Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil* * Department of Dermatology and Radiotherapy, Faculdade de Medicina de Botucatu - Universidade Estadual Paulista (UNESP) - Botucatu (SP), Brazil.

Helena Maciel-Guerra Mariana Álvares Penha Marília Formentini Scotton Jorge Ricardo da Silva Libório Ana Cláudia Nazareno dos Anjos Carrijo Maria Rita Parise-Fortes Hélio Amante Miot About the authors

Abstract:

Background:

Several dermatoses are mediated by histamine, such as urticaria, angioedema, and papular urticaria. There are no Brazilian studies comparing the potency of antihistamines.

Objectives:

To evaluate the tolerability and efficacy of the main commercial brand and generic H1 antihistamines, regarding the suppression of the wheal and flare to the histamine test.

Methods:

A quasi-experimental, open study with 10 healthy adults submitted to the histamine test on the ventral aspect of the forearms. After 20 minutes, wheal and flares were measured. The tests were performed after two hours of intake of dexchlorpheniramine, hydroxyzine, levocetirizine, fexofenadine, cetirizine, loratadine, ebastine, desloratadine, epinastine and rupatadine, as well as generics of loratadine, cetirizine and fexofenadine.

Results:

All antihistamines presented a reduction in the wheal compared to the control (p <0.02), as well as in the flare, except for rupatadine (p = 0.70). In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1). As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1). The most common adverse effect was drowsiness, which was more prevalent among first-generation drugs (p < 0.01). Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p <0.03)..

Study limitations:

A single-center study evaluating only aspects related to histamine.

Conclusions:

Brazilian commercial antihistamines presented different profiles of inhibition of wheal and flares in the histamine test, as well as adverse effects. Generic loratadine, fexofenadine and cetirizine presented larger flares than brand drugs.

Keywords:
Angioedema; Histamine antagonists; Histamine H1 antagonists; Histamine H2 antagonists; Urticaria

INTRODUCTION

Many skin conditions are mediated by histamine, such as urticaria (physical and immunomediated) angioedema and papular urticaria, supporting the frequent use of type I histamine receptor blockers (AH) in dermatology.11 Criado PR, Criado RF, Maruta CW, Machado Filho C. Histamine, histamine receptors and antihistamines: new concepts. An Bras Dermatol. 2010;85:195-210.,22 Geveaux C, Leroy T, Van Neste D. A comparative study of skin reaction after mosquito bite with either Aedes aegypti or Anopheles stephensi species. Nouv Dermatol 1999;18:79-82.

Urticaria is the main histamine-mediated condition in dermatology; it is common and affects patient's quality of life.33 Silvares MR, Fortes MR, Miot HA. Quality of life in chronic urticaria: a survey at a public university outpatient clinic, Botucatu (Brazil). Rev Assoc Med Bras (1992). 2011;57:577-82. Its prevalence is estimated in 1-1.5%, and up to 10-15% of the population will have one episode sometime in their life.44 Wedi B, Wieczorek D, Raap U, Kapp A. Urticaria. J Dtsch Dermatol Ges. 2014;12:997-1007.,55 Lapi F, Cassano N, Pegoraro V, Cataldo N, Heiman F, Cricelli I, et al. Epidemiology of chronic spontaneous urticaria: results from a nationwide, population-based study in Italy. Br J Dermatol. 2016;174:996-1004.

The main effector cell in the physiopathology of most causes of urticaria is the mast cell, that releases mediators such as histamine, inflammatory cytokines, chemokines, leukotrienes, prostaglandins and platelet-activating factor upon degranulation. These mediators are responsible for vasodilation, sensory activation, plasma leakage and recruitment of cells for the site of these lesions.66 Nosbaum A, Augey F, Nicolas JF, Bérard F. Pathophysiology of urticaria. Ann Dermatol Venereol. 2014;141:S559-64.

AH show good absorption when administered orally and, therefore, are capable of reaching effective plasma levels in less than two hours after intake (Table 1). Most are metabolized in the liver and excreted by the kidneys. They are divided into first and second (or more) generation AH.

