Suppressive Effects of Histamine Skin Reactivity by a Nonsedating Antihistamine- Mequitazine

Asian Pacific Journal of Allergy and Immunology (1991) 9: 141-146

Paklt Vlchyanond, Supol Jongpanichkultorn, Napa Aranyanark and Montri Tuchinda

Mequitazine (10-3 quinuclidi SUMMARY The suppressive activity of mequltazlne (Mal) on histamine skin nylmethyl phenothiazine-MQZ, trade reactivity was evaluated In 29 healthy subjects (age 22·25 years) in a slngl.bllnd name-Primalan, Pharmuka Labo study. Fifteen subjects received MOZ, at a dosage of 5 mg BID, for 7 days while 14 ratory, France) is a new nonsedating served as controls. A prick skin test with saline or histamine hydrochloride (1 mglml H-l specific antihistamine, widely and 10 mglml) was performed in duplicate, on both forearms, starting from the used in Europe for treating a variety baseline day and continuing for 4 days after medication had been discontinued (total of 11 days). The skln·test subject and the reader was unaware of the reno of allergic conditions. MQZ has domlzation process. Mean diameters of wheal and flare as well as the skin Index been commercially available in Thai scores (after Voorhost) were used in the analysis. Maximal flare suppression (as land since 1986. The lack of central compared to the baseline values) was observed on day 6 (97% suppression for 1 nervous system (CNS) side effects mglml and 54% suppression for 10 mglml, p < 0.01). Suppression of wheal size was has been well documented. I Besides significant (19% for 1 mglml and 28% for 10 mg/ml) but was not clinically relevant. its antihistaminic effect, MQZ was Suppression of skin Index scores was maximal on day 6 (71% for 1 mglml and 43% also found to possess activities anta for 10 mglml, p <0.01). After MOZ had been discontinued, all measurements gra· gonistic to several steps in the process dually returned to baseline values and were not different therefrom within 3 days. of mast cell mediator release. 2 Clini However, final measurements of wheal and flare were smaller than baseline values cally, MQZ has been shown to be as (60-94% of baselines). We conclude that Mal, at the manufacturers's recommended effective as conventional antihis dose of 5 mg BID, significantly suppressed flare size of histamine skin tests and recommend that MOZ be discontinued for at least 3 days prior to performing allergy tamines such as brompheniramine skin tests. in alleviating allergic symptoms of allergic rhinitis.3 As compared to other nonsedating antihistamines, prick skin testing without histamine tocol was reviewed and approved by MQZ was also found to be as effec suppressive effect from MQZ. Data the Human Rights Committee of tive as terfenadine 4 and loratidine 5 on its pharmacodynamics in healthy the hospital and a written informed in its antihistaminic effects. volunteers were also presented. consent was obtained. All subjects Despite its accessibility and the were interviewed, were found to be in healthy condition and were not knowledge of its pharmacokinetics, 6 MATERIALS AND METHODS few data exist in regard to the phar taking any other medications. Fifteen macodynamics of MQZ. The primary Subjects purpose of this investigation was to Twenty nine healthy adult volun From the Division of Allergy and Immunology, determine the length of the interval be teers (age range 22-25 years) from Department of Pediatrics, Faculty of Medi tween the discontinuation of a short the Faculty of Medicine, Siriraj Hos cine Siriraj Hospital, Bangkok 10700, Thai term use of MQZ and the time point pital were recruited into the study land. when one can perform a diagnostic (18 males and 10 females). The pro Correspondence: Pakit Vichyanond, M.D. 142 VICHYANOND, ET AL

