The Journal of International Medical Research 1991; 19: 479 - 483
Comparative Effect of Dimethindene Maleate and Chlorpheniramine Maleate on Histamine-induced Weal and Flare A.D. BhattI, A.B. Vaidya', S.P. Sane', S. Sahani', R. Koya', A. Rajaseharan", S.V. Perumal", c.K. Chauhan', K.J. Pathak', B.R. Sainath", V. Vijayasekaran4 and H.L. Dhar I Medical Department, Hindustan Ciba-Geigy Ltd, Bombay, India; 2Department of Pharmacology, Lokmanya Tilak Memorial Medical College and Sion Hospital, Bombay, India; 3Department of Medicine, Medical College and Shrimant Sayajirao Gaekwad Hospital, Vadodara, India; "Department of Clinical Pharmacology, Madras Medical College and Government Hospital, Madras, India; "Departmeni of Pharmacology, Medical College and Shrimant Sayajirao Gaekwad Hospital, Vadodara, India
Antihistaminic activity of 3 or 6 mg dimethindene maleate was compared with that of placeho and 12 mg chlorpheniramine maleate in 60 healthy volunteers in a randomized, crossover study. Activity of each drug was assessed by measuring 21lghistamine-induced weal and flare areas. Compared with placebo, both doses of dimethindene and chlorpheniramine significantly (P < 0.001) reduced weal area. Both doses of dimethindene (P < 0.001) and chlorpheniramine (P < 0.05) also significantly reduced flare area. Dimethindene (6 mg) brought about the maximum reduction in weal area (28.8%) and flare area (39.1%). Dimethindene (6 mg) also reduced weal area significantly (P < 0.01) compared with chlorpheniramine and reduced flare area
Received for publication 9 August 1991; accepted 14 August 1991. Address for correspondence: Dr A.D. Bhatt, Medical Department, Hindustan Ciba-Geigy Ltd, 14 J. Tata Road, Churchgate, Bombay 400 014, India.
© Copyright 1991 by Cambridge Medical Publications Ltd
479
A.D. Bhatt, A.B. Vaidya, S.P. Sane et at.
significantly (P < 0.05) compared with 3 mg dimethindene. Using a 100 mm visual analogue scale for assessment of weal and flare intensities, 6 mg dimethindene again produced the maximum response. The study confirmed that the antihistamine activity of dimethindene was better than that of chlorpheniramine. KEY WORDS: Dimethindene; chlorpheniramine; antihistaminic activity; histamine-induced weal and flare.
trzx: INTRODUCTION
maleate (Foristal" ) is a well-known antihistamine that has been used for the last 25 years in treatmentof allergic conditions, e.g. urticaria, rhinitis, etc. In patients suffering from a variety of allergic diseases, clinical efficacyof dimethindene has been reported by Western, I - 3 as well as by Indian authors.' - 6 In all these studies the end-point was clinical response and hardly any studies have used sensitive models to assess antihistaminic activity in humans. The present study was planned to determine the antihistaminic activity of dimethindene maleate on the weal and flare reaction induced by histamine in a sensitive human volunteer model.'
SUBJECTS AND METHODS
Subjects A total of 60 adult male volunteers who were not suffering from any dermatological or allergic conditions and who were free from other systemic diseases were selected for the study. Informed consent was obtained from each of the volunteers. Treatment Each volunteer was given single oral doses of the following drugs: placebo; 3 mg dimethindene maleate (three tablets of 1 mg each); 6 mg dimethindene maleate (six tablets of 1 mg each); 12 mg chlorphenirarnine maleate (three tablets of 4 mg each).
Foristal" is a registered tradename of Ciba-Geigy AG, Switzerland.