Table 1
Main commercially antihistamines (anti-H1) available in Brazil, their chemical groups and pharmacologic characteristics, cost and doses tested by posological unit

First generation AH cross the blain-blood barrier and act on muscarinic, serotonin, adrenergic receptors, among others, causing adverse effects like drowsiness, hyperactivity, insomnia and seizures.11 Criado PR, Criado RF, Maruta CW, Machado Filho C. Histamine, histamine receptors and antihistamines: new concepts. An Bras Dermatol. 2010;85:195-210. On the other hand, second and third generation AH, besides more potent and longer lasting, have few adverse effects because the brain-blood barrier is less permeable to them, and they have a high affinity to H1 receptors.77 Pastorino AC. Revisão sobre a eficácia e segurança dos anti-histamínicos de primeira e segunda geração. Rev Bras Alerg Imunopatol. 2010;33:88-92. There are no studies in Brazil comparing the efficacy to histamine challenge and tolerability of commercial AH.

The epicutaneous histamine test allows for a comparison of the efficacy between drugs regarding the blockage to vascular permeability (wheal) and neuro-mediated reflex vasodilation (flare) by the activation of histamine receptors in the skin.88 Monroe EW, Daly AF, Shalhoub RF. Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines. J Allergy Clin Immunol. 1997;99:S798-806.

This study aims at evaluating the efficacy of wheal and flare suppression to the histamine test, besides the tolerability profile of the main antihistamines (anti-H1) commercialized in Brazil, and compare the performance with generic drugs.

METHODS

Quasi-experimental, open, self-controlled study, approved by the Ethics Committee of the Institution (CAAEE: 58849716.4.0000.5411). Ten healthy volunteers of both genders, older than 18 years of age and younger than 60, with no past history of anaphylaxis, asthma or urticaria, non-pregnant and not breastfeeding, with no recent history of AH and corticosteroid use were included in the study.

The study was conducted at the Dermatology Outpatient Clinic of FMB-Unesp (Botucatu-SP) from June to November, 2016.

Firstly, we performed a control test. A drop of histamine (histamine dihydrochloride 1:1,000) was introduced in each forearm (2cm from the antecubital fossa) with a disposable lancet. After 20 minutes, the diameter of the papules and wheals formed was measured (Figure 1).99 dos Santos RV, Magerl M, Mlynek A, Lima HC. Suppression of histamine- and allergen-induced skin reactions: comparison of first- and second-generation antihistamines. Ann Allergy Asthma Immunol. 2009;102:495-9.

10 Clough GF, Boutsiouki P, Church MK. Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy. 2001 ;56:985-8.
-1111 Levy JH, Gottge M, Szlam F, Zaffer R, McCall C. Weal and flare responses to intradermal rocuronium and cisatracurium in humans. Br J Anaesth. 2000;85:844-9.

Figure 1
Flare and wheal triggered by histamine test. Representation of the measurement of the wheal with a pen

In the subsequent tests, the same procedure was performed two hours after the intake of one of the commercial AH of the following brands: dexchlorpheniramine 6mg (Polaramine), hydroxyzine 25mg (Hixizine), levocetirizine 5mg (Zina), fexofenadine 180mg (Allegra), cetirizine 10mg (Zyrtec), loratadine 10mg (Claritin), ebastine 10mg (Ebastel), desloratadine 5mg (Desalex), epinastine 20mg (Talerc) and rupatadine 10mg (Rupafin), besides generic fexofenadine 180mg (Ranbaxy), loratadine 10mg (Merck) and cetirizine 10mg (Medley) (Table 1).

Volunteers were also questioned about possible side effects related to the medication, in particular drowsiness and dry mouth.