subjects (11 males and 4 females, total duration of eleven days (starting where L (length) and W (width) mean age 20.9 years) were randomized from the baseline day, just before represent the two diameters measured. to the MQZ group and 14 (8 males the administration of the first dose Percent suppression of skin test size and 6 females, mean age 21.8 years) until 72 hours after the discontinua was defined as the difference between were allocated to serve as controls. tion of the last dose) as shown in the size measured on a particular Fig. 1. Skin tests were performed day and the baseline size expressed Medications with a straight surgical needle size in percentage of the baseline. Mequitazine (Primalan, 5 mg/ #27 with skin test site placed 5 centi Statistics tablet) was administered to the MQZ meters apart using a template. All group at the manufacturer's recom skin tests were read at approximately The comparisons of wheal and mended dosage of 5 mg BID for 7 ten minutes after the prick with a flare sizes as well as of skin indices days while the control group received transparent tape technique. In brief, from various days, were made using no medication during the same period. the wheals and flares were outlined an analysis of variance with repeated The skin-test subject and the reader with a ball-point pen; these outlines measures (Fisher'S exact test) using (S1) were blinded to the randomization were then transferred to permanent the StatView 512 + program package process; the study was thus considered records with transpore tape (3M (Brain Power, Calabacas, CAl on a single blind study. a Maclntosh-SE computer (Apple Riker, St Paul MN). The largest Co., Cupertino, California). Skin test diameters and their orthogonal dia Prick skin testing with 1 and meters (in mm) of wheal and flare RESULTS IO mg/ml of histamine hydrochloride were measured and were used in the solution (prepared from dry powder comparisons. Composite values of The mean diameters of histamine of histamine hydrochloride, Sigma wheal and flare or skin index score wheals from the MQZ group are Laboratory, S1. Louis, MO) and were computed using formula as shown in Fig. 2. Suppression of wheal sizes by MQZ (striped and saline control solution were carried described by Voorhost. 7 out in duplicate on both forearms solid bars) was minimal and was not of each subject, daily, between 7 to Skin index score == % [ (L + 'v'll) wheal clinically apparent for 1 mg/ml of 8 a.m. each day (to minimize circadian + 3.7 + 11.5 log (L + W) flare] variation in skin reactivity) for a

Start IMQZ I IStopMQZ I ~ I I I I I I I I 2 3 4 5 6 7 1P 2P 3P 4P ...... 1---/ Prick Skin Testing DailYI ....

Fig. 1 Diagram illustrating the schema of the study. First dose of MaZ was administered immediately after skin testing on the first day and was continued at the dosage of 5 mg BID until the last dose, which was given on the morning of day 7. Day 1P through 4P represent the first through fourth day after MaZ discontinuation. SUPPRESSIVE EFFECTS OF MEOUITAZINE 143

• 1 mg/ml, MOZ Wheal Diameter (mm) 1'1 10 mg/ml, MOZ -0--·1 mg/ml, Contlol 7 ...-10 mg/ml, Control

" p < 0.05 6 ··,p

2 2 3 4 5 6 7 1P 2P 3P 4P Day of Skin Test

Fig. 2 Suppression of histamine wheal diameters. Measurement of histamine wheals (in mm) from the MOZ group (filled and striped bars) and the control group (solid and broken lines) tested with 1 mg/ml and 10 mg/ml of histamine hydrochloride is shown. Standard error of the means, in the control group, has been omitted for clarity of the illustration. Signi ficance denotes difference from the baseline measurement.

• 1 mg/ml, MOZ Flare diameter (mm) II 10 mg/ml. MOZ 30 -0- - 1 mg/ml. Control ...10 mg/ml. Control " p < 0.05 ". P < 0.01 20

o 2 3 4 5 6 7 1P 2P 3P 4P Day of skin testing

Fig.3 Suppression of histamine flare diameters. Measurement of histamine flares (in mm) from the MOZ group and the control group tested with 1 mg/ml and 10 mg/ml is shown. Significance denotes difference from the baseline measurements. As in Fig. 2, standard errors of controls are omitted for the purpose of clarity; annotations used are the same as in Fig. 2 144 VICHYANOND, ET AL

• 1 mg/ml, MOZ. Skin Indices ra 10 mg/ml, MOZ 40 '0"'" 1 mg/ml, Control .. 10 mg/ml. Control

" P < 0.05 30 ··,p<0.01

o 2 3 4 5 6 7 1P 2P 3P 4P Day of skin test

Fig.4 Skin indices in the MOZ group and the control group. Annotations used are the same as in previous figures. See text for details.