480
Study design A within-volunteer, randomized, crossover design with a washout period of 5 - 7 days between each treatment was utilized for the study. Each volunteer reported in the morning at 09.00 h after breakfast. The drug/placebo was administered according to the randomization schedule and volunteers were instructed to lie in a supine position near a well-lit area. After 2 h, freshly prepared 2 ug histamine hydrochloride in 0.1 ml distilled water was injected intradermally into the forearm to raise a small bleb. The weal and flare (erythema) were marked with a ball-point pen and tracings were transferred via adhesive tape onto tracing paper. Using graph paper, the areas of the weal and flare were measured in mm-. In addition, the investigators, who were unaware of the randomized treatment, also assessed the size of weal and flare using a 100 mm visual analogue scale. Statistical analysis Antihistaminic activity of each drug was assessed by the reduction in the area of the weal and the flare. The drug therapies were compared with placebo and also with each other. Statistical analysis was performed using Student's paired r-test. RESULTS
Of the 60 volunteers, one showed an unusually large weal due to faulty injection technique and was excluded from analysis. In addition, one volunteer did not return for last follow-up when receiving chlorpheniramine. For the efficacy analysis,
Antihistaminic activity of dimethindene
Table 1 Effect of placebo, 3 and 6 mg dimetbindene maleate, and 12 mg cblorpbeniramine maleate on 21lghistamine hydrochloride-induced weal and flare area in 60 healthy male volunteers Weal
Treatment Placebo 3 mg dimethindene 6 mg dimethindene 12 mg chlorpheniramine a h
c d
Flare
Mean (± SE) area
Reduction
(mm')
(%)
158.32 122.22 112.65 124.04
Mean (± SE) area Reduction
± 5.67
± 5.40 ± 4.96 ± 3.80
22.8" 28.8"·b 21.7"
(mm') 937.73 671.78 571.40 774.50
(%)
± 52.02
± 48.80 ± 40.75 ± 53.88
28.4" 39.1",b,c 17.4d
p < 0.001 vs placebo. p < 0,01 vs 12 mg chlorpheniramine.
P < 0.05 vs 3 mg dimethindene. P < 0.05 vs placebo.
therefore, 59 subjects had been treated with both doses of dimethindene and 58 with chlorpheniramine. The anthropometric data of the volunteers [mean ± (SE)] were age 22.5 ± 0.5 years, height 170.3 ± 0.9 em and weight 59.9 ± 1.4 kg.
Effect on weal area The maximum reduction in weal area (28.8%) was achieved using 6 mg dimethindene (Table 1). Compared with placebo, all the drugs showed a significant (P < 0.001) reduction in the weal area but there was no significant difference in reduction in weal area between 3 and 6 mg dimethindene. Compared with chlorpheniramine, 6 mg dimethindene showed a significantly (P < 0.01) better reduction in weal area. Effect on flare area The reduction in the flare area (39.1 %) was maximal using 6 mg dimethindene (Table 1). Compared with placebo, both dimethindene (P < 0.001) and chlorpheniramine (P < 0.05) showed significant reduction in the flare area. The magnitude of the
reduction in flare area was significantly better using 6 mg dimethindene than with 3 mg dimethindene (P < 0.05) or chlorphenirarnine (P < 0.01). The antihistaminic activity of 3 mg dimethindene was comparable to that of chlorpheniramine.
Visual analogue scale for weal and flare intensities The reduction in weal and flare intensities as judged on the visual analogue scale showed a pattern similar to the actual measurements of the area (Table 2). Dimethindene (6 mg) produced a maximum inhibition of weal (14.7%) and flare (26.8%). Statistically significant reductions were seen with 6 mg dimethindene (weal, P < 0.01; flare, P < 0.(01) and 3 mg dimethindene (weal, P < 0.05; flare, P < 0.(01). Chlorpheniramine did not bring about any significant reduction in the visual analogue scale assessment. DISCUSSION
The present study showed that dimethindene and chlorpheniramine were effective in reducing histamine-induced weal and flare. The magnitude of weal reduction was 21.7 481
A.D. Bhatt, A.B. Vaidya, S.P. Sane et al.