All tests were performed in duplicates (bilateral), in the afternoon (14h-16h), with a minimal interval of 48h so that one would not affect the other. As reference we adopted the product of the diameters of flares and wheals. The results were compared among the evaluators with a generalized linear mixed model (gamma with log link). Adherence to the probability distribution was tested by the Q-Q plot and the adjustment of the model compared by the corrected Akaike information criterium.1212 Miot HA. Assessing data normality in clinical and experimental trials. J Vasc Bras. 2017;16:88-91.,1313 Norman GR, Streiner DL. Biostatistics: the bare Essentials with SPSS. 4th ed. Shelton: People’s Medical Publishing House-USA; 2014.

The primary outcome was the analysis of the efficacy of antihistamines compared to control. For this test we used the Holm-Bonferroni post-hoc correction and considered significant one-sided p-values of ≤ 0,05.1313 Norman GR, Streiner DL. Biostatistics: the bare Essentials with SPSS. 4th ed. Shelton: People’s Medical Publishing House-USA; 2014.

The secondary outcome was the internal comparison of efficacy between the antihistamine groups among themselves and brand medications with their generic. For these tests we used the Holm-Bonferroni post-hoc correction and considered significant two-sided p-values of ≤ 0,05.1313 Norman GR, Streiner DL. Biostatistics: the bare Essentials with SPSS. 4th ed. Shelton: People’s Medical Publishing House-USA; 2014.

The comparison between the frequencies of adverse effects between AH groups was tested using McNemar, chi-square and Fisher's exact tests.1313 Norman GR, Streiner DL. Biostatistics: the bare Essentials with SPSS. 4th ed. Shelton: People’s Medical Publishing House-USA; 2014.

The concordance between the values of the forearms was calculated by the Intraclass Correlation Coefficient (ICC) for a perfect concordance.1414 Miot HA. Agreement analysis in clinical and experimental trials. J Vasc Bras. 2016;15:89-92. The correlation between the values of flares and wheals was assessed by Spearman's correlation coefficient (rho).1313 Norman GR, Streiner DL. Biostatistics: the bare Essentials with SPSS. 4th ed. Shelton: People’s Medical Publishing House-USA; 2014.

Sample size was calculated after a pre-test with 10 volunteers in order to detect a difference of up to 5mm in the wheal of the histamine test in comparison to control.1515 Miot HA. Sample size in clinical and experimental trials. J Vasc Bras 2011;10:275-8.

RESULTS

The cases were made up of seven female subjects and three male subjects, with ages between 23 and 51 years. Figures 2 and 3 show the values of the measurement of wheals and flares of the histamine tests with brand and generic AH.

Figure 2
Measurements of the products of the diameters of wheals (A) and flares (B) resulting from histamine tests for the different commercial antihistamines (reference drug) tested (n = 220)

HIST: Histamine; CET: Cetirizine; DESLO: Desloratadine; DEX: Dexchlorpheniramine; EBAS: Ebastine; EPI: Epinastine; FEXO: Fexofenadine; HIX: Hydroxyzine; LEVO: Levocetirizine; LORA: Loratadine; RUPA: Rupatadine


Figure 3
Measurements of the products of the diameters of wheals (A) and flares (B) resulting from histamine tests for the different commercial antihistamines (reference drug) tested in comparison to their generics (n = 120)

FEXO: Fexofenadine; CET: Cetirizine; LORA: Loratadine; GEN: Generic drug


There was a high concordance between the values of flares (ICC = 0.89; p < 0.01) and a substantial concordance between wheals (ICC = 0.67; p < 0.01) for the right and left forearm, however, there was no correlation between the diameter of flares and wheals for the histamine test (rho = 0.20; p = 0.39).

All AH showed a profile of wheal reduction in comparison to control (p < 0.02), as well as flares, except for rupatadine (p = 0.70) (Figure 2).

In the internal comparison, regarding wheal suppression, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1); the worst performances when compared to the other AH tested, were related to desloratadine, ebastine and rupatadine (p < 0.05) (Figure 2). Loratadine showed an intermediate potency and a variable significance among AH.

Regarding suppression of flare, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1); the worst performances when compared to the other AH were related to desloratadine and ebastine (p < 0.05) (Figure 2). Loratadine, rupatadine and dexchlorpheniramine show intermediate potency and variable significance among AH.