histamine; the differences were just mg/ml (97070 suppression) and 10 (p» 0.05) with the final indices being barely appreciable for 10 mg/ml mg/ml (54070 suppression). After smaller than baseline (70070 and 80070 solution. Nevertheless, the differences discontinuation of MQZ, flare sizes of baseline for I mg/ml and 10 mg/ became statistically significant on gradually returned to baseline and ml, respectively). day 7 of the medications and for one became statistically similar to the more day after MQZ had been dis baseline on the day 3 after stopping continued. The maximal suppression the drug (p > 0.05). As with hista DISCUSSION of wheals observed was 19070 and mine wheals, the final sizes of his MQZ, a nonsedating anti H-I 28070 for 1 (day 7) and 10 mg/ml tamine flare (as measured on day 4 antihistamine, is a derivative of pheno (day IP) of histamine hydrochloride, after the discontinuation of MQZ) thiazine (10-3 quinuclidinylmethyl respectively. Histamine wheal sizes were also smaller than their baseline phenothiazine). Despite its pheno gradually returned to the' baseline values (60076 and 80070 of baseline for thiazine structure, MQZ has been found values and became insignificant from I mg/ml and 10 mg/ml, respectively). to possess low central nervous system the baselines on the day 2 after the However, these differences were not (CNS) side effects due to its low discontinuation of MQZ. It is to be statistically significant (p> 0.05). affinity with the CNS H -1 receptor noted that the final wheal sizes were In the control group, as with wheals, rather than poor penetrability of the smaller than the baseline sizes (88070 no significant suppression of flares compound into cerebral tissue. 8 and 94070 of baseline for I and 10 was noted. Clinical studies have indicated that mg/ml of histamine, respectively). The skin indices, representing the use of MQZ at the recommended No significant suppression of his the composite values for wheal and dose is not associated with an impair tamine wheal diameters within the flare measurements, are shown in ment of visual-motor coordination, control group was observed. In con Fig. 4. Suppression of histamine nor with digit symbol substitution trast to wheal measurements, the reactivity gradually occurred during or dynamic visual activity.9 More suppression of histamine flares by the first three days of MQZ adminis over, MQZ has been found to lack MQZ was clearly very perceptible, tration and reached the minimum by anticholinergic effects. 10 especially with the I mg/ml solution day 7 (71070 and 43076 of baseline for However, it has recently been (Fig. 3). This suppression occurred I mg/ml and 10 mg/ml, respectively). shown that MQZ could induce EEG gradually over the first three days of After the discontinuation of MQZ, changes typical of a subconvulsive MQZ administration and reached the skin indices became insignificantly state in laboratory animals while the maximum on day 7 for both I different from the baseline by day 3 loratidine and astemizole lack such SUPPRESSIVE EFFECTS OF MEQUITAZINE 145