Table 2 Effect of placebo, 3 and 6 mg dimethindene maleate, and 12 mg chlorpheniramine maleate on 21lg histamine hydrochloride-induced weal and flare assessed using 100 mm visual analogue scale (VAS) in 60 healthy male volunteers Weal
Treatment
Mean (± SE) VAS (mm)
Placebo 3 mg dimethindene 6 mg dimethindene 12 mg chlorpheniramine
b
p < 0.05 vs placebo. p < 0.00 I vs placebo.
c
P < 0.01 vs placebo.
a
50.17 44.39 42.81 47.98
± 3.79 ± 3.50 ± 3.62 ± 3.54
28.8% andof flarereduction was 17.1- 39.1%. The higher dose of dimethindene (6 mg) resulted in the maximum reduction in weal (28.8%) and flare (39.1%). Compared with 6 mg dimethindene, the reduction in weal and flare was less with the lower dose of 3 mg dimethindene; however, the difference was only significant for flare. The sensitivity to histamine has been demonstrated to be different in patients and healthy volunteers." The log dose - response curves of histamine have been shown to be shifted to the left in patients with chronic idiopathic urticaria and potency of antihistamines appeared greater in these patients." A dose of 3 mg dimethindene is likely to have potent effects in patients and a 6 mg dose may only be needed infrequently. The magnitude of reduction in weal and flare area in the present study using tablets of dimethindene maleate was comparable to that previously reported using dimethindene gel in volunteers and patients.";'! In common with the present study, Rampini et al," observed that the activity of dimethindene 482
Flare Reduction (%)
11.5" 14.7 a .b 4.4 a
Mean (± SE) VAS (mm) 55.72 41.74 40.79 51.04
± 3.21 ± 3.23 ± 3.09 ± 3.57
Reduction (%)
25.1"
zs.s-» 8.4d
maleate gel was significantly better than that of chlorpheniramine maleate gel in volunteers. Of the two responses, weal is considered more consistent; hence, the inhibitory effect of antihistamines on weal is more commonly reported.i'Ihe magnitude of reduction in weal area in the present study was comparable to that found in previous re-ports on other antihistamines. 12.13 The percentage reduction in weal and flare assessed using a visual analogue scale was less compared to the actual measurements and was not significant for chlorpheniramine. This is probably due to the subjective nature of the visual analogue scale. It is concluded that the present study demonstrated significantly better antihistaminic activity of dimethindene compared with chlorpheniramine in healthy human volunteers, thus confirming the clinical responses previously reported. REFERENCES I. May KL, Nelemans FA: The antipruritic effect of Fenistil (dimethpyrindene) in allergic conditions:
Antihistaminic activity of dimethindene
2.
3. 4.
5. 6.
7.
8.
double-blind clinical study. Acta Allergol 1966; 21: 337 - 342. Heim EB: Results obtined with Fenistil in pruriginous and allergic disorders. Praxis 1966; 55: 308 - 310. Sagami S: Experience with Foristal Lontabs in pruritic skin diseases. Hifu 1967; 9: 130 - 132. Banerjee BN, Okhandiar RP: Ciba 6518-Su in dermatoses of allergic origin: a preliminary observation. Indian J Dermatol1961; 7: 25 - 27. Gupta SR: Forhistal in the treatment of urticaria. Curr Med Pract 1963; 7: 531- 533. Hatua NR, Chatterjee S: Clinical evaluation of a new antihistaminic (Forhistal). Curr Med Pract 1964; 8: 749 -750. Huther KJ, Renftle G, Barraud N, et al: Inhibitory activity ofterfenadine on histamine-induced skin wheals in man. Eur J CUn Pharmacol 1977; 12: 195 - 199. Krause LB, Shuster S: Enhanced weal and flare
9.
10.
II.
12.
13.
response to histamine in chronic idiopathic urticaria. Br J Clin Pharmaco11983; 20: 486 - 488. Humphreys F, Shuster S: The effect of topical dimethindene maleate on weal reactions. Br J CUn Pharmacol1987; 23: 234 - 236. Rampini E, Oberihauser V, Nunzi E: Evaluation of the local antihistaminicactivityof dimethindene maleate by a quantitative method. Dermatologia 1978; 157: 105 - 109. Denes M, Temesvari E, Soos GY: Objectiveness of the effectiveness of Fenistil. Med Monatsschr Pharm 1977; 31: 432 - 434. Reinberg A, Levi F, Guillet P, et al: Chronopharmacological study of antihistamines in man with special references to terfenadine. Eur J CUn Pharmacol 1978; 14: 245 - 252. Hedges A, Hills M, Maclay WP, et al: Some central and peripheral effects of meclastine, a new antihistaminic drug in man. J CUn Pharmacol 1971; 11: 112 - 119.