The most commonly reported adverse effect was drowsiness, more prevalent between first generation AH (70% vs 21%; p < 0.01). Dry mouth was not significantly different between the groups (0% vs 8%; p = 0.34) (Table 2).

Table 2
Frequency of drowsiness and dry mouth between the antihistamine tested (n = 130)

When brand medications were compared to their generics, there was difference between the values of flare for fexofenadine (p < 0.01), cetirizine (p < 0.01) and loratadine (p = 0.02); however, there was no difference between the wheal values (p > 0.1) (Figure 3). The frequency of drowsiness and dry mouth were not different between the groups (p > 0.50) (Table 2).

DISCUSSION

There was a great variability in the suppression profiles of flare and wheal to the histamine test, as well as adverse effects between AH in the dose and regime tested, and even between the volunteers, what reflects different response patterns found in clinical practice.

Other studies with slightly different methodologies confirm our results regarding the superiority of cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine in the suppression of the histamine-induced wheal.99 dos Santos RV, Magerl M, Mlynek A, Lima HC. Suppression of histamine- and allergen-induced skin reactions: comparison of first- and second-generation antihistamines. Ann Allergy Asthma Immunol. 2009;102:495-9.,1010 Clough GF, Boutsiouki P, Church MK. Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy. 2001 ;56:985-8.,1616 Leroy T, Tasset C, Valentin B, Van Neste D. Comparison of the effects of cetirizine and ebastine on the skin response to histamine iontophoresis monitored with laser Doppler flowmetry. Dermatology. 1998;197:146-51.

17 Van Neste D, Coussement C, Ghys L, Rihoux JP. Agonist-antagonist interactions in the skin: comparison of effects of loratadine and cetirizine on skin vascular responses to prick tests with histamine and substance P. J Dermatol Sci. 1992;4:172-9.

18 Rihoux JP, Van Neste DJ. 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. Dermatologica. 1989;179:129-34.

19 Van Neste D, Rihoux JP. Inhibition of the cutaneous response to histamine by H1- blocking agents. Quantitative evaluation of microvascular changes in the skin after histamine challenge and a comparison of the effects of a single intake of cetirizine and terfenadine. Skin Pharmacol. 1988;1:192-9.
-2020 Grant JA, Riethuisen JM, Moulaert B, DeVos C. A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced whealand- flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol. 2002;88:190-7. These data do not discredit the efficacy of the other AH tested, since they effectively suppressed the wheal in comparison to control, however, our results can influence in the decision to change AH in cases of unsatisfactory control of the condition.

The triple response of Lewis, described almost a century ago, assumes that the wheal and flare formation to the histamine test are independent phenomena that depend on vascular and neurologic integrity.2121 Lewis T, Harmer I. Vascular reactions of the skin to injury, Part IX. Further evidence of the release of a histamine-like substance from the injured skin. Heart. 1927;14:19-26. Papules are mainly formed by interstitial edema and should correlate to the intensity of wheals and rhinitis effusion, being the most clinically relevant measurement.1010 Clough GF, Boutsiouki P, Church MK. Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy. 2001 ;56:985-8. The flare is a vasodilation phenomenon that depends on the neural reactivity and can correlate to the pruritus. In fact, there was no correlation between the diameters of the flare and the wheal for the patients in this study, confirming their independence. As different AH show individualized performances regarding the suppression of the wheal and the flare, this study subsidizes possibilities of therapeutic success of different drugs in different histamine-mediated conditions.

The reactivity to the histamine test should not be interpreted as absolute, since the individual response can vary according to circadian rhythm, underlying infections/inflammations, room temperature, site of the test, neurologic integrity, other drugs and emotional stress levels.2222 Zachariae R, Jørgensen MM, Egekvist H, Bjerring P. Skin reactions to histamine of healthy subjects after hypnotically induced emotions of sadness, anger, and happiness. Allergy. 2001;56:734-40.,2323 Van Neste D. Skin response to histamine. Reproducibility study of the dry skin prick test method and of the evaluation of microvascular changes with laser Doppler flowmetry. Acta Derm Venereol. 1991;71:25-8. The study design using repeat measurements in both forearms, at the same time and in a homogenous group of healthy volunteers favors the internal validity of the results.