effect. 11 Thus, MQZ is perhaps not up by the liver and is released from be generalized to other nonsedating completely devoid of CNS effects lysozymes as an active metabolite. anti-HI agents such as to loratidine but, rather, bears a higher therapeutic Its onset of action is therefore slow and cetirazine since their different index in this regard than classic anti and because it is only slowly disso metabolic pathways may be res H I antihistamines. Clinical efficacy ciated from HI receptor, it also has ponsible to the difference in their . f . 523-25 of MQZ has been demonstrated in a prolonged duration of action. 19 onset and duratIOn 0 actIOn. ' various allergic states such as in Similar to astemizole, it is apparent It is to be noted that most of perennial rhinitis, 4 seasonal rhinitis 12 that suppression of histamine skin the studies in this field have utilized as well as in urticarial therapy. 13,14 reactivity by MQZ gradually occurred intradermal skin test techniques Hence, MQZ can be considered as over the first three days of therapy rather than prick skin tests as used an alternative for those who could and by the end of the study period in our study. The finding that anti not tolerate the sedative effects of (day 11) histamine skin reactivity HI antihistamine suppresses wheals the classic first generation antihis had not returned to the baseline to a lesser degree than flares is in tamines such as chlorpheramine, values indicating that MQZ may have triguing to us. This finding has been hydroxyzine, diphenhydramine and high affinity to peripheral HI recep previously observed but has never the like. In addition, MQZ was tor and may require several days for been emphasized with prick tech found to be equally effective to, if its complete dissociation from HI niques 24 or with intradermal tech not, more than the more popular receptor to occur. Recently, data niques. 26 This phenomenon is of nonsedating antihistamine-terfena reported by Ylitalo et al 6 have indi clinical importance since several dine. 4,15 Moreover, repeated admi cated that the elimination half-life atopic patients, such as those with nistration of MQZ to laboratory of MQZ is exceedingly long (45 ± 26 atopic dermatitis, react to prick skin animals did not produce drug-induced hours) confirming our contention tests in this manner (residual wheal tolerance as with the chlorpromazine in this regard. Notwithstanding, with no flare). Nonetheless, taken parent compound. 16 at the end of day 3 after the discon into account with both flares and tinuation MQZ, histamine skin wheals, delaying the time of skin test MQZ has been shown to possess indices were not statistically different performance for at least three or anti-allergic properties such as an from the baseline (although the more days after the stopping of MQZ antagonistic effect to LTD4 on the actual values were smaller); thus, would be adequate not to interfere contraction of isolated lung tissues, it was considered adequate to delay with the interpretation of the his an inhibition of histamine release diagnostic prick skin testing for at tamine skin reactivity. by phospholipase A2, calcium iono least 3 days after discontinuation phore and an inhibition of cyclic MQZ. It is possible that with its ACKNOWLEDGEMENTS AMP-dependent phosphodiesterase anti-mediator effects, the suppressive We thank the Pacific Health activity. 2 These antagonistic effects effect of MQZ on antigen-induced Care (Thailand) and the Pharmuka of MQZ have been demonstrated in wheals and flares could even be more situations such as in the blocking of Laboratory (France) for their support pronounced than on histamine and the provision of mequitazine agonist induced-bronchospasm (his induced ones. Nonetheless, patterns tablets for the study. tamine, acetylcholine, LTC4) as of suppression of skin reactions well as in the blocking of allergen from allergen, codeine and histamine REFERENCES induced-bronchospasm both in vivo by other antiallergic antihistamines I. Dhorraninta B, Sriprason T. Limsuvan and in vitro, 17 thus, making MQZ were found to be similar for both very attractive to clinicians who are S, et al. A study of CNS-side effects of the time course and the magnitude mequitazine, an H I-specific antihistamine treating chronic allergic conditions, of suppression. 20,21 At the time of currently believed to encompass in in healthy Thai volunteers. Asian Pac J our investigation, reagents which Allergy Immunol199O; 8: 39-44. flammatory mediators as playing induce mast cell mediator release 2. central roles in its pathogenesis. LG Kohno S, Yamamura H, Ohata K, et al. such as compound 48/80 and codeine Antiallergic effects of mequitazine. I In 30465, a derivative of MQZ, is per phosphae were not available to us. vitro experiments. Nippon Yakurigaku haps an even more interesting com Therefore, this hypothesis was not Zasshi 1988; 92: 145-57. pound since its bronchodilator effect scrutinized in this investigation but 3. Blamoutier J. Comparative trial of two was found to be 500 times as effective is being investigated in our ongoing antihistamines, mequitazine and brom as MQZ and it is poorly absorbed research. Our findings that histamine pheniramine. Curr Med Res Opin 1978; from the lung when delivered by an skin suppression by MQZ at 5 mg/ 5: 366-70. aerosol route. 18 kg dose was only 60010 of the baseline 4. Beaumont G, Dobbins, Latta D, et al. Among the new non-sedating is similar to that of Malet et al. 22 Mequitazine in the treatment of hay antihistamines, astemizole is taken Nevertheless, these findings can not fever. Br J Clin Pract 1990; 44 : 183-8. 146 VICHVANOND, ET AL