483
Comparative Effect of Dimethindene Maleate and Chlorpheniramine Maleate on Histamine-induced Weal and Flare A.D. BhattI, A.B. Vaidya', S.P. Sane', S. Sahani', R. Koya', A. Rajaseharan", S.V. Perumal", c.K. Chauhan', K.J. Pathak', B.R. Sainath", V. Vijayasekaran4 and H.L. Dhar I Medical Department, Hindustan Ciba-Geigy Ltd, Bombay, India; 2Department of Pharmacology, Lokmanya Tilak Memorial Medical College and Sion Hospital, Bombay, India; 3Department of Medicine, Medical College and Shrimant Sayajirao Gaekwad Hospital, Vadodara, India; "Department of Clinical Pharmacology, Madras Medical College and Government Hospital, Madras, India; "Departmeni of Pharmacology, Medical College and Shrimant Sayajirao Gaekwad Hospital, Vadodara, India
Antihistaminic activity of 3 or 6 mg dimethindene maleate was compared with that of placeho and 12 mg chlorpheniramine maleate in 60 healthy volunteers in a randomized, crossover study. Activity of each drug was assessed by measuring 21lghistamine-induced weal and flare areas. Compared with placebo, both doses of dimethindene and chlorpheniramine significantly (P < 0.001) reduced weal area. Both doses of dimethindene (P < 0.001) and chlorpheniramine (P < 0.05) also significantly reduced flare area. Dimethindene (6 mg) brought about the maximum reduction in weal area (28.8%) and flare area (39.1%). Dimethindene (6 mg) also reduced weal area significantly (P < 0.01) compared with chlorpheniramine and reduced flare area
Received for publication 9 August 1991; accepted 14 August 1991. Address for correspondence: Dr A.D. Bhatt, Medical Department, Hindustan Ciba-Geigy Ltd, 14 J. Tata Road, Churchgate, Bombay 400 014, India.
© Copyright 1991 by Cambridge Medical Publications Ltd
479
A.D. Bhatt, A.B. Vaidya, S.P. Sane et at.
significantly (P < 0.05) compared with 3 mg dimethindene. Using a 100 mm visual analogue scale for assessment of weal and flare intensities, 6 mg dimethindene again produced the maximum response. The study confirmed that the antihistamine activity of dimethindene was better than that of chlorpheniramine. KEY WORDS: Dimethindene; chlorpheniramine; antihistaminic activity; histamine-induced weal and flare.
trzx: INTRODUCTION
maleate (Foristal" ) is a well-known antihistamine that has been used for the last 25 years in treatmentof allergic conditions, e.g. urticaria, rhinitis, etc. In patients suffering from a variety of allergic diseases, clinical efficacyof dimethindene has been reported by Western, I - 3 as well as by Indian authors.' - 6 In all these studies the end-point was clinical response and hardly any studies have used sensitive models to assess antihistaminic activity in humans. The present study was planned to determine the antihistaminic activity of dimethindene maleate on the weal and flare reaction induced by histamine in a sensitive human volunteer model.'
SUBJECTS AND METHODS
Subjects A total of 60 adult male volunteers who were not suffering from any dermatological or allergic conditions and who were free from other systemic diseases were selected for the study. Informed consent was obtained from each of the volunteers. Treatment Each volunteer was given single oral doses of the following drugs: placebo; 3 mg dimethindene maleate (three tablets of 1 mg each); 6 mg dimethindene maleate (six tablets of 1 mg each); 12 mg chlorphenirarnine maleate (three tablets of 4 mg each).
Foristal" is a registered tradename of Ciba-Geigy AG, Switzerland.