Our data add new information in Brazil regarding the potency of histamine blockage. The choice of AH should contemplate different clinical, pharmacologic, economic, dosing aspects and side effects. Even drowsiness, the main side effect of first generation AH can be strategic in pruritic conditions of central origin, such as uremic pruritus from hemodialysis, and its safety profile permissive in this group of patients.2424 Mettang T, Kremer AE. Uremic pruritus. Kidney Int. 2015;87:685-91.

Generics were regulated in Brazil in 1999 as drugs with proven bioequivalence in laboratories certified by ANVISA. There is a concern of the medical community that the bioequivalence of the active ingredient does not ascertain adequate bioavailability, solubility and pharmacokinetics as reference brand drugs.2525 Storpirtis S, Marcolongo R, Gasparotto FS, Vilanova CM. A equivalência farmacêutica no contexto da intercambialidade entre medicamentos genéricos e de referência: bases técnicas e científicas. Infarma. 2004;16:51-6.

26 Yacubian EMT. Medicamentos genéricos no tratamento das epilepsias: uma reflexão. J Epilepsy Clin Neurophysiol. 2007;13:127-30.

27 Silveira GS, Silva LD, Mosqueira VCF, de Souza J. Estudo biofarmacotécnico comparativo entre medicamentos referência, genérico, similar e magistral contendo furosemida, um fármaco de baixa solubilidade e baixa permeabilidade. Rev Bras Farm. 2011;92:306-13.

28 Köhler LF, Nascimento H, Schwengber ELL, Bandeira ZMP, Pazin GV, Machado SRP. Avaliação biofarmacotécnica e perfil de dissolução de comprimidos de dipirona: equivalências farmacêutica entre medicamentos de referência, genéricos e similares. Rev Bras Farm. 2009;90:309-15.
-2929 de Oliveira SY. Avaliação e comparação do perfil de dissolução do Fluconazol 150mg cápsulas produto referência, genérico e similar. [monografia]. Araraquara (SP): Universidade Estadual Paulista "Júlio de Mesquita Filho"; 2013. 25 f.

Generic AH drugs showed some discrepancies regarding suppression potency of flares when compared to brand medications, however, there was no difference regarding wheals, what is more relevant clinically.1010 Clough GF, Boutsiouki P, Church MK. Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy. 2001 ;56:985-8. These results should raise attention for the possibility that therapeutic failures could be due to intrinsic properties of a specific generic preparation.2626 Yacubian EMT. Medicamentos genéricos no tratamento das epilepsias: uma reflexão. J Epilepsy Clin Neurophysiol. 2007;13:127-30.,2929 de Oliveira SY. Avaliação e comparação do perfil de dissolução do Fluconazol 150mg cápsulas produto referência, genérico e similar. [monografia]. Araraquara (SP): Universidade Estadual Paulista "Júlio de Mesquita Filho"; 2013. 25 f.,3030 de Brum TF, Laporta LV, Pons Junior FdR, Gonçalves CA, Santos MRd. Equivalência farmacêutica e estudo comparativo dos perfis de dissolução de medicamentos genéricos contendo paracetamol. Rev Ciênc Farm Bas Aplic. 2012;33:373-8.

The study shows limitations related to the investigation of healthy individuals, single center, in a controlled situation, with only histamine challenge and a single dose of AH; this favors the internal comparison of the drugs but does not take into consideration the inflammatory and psychogenic aspects involved in histamine-dependent conditions.88 Monroe EW, Daly AF, Shalhoub RF. Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines. J Allergy Clin Immunol. 1997;99:S798-806.,3131 Heffner KL, Kiecolt-Glaser JK, Glaser R, Malarkey WB, Marshall GD. Stress and anxiety effects on positive skin test responses in young adults with allergic rhinitis. Ann Allergy Asthma Immunol. 2014;113:13-8.,3232 Galant SP, Bullock J, Wong D, Maibach HI. The inhibitory effect of antiallergy drugs on allergen and histamine induced wheal and flare response. J Allergy Clin Immunol. 1973;51:11-21.