5. Skass-Brociek W, Bousquet J, Montes dine and mequitazine in the symptomatic 20. Lantin JP, Huguenot C, Pecoud AR. F, et (II. Double-blind placebo-con treatment of acute pollinosis. J Int Med Effects of astemizole on skin test with trolled study of loratidine, mequitazine, Res 1986; 14: 124-30. histamine, codience and allergens and placebo in the symptomatic treatment 13. Harto A, Sendagorta E, Ledo A. Doxepin (abstr #180). J Alergy Clin Immunol of seasonal allergic rhinitis. J Allergy in the treatment of chronic urticaria. 1988; 81 : 213. Clin Immunol 1988; 81 : 725-30. Dermatologica 1985; 170: 90-3. 21. Wang SM, Wang SR, Chiang BN. Sup 6. Ylitalo P, Nieminen K, Wilen-Rosenqvist 14. Demaubeuge.J,Tennstedt D, Broux R. pressive effects of oral ketotifen on G, et (II. Serum levels and urinary excre Does mast cell protection plus mediator skin responses to histamine, codeine, tion of mequitazine after a single oral antagonism surpass the effect of classic and allergy skin tests. Ann Allergy 1985; dose. Int J Clin Pharmacol Res 1989; antihistaminic in the treatment of 55: 57-61. 9: 305-8. chronic urticaria? A double-blind 7. Voorhost R. A review of perfection of 22. Malet I,Casajuana A, Ruis de Leon J. comparison of oxatomide and mequi et (II. "In viV()" and "in vitro" evaluation skin testing technique. Allergy 1980; tazine. Dermatologica 1982; 164 : 386-94. 35: 247-61. of four antihistamines (astemizole, azati 15. Leophonte P, Leophonte-Domairon F, dine, mequitazine, terfenadine). A1lergol 8. Le Fur G, Malgouris C, Uzan A. Effect Carme S, et al. Etude comparative de Immunopathol (Madr) 1989; 17 : 85-93. of mequitazine, a nonsedative antihis la mequitazine de la terfenad:ne dans 23. Kassim N, Roman I,Gural R, et al. tamine on brain HI receptor. Life Sci les rhinitis allergiques. Allerg Immunol Effects of loratidine (SCH 29851) in 1981; 29: 547-52. 1984; 3 : 213-22. suppression of histamine-induced skin 9. Nicholson AN, Stone BM. The HI 16. Kaneto H. Studies of barbital-type wheals. Ann Allergy 1988; 60 : 505-7. antagonist mequitazine : studies on physical dependence liability of mequi performance and visual function. Eur J 24. Rihoux JP, Ghys L. Coulie P. Com tazine in mice and rats. J Toxicol Sci Clin Pharmacol1983; 25; 563-6. 1981; 6: 61-70. pared peripheral HI inhibiting effects of 10. Briol1 N, Beaumont D, Advenier C. centirizine 2 HCL and loratidine. Ann Evaluation of the antimuscarinic activity 17. Rossoni G, Omini C, Foico GC, et al. Allergy 1990; 65 : 139-42. Bronchodilating activity of mequitazine. of atropine, terfenadine and mequitazine 25. Simons FER, Watson WTA, Simons Arch Int Pharmacodyn Ther 1984; 268 : in healthy volunteers. Br J Clin Pharrnacol KJ. The pharmacokinetics and phar 128-40. 1988; 25: 27-32. macodynamics of terfenadine in children. 11. Marzanatti M, MonopoIi A, Trampus 18. Subissi A, Criscuoli M, Renzetti AR. J Allergy Clin Immuno11987; 80 : 884-90. M, Ongini E. Effects on nonsedating LG 30435 is a new bronchodilator 26. Gendreau-Reid L, Simons KJ, Simons histamine HI-antagonists on EEG agent with multiple sites of action. Eur FER. Comparison of the suppressive activity and behaviour in cat. Pharmacol J Pharmacol 1986; 126: 81-9. effect of astemizole, terfenadine, and Biochem Behav 1989; 32 : 861-6. 19. Rafferty P, Holgate ST. Histamine and hydroxyzine on histamine-induced 12. Hogonot L, Hogonot R, Beaumont D. its antagonists in asthma. J Allergy Clin wheals and flares in humans. J Allergy A double-blind comparison of terfena Immunol1989; 82: 144-51. Clin Immunol1986; 77 : 355-40.