480
Study design A within-volunteer, randomized, crossover design with a washout period of 5 - 7 days between each treatment was utilized for the study. Each volunteer reported in the morning at 09.00 h after breakfast. The drug/placebo was administered according to the randomization schedule and volunteers were instructed to lie in a supine position near a well-lit area. After 2 h, freshly prepared 2 ug histamine hydrochloride in 0.1 ml distilled water was injected intradermally into the forearm to raise a small bleb. The weal and flare (erythema) were marked with a ball-point pen and tracings were transferred via adhesive tape onto tracing paper. Using graph paper, the areas of the weal and flare were measured in mm-. In addition, the investigators, who were unaware of the randomized treatment, also assessed the size of weal and flare using a 100 mm visual analogue scale. Statistical analysis Antihistaminic activity of each drug was assessed by the reduction in the area of the weal and the flare. The drug therapies were compared with placebo and also with each other. Statistical analysis was performed using Student's paired r-test. RESULTS
Of the 60 volunteers, one showed an unusually large weal due to faulty injection technique and was excluded from analysis. In addition, one volunteer did not return for last follow-up when receiving chlorpheniramine. For the efficacy analysis,
Antihistaminic activity of dimethindene
Table 1 Effect of placebo, 3 and 6 mg dimetbindene maleate, and 12 mg cblorpbeniramine maleate on 21lghistamine hydrochloride-induced weal and flare area in 60 healthy male volunteers Weal
Treatment Placebo 3 mg dimethindene 6 mg dimethindene 12 mg chlorpheniramine a h
c d
Flare
Mean (± SE) area
Reduction
(mm')
(%)
158.32 122.22 112.65 124.04
Mean (± SE) area Reduction
± 5.67
± 5.40 ± 4.96 ± 3.80
22.8" 28.8"·b 21.7"
(mm') 937.73 671.78 571.40 774.50
(%)
± 52.02
± 48.80 ± 40.75 ± 53.88
28.4" 39.1",b,c 17.4d
p < 0.001 vs placebo. p < 0,01 vs 12 mg chlorpheniramine.
P < 0.05 vs 3 mg dimethindene. P < 0.05 vs placebo.
therefore, 59 subjects had been treated with both doses of dimethindene and 58 with chlorpheniramine. The anthropometric data of the volunteers [mean ± (SE)] were age 22.5 ± 0.5 years, height 170.3 ± 0.9 em and weight 59.9 ± 1.4 kg.
Effect on weal area The maximum reduction in weal area (28.8%) was achieved using 6 mg dimethindene (Table 1). Compared with placebo, all the drugs showed a significant (P < 0.001) reduction in the weal area but there was no significant difference in reduction in weal area between 3 and 6 mg dimethindene. Compared with chlorpheniramine, 6 mg dimethindene showed a significantly (P < 0.01) better reduction in weal area. Effect on flare area The reduction in the flare area (39.1 %) was maximal using 6 mg dimethindene (Table 1). Compared with placebo, both dimethindene (P < 0.001) and chlorpheniramine (P < 0.05) showed significant reduction in the flare area. The magnitude of the
reduction in flare area was significantly better using 6 mg dimethindene than with 3 mg dimethindene (P < 0.05) or chlorphenirarnine (P < 0.01). The antihistaminic activity of 3 mg dimethindene was comparable to that of chlorpheniramine.
Visual analogue scale for weal and flare intensities The reduction in weal and flare intensities as judged on the visual analogue scale showed a pattern similar to the actual measurements of the area (Table 2). Dimethindene (6 mg) produced a maximum inhibition of weal (14.7%) and flare (26.8%). Statistically significant reductions were seen with 6 mg dimethindene (weal, P < 0.01; flare, P < 0.(01) and 3 mg dimethindene (weal, P < 0.05; flare, P < 0.(01). Chlorpheniramine did not bring about any significant reduction in the visual analogue scale assessment. DISCUSSION
The present study showed that dimethindene and chlorpheniramine were effective in reducing histamine-induced weal and flare. The magnitude of weal reduction was 21.7 481
A.D. Bhatt, A.B. Vaidya, S.P. Sane et al.