There is a large variety of generic and similar AH in the Brazilian market. The choice of these manufacturers was due to the lowest price at the moment of purchase and their results do not allow generalization for other brands, which should be subsequently investigated.

Also, some AHs are known to be anti-inflammatory and act in the synthesis of leukotrienes and prostaglandins, and can have a more favorable performance in inflammatory and pruritic conditions than in this experimental comparison.3333 Antonijoan R, Coimbra J, García-Gea C, Puntes M, Gich I, Campo C, et al. Comparative efficacy of bilastine, desloratadine and rupatadine in the suppression of wheal and flare response induced by intradermal histamine in healthy volunteers. Curr Med Res Opin. 2017;33:129-136.

Clinical trials should be performed in order to counterproof these results and, in addition, future comparisons should consider the association between AH, consecutive day use, variation in doses, combination with H2 and H3 receptor blockers, besides mast cell membrane stabilizers, since they are also strategies used for the treatment of refractory urticaria.3434 Vestergaard C, Toubi E, Maurer M, Triggiani M, Ballmer-Weber B, Marsland A, et al. Treatment of chronic spontaneous urticaria with an inadequate response to H1- antihistamines: an expert opinion. Eur J Dermatol. 2017;27:10-19.,3535 Staubach P, Zuberbier T, Vestergaard C, Siebenhaar F, Toubi E, Sussman G. Controversies and challenges in the management of chronic urticaria. J Eur Acad Dermatol Venereol. 2016;30:16-24.

CONCLUSION

The main Brazilian commercial AH showed different profiles of flare and wheal suppression in the histamine test, as well as of adverse effects. Loratadine, fexofenadine and cetirizine showed different flare profiles among the brand and generic medications tested. The choice of the drug for treatment of histamine-mediated conditions should take into account clinical, tolerability and pharmacoeconomic aspects.

  • Financial support: None.
  • *
    Department of Dermatology and Radiotherapy, Faculdade de Medicina de Botucatu - Universidade Estadual Paulista (UNESP) - Botucatu (SP), Brazil.

