat peritoneal mast cells

Summary Substance P is known to be a potent histamine liberator for mast cells. The influence of antianaphylactic agents, disodium cromoglycate (DSCG), ketotifen, and tranilast was studied on substance-P and compound 48/80-induced histamine release from rat peritoneal mast cells. Substance-P induced histamine release was inhibited by these agents, while compound 48/80-induced histamine release was not inhibited by tranilast. Our findings suggest that these antianaphylactic agents are assumed to be effective for cutaneous diseases which might be concerned with substance P and histamine.     

Quantitative time course study of the skin response to histamine and the effect of H1 blockers. A 3-week crossover double-blind comparative trial of cetirizine and terfenadine

A controlled, randomized, double-blind, crossover study was performed in 10 healthy volunteers to compare changes of cutaneous blood flow values (CBFV) determined by laser Doppler flowmetry before and after intake of a capsule containing either 10 mg cetirizine or 60 mg terfenadine. After the determination of the initial response to the anti-H1 agents, drugs were taken daily (cetirizine 10 mg, terfenadine 120 mg) over a 3-week period and the cutaneous response to histamine and saline was evaluated weekly, exactly 4 h after the last drug intake. The following significant variations were observed (analysis of variance for repeated measurements, p less than 0.05): (1) there is a decrease of histamine-induced wheal and flare under antihistamines (anti-H1), cetirizine being more potent than terfenadine; (2) CBFV, measured on the usual flare area, i.e. at 1 cm of the site of agonist injection, decreased after drug intake. There was a gradual increase of the CBFV inhibition over the 3-week follow-up, cetirizine being more effective than terfenadine, and (3) at the site of agonist injection, reduction of the edematous wheal was associated with significant increases of CBFV after drug intake. This quantitative pharmacologic in vivo assay on the agonist action indicates that at lower doses, cetirizine has a significantly higher anti-H1 activity than terfenadine and that this effect is maintained over a 3-week period. There was no tachyphylaxis.     

Failure of terfenadine in relieving the pruritus of atopic dermatitis

We report the results of a double-blind, placebo-controlled, cross-over study of terfenadine 120 mg twice daily for pruritus in atopic dermatitis. Twenty-eight subjects with chronic atopic dermatitis received both terfenadine 120 mg b.d. and placebo each for a period of 1 week. Response was recorded by the subjects using visual analogue scales for severity of pruritus twice daily for the last 4 days of each treatment phase. There was no benefit from terfenadine.     

Separate effects of topical indomethacin on the itch response and on the flare reaction induced by histamine in human skin

The effects of topical indomethacin on histamine responses and histamine release were studied in 15 healthy volunteers. Three hours before testing, the indomethacin solution was applied under occlusion on one arm and the corresponding vehicle on the other. Solutions of histamine and the histamine releasing compound 48/80 were injected intradermally in both arms. Indomethacin treatment inhibited the flare reactions induced by histamine and compound 48/80 to about 50%, whereas no influence was seen on the itch responses. Our results indicate that indomethacin has no effect on the release of histamine, but it selectively suppresses the histamine-induced flare reaction leaving the itch duration unaffected.     

The efficacy of histamine antagonists as antipruritics in experimentally induced pruritus

1. The antipruritic ability of histamine (H1 and H2) antagonists alone and in combination in experimentally induced pruritus has been investigated in 12 normal human volunteers. 2. A combination of cimetidine (H2 anatagonist) and chlorpheniramine (H1 antagonist) proved effective in suppressing itch that was artificially induced by the application of papain and histamine. 3. The combination was more effective than chlorpheniramine or cimetidine alone or placebo. 4. The results suggest that both H1 and H2 receptors are involved in the mediation of pruritus.