Table 2 Effect of placebo, 3 and 6 mg dimethindene maleate, and 12 mg chlorpheniramine maleate on 21lg histamine hydrochloride-induced weal and flare assessed using 100 mm visual analogue scale (VAS) in 60 healthy male volunteers Weal
Treatment
Mean (± SE) VAS (mm)
Placebo 3 mg dimethindene 6 mg dimethindene 12 mg chlorpheniramine
b
p < 0.05 vs placebo. p < 0.00 I vs placebo.
c
P < 0.01 vs placebo.
a
50.17 44.39 42.81 47.98
± 3.79 ± 3.50 ± 3.62 ± 3.54
28.8% andof flarereduction was 17.1- 39.1%. The higher dose of dimethindene (6 mg) resulted in the maximum reduction in weal (28.8%) and flare (39.1%). Compared with 6 mg dimethindene, the reduction in weal and flare was less with the lower dose of 3 mg dimethindene; however, the difference was only significant for flare. The sensitivity to histamine has been demonstrated to be different in patients and healthy volunteers." The log dose - response curves of histamine have been shown to be shifted to the left in patients with chronic idiopathic urticaria and potency of antihistamines appeared greater in these patients." A dose of 3 mg dimethindene is likely to have potent effects in patients and a 6 mg dose may only be needed infrequently. The magnitude of reduction in weal and flare area in the present study using tablets of dimethindene maleate was comparable to that previously reported using dimethindene gel in volunteers and patients.";'! In common with the present study, Rampini et al," observed that the activity of dimethindene 482
Flare Reduction (%)
11.5" 14.7 a .b 4.4 a
Mean (± SE) VAS (mm) 55.72 41.74 40.79 51.04
± 3.21 ± 3.23 ± 3.09 ± 3.57
Reduction (%)
25.1"
zs.s-» 8.4d
maleate gel was significantly better than that of chlorpheniramine maleate gel in volunteers. Of the two responses, weal is considered more consistent; hence, the inhibitory effect of antihistamines on weal is more commonly reported.i'Ihe magnitude of reduction in weal area in the present study was comparable to that found in previous re-ports on other antihistamines. 12.13 The percentage reduction in weal and flare assessed using a visual analogue scale was less compared to the actual measurements and was not significant for chlorpheniramine. This is probably due to the subjective nature of the visual analogue scale. It is concluded that the present study demonstrated significantly better antihistaminic activity of dimethindene compared with chlorpheniramine in healthy human volunteers, thus confirming the clinical responses previously reported. REFERENCES I. May KL, Nelemans FA: The antipruritic effect of Fenistil (dimethpyrindene) in allergic conditions:
Antihistaminic activity of dimethindene
2.
3. 4.
5. 6.
7.
8.
double-blind clinical study. Acta Allergol 1966; 21: 337 - 342. Heim EB: Results obtined with Fenistil in pruriginous and allergic disorders. Praxis 1966; 55: 308 - 310. Sagami S: Experience with Foristal Lontabs in pruritic skin diseases. Hifu 1967; 9: 130 - 132. Banerjee BN, Okhandiar RP: Ciba 6518-Su in dermatoses of allergic origin: a preliminary observation. Indian J Dermatol1961; 7: 25 - 27. Gupta SR: Forhistal in the treatment of urticaria. Curr Med Pract 1963; 7: 531- 533. Hatua NR, Chatterjee S: Clinical evaluation of a new antihistaminic (Forhistal). Curr Med Pract 1964; 8: 749 -750. Huther KJ, Renftle G, Barraud N, et al: Inhibitory activity ofterfenadine on histamine-induced skin wheals in man. Eur J CUn Pharmacol 1977; 12: 195 - 199. Krause LB, Shuster S: Enhanced weal and flare
9.
10.
II.
12.
13.
response to histamine in chronic idiopathic urticaria. Br J Clin Pharmaco11983; 20: 486 - 488. Humphreys F, Shuster S: The effect of topical dimethindene maleate on weal reactions. Br J CUn Pharmacol1987; 23: 234 - 236. Rampini E, Oberihauser V, Nunzi E: Evaluation of the local antihistaminicactivityof dimethindene maleate by a quantitative method. Dermatologia 1978; 157: 105 - 109. Denes M, Temesvari E, Soos GY: Objectiveness of the effectiveness of Fenistil. Med Monatsschr Pharm 1977; 31: 432 - 434. Reinberg A, Levi F, Guillet P, et al: Chronopharmacological study of antihistamines in man with special references to terfenadine. Eur J CUn Pharmacol 1978; 14: 245 - 252. Hedges A, Hills M, Maclay WP, et al: Some central and peripheral effects of meclastine, a new antihistaminic drug in man. J CUn Pharmacol 1971; 11: 112 - 119.
483