REFERENCES

  • 1
    Criado PR, Criado RF, Maruta CW, Machado Filho C. Histamine, histamine receptors and antihistamines: new concepts. An Bras Dermatol. 2010;85:195-210.
  • 2
    Geveaux C, Leroy T, Van Neste D. A comparative study of skin reaction after mosquito bite with either Aedes aegypti or Anopheles stephensi species. Nouv Dermatol 1999;18:79-82.
  • 3
    Silvares MR, Fortes MR, Miot HA. Quality of life in chronic urticaria: a survey at a public university outpatient clinic, Botucatu (Brazil). Rev Assoc Med Bras (1992). 2011;57:577-82.
  • 4
    Wedi B, Wieczorek D, Raap U, Kapp A. Urticaria. J Dtsch Dermatol Ges. 2014;12:997-1007.
  • 5
    Lapi F, Cassano N, Pegoraro V, Cataldo N, Heiman F, Cricelli I, et al. Epidemiology of chronic spontaneous urticaria: results from a nationwide, population-based study in Italy. Br J Dermatol. 2016;174:996-1004.
  • 6
    Nosbaum A, Augey F, Nicolas JF, Bérard F. Pathophysiology of urticaria. Ann Dermatol Venereol. 2014;141:S559-64.
  • 7
    Pastorino AC. Revisão sobre a eficácia e segurança dos anti-histamínicos de primeira e segunda geração. Rev Bras Alerg Imunopatol. 2010;33:88-92.
  • 8
    Monroe EW, Daly AF, Shalhoub RF. Appraisal of the validity of histamine-induced wheal and flare to predict the clinical efficacy of antihistamines. J Allergy Clin Immunol. 1997;99:S798-806.
  • 9
    dos Santos RV, Magerl M, Mlynek A, Lima HC. Suppression of histamine- and allergen-induced skin reactions: comparison of first- and second-generation antihistamines. Ann Allergy Asthma Immunol. 2009;102:495-9.
  • 10
    Clough GF, Boutsiouki P, Church MK. Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy. 2001 ;56:985-8.
  • 11
    Levy JH, Gottge M, Szlam F, Zaffer R, McCall C. Weal and flare responses to intradermal rocuronium and cisatracurium in humans. Br J Anaesth. 2000;85:844-9.
  • 12
    Miot HA. Assessing data normality in clinical and experimental trials. J Vasc Bras. 2017;16:88-91.
  • 13
    Norman GR, Streiner DL. Biostatistics: the bare Essentials with SPSS. 4th ed. Shelton: People’s Medical Publishing House-USA; 2014.
  • 14
    Miot HA. Agreement analysis in clinical and experimental trials. J Vasc Bras. 2016;15:89-92.
  • 15
    Miot HA. Sample size in clinical and experimental trials. J Vasc Bras 2011;10:275-8.
  • 16
    Leroy T, Tasset C, Valentin B, Van Neste D. Comparison of the effects of cetirizine and ebastine on the skin response to histamine iontophoresis monitored with laser Doppler flowmetry. Dermatology. 1998;197:146-51.
  • 17
    Van Neste D, Coussement C, Ghys L, Rihoux JP. Agonist-antagonist interactions in the skin: comparison of effects of loratadine and cetirizine on skin vascular responses to prick tests with histamine and substance P. J Dermatol Sci. 1992;4:172-9.
  • 18
    Rihoux JP, Van Neste DJ. 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. Dermatologica. 1989;179:129-34.
  • 19
    Van Neste D, Rihoux JP. Inhibition of the cutaneous response to histamine by H1- blocking agents. Quantitative evaluation of microvascular changes in the skin after histamine challenge and a comparison of the effects of a single intake of cetirizine and terfenadine. Skin Pharmacol. 1988;1:192-9.
  • 20
    Grant JA, Riethuisen JM, Moulaert B, DeVos C. A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced whealand- flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol. 2002;88:190-7.
  • 21
    Lewis T, Harmer I. Vascular reactions of the skin to injury, Part IX. Further evidence of the release of a histamine-like substance from the injured skin. Heart. 1927;14:19-26.
  • 22
    Zachariae R, Jørgensen MM, Egekvist H, Bjerring P. Skin reactions to histamine of healthy subjects after hypnotically induced emotions of sadness, anger, and happiness. Allergy. 2001;56:734-40.
  • 23
    Van Neste D. Skin response to histamine. Reproducibility study of the dry skin prick test method and of the evaluation of microvascular changes with laser Doppler flowmetry. Acta Derm Venereol. 1991;71:25-8.
  • 24
    Mettang T, Kremer AE. Uremic pruritus. Kidney Int. 2015;87:685-91.
  • 25
    Storpirtis S, Marcolongo R, Gasparotto FS, Vilanova CM. A equivalência farmacêutica no contexto da intercambialidade entre medicamentos genéricos e de referência: bases técnicas e científicas. Infarma. 2004;16:51-6.
  • 26
    Yacubian EMT. Medicamentos genéricos no tratamento das epilepsias: uma reflexão. J Epilepsy Clin Neurophysiol. 2007;13:127-30.
  • 27
    Silveira GS, Silva LD, Mosqueira VCF, de Souza J. Estudo biofarmacotécnico comparativo entre medicamentos referência, genérico, similar e magistral contendo furosemida, um fármaco de baixa solubilidade e baixa permeabilidade. Rev Bras Farm. 2011;92:306-13.
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Publication Dates

  • Publication in this collection
    Mar-Apr 2018

History

  • Received
    16 Dec 2016
  • Accepted
    14 Feb 2017
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