RESUMO
BACKGROUND: Bilastine, a novel non-sedating second-generation H1-antihistamine, has been widely used in the treatment of allergic rhinoconjunctivitis and urticaria with a recommended dose of 20 mg once daily in most European countries since 2010. We evaluated its efficacy and safety in Japanese patients with chronic spontaneous urticaria (CSU). METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled phase II/III study (trial registration No. JapicCTI-142574). Patients (age, 18-74 years) were randomly assigned to receive bilastine 20 mg, 10 mg or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline (Day -3 to 0) in total symptom score (TSS) at 2 weeks (Day 8-14), consisting of the itch and rash scores. RESULTS: A total of 304 patients were randomly allocated to bilastine 20 mg (101 patients), bilastine 10 mg (100 patients), and placebo (103 patients). The changes in TSS at 2 weeks were significantly decreased by bilastine 20 mg than did placebo (p < 0.001), demonstrating the superiority of bilastine 20 mg. Bilastine 10 mg also showed a significant difference from placebo (p < 0.001). The TSS changes for the bilastine showed significant improvement from Day 1, and were maintained during the treatment period. The Dermatology Life Quality Index scores were also improved in bilastine than in placebo. The bilastine treatments were safe and well tolerated. CONCLUSIONS: Two-week treatment with bilastine (20 or 10 mg) once daily was effective and tolerable in Japanese patients with CSU, demonstrating an early onset of action.
Assuntos
Benzimidazóis/uso terapêutico , Antagonistas não Sedativos dos Receptores H1 da Histamina/uso terapêutico , Piperidinas/uso terapêutico , Urticária/tratamento farmacológico , Adolescente , Adulto , Idoso , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Doença Crônica , Feminino , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Qualidade de Vida , Resultado do Tratamento , Urticária/diagnóstico , Urticária/etiologia , Adulto JovemRESUMO
BACKGROUND: Environmental exposure chambers have been used to expose subjects to aeroallergens to investigate the efficacy of prophylactic treatment with symptomatic agents in Japan. We first examined the therapeutic effect of bilastine (BIL), a novel non-sedative second-generation H1-antihistamine, in subjects with Japanese cedar pollinosis using an artificial exposure chamber (OHIO Chamber). METHODS: This was a randomized, double-blind, four-way crossover, placebo- and active-controlled phase II study (trial registration number JapicCTI-132213). Subjects were exposed to cedar pollen (8000 grains/m3) for 2 h on Day -1 and 4 h each on Day 1 and 2. BIL 10 or 20 mg, placebo, or fexofenadine hydrochloride (FEX) 60 mg was administered orally 1 h after the start of pollen exposure on Day 1. Placebo or FEX was administered 12 h after the first dosing. The primary efficacy endpoint was the sum of total nasal symptom score (TNSS) from 0 to 3 h after the Day 1 dosing. RESULTS: We enrolled 136 subjects and the sum of TNSS on Day 1 of the three active treatments was significantly lower than that of placebo and was maintained up to 26 h after the first dosing (Day 2). The sum of TNSS or sneezing score on Day 1 after BIL 20 mg was more significantly decreased than after FEX. Moreover, BIL showed a faster onset of action than FEX. CONCLUSIONS: We demonstrated the efficacy, rapid onset, and long duration of action of BIL in subjects with Japanese cedar pollinosis exposed to cedar pollen using the OHIO Chamber.
Assuntos
Benzimidazóis/administração & dosagem , Cryptomeria , Piperidinas/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Adulto , Benzimidazóis/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Rinite Alérgica Sazonal/imunologiaRESUMO
BACKGROUND: Bilastine, a novel non-sedating second-generation H1 antihistamine, has been approved in most European countries since 2010. This study aimed to evaluate the superiority of bilastine over placebo in Japanese patients with perennial allergic rhinitis (PAR). METHODS: This randomized, double-blind, placebo-controlled, parallel-group, phase III study (trial registration number JapicCTI-142600) evaluated the effect of a 2-week treatment period with bilastine (20 mg once daily), fexofenadine (60 mg twice daily), or a matched placebo (double dummy) in patients with PAR. All patients were instructed to record individual nasal and ocular symptoms in diaries daily. The primary endpoint was the mean change in total nasal symptom scores (TNSS) from baseline to Week 2 (Days 10-13). RESULTS: A total of 765 patients were randomly allocated to receive bilastine, fexofenadine, or placebo (256, 254, and 255 patients, respectively). The mean change in TNSS from baseline at Week 2 was significantly decreased by bilastine (-0.98) compared to placebo (-0.63, P = 0.023). Bilastine and fexofenadine showed no significant difference in the primary endpoint. However, the mean change in TNSS from baseline on Day 1 was more significantly decreased by bilastine (-0.99) than by placebo (-0.28, P < 0.001) or fexofenadine (-0.62, P = 0.032). The active drugs also improved instantaneous TNSS 1 h after the first and before the second drug administration on Day 1 (P < 0.05). The study drugs were well tolerated. CONCLUSIONS: After 2-week treatment period, bilastine 20 mg once daily was effective and tolerable in Japanese patients with PAR, and exhibited a rapid onset of action.
Assuntos
Benzimidazóis/administração & dosagem , Piperidinas/administração & dosagem , Rinite Alérgica Sazonal/tratamento farmacológico , Adulto , Povo Asiático , Benzimidazóis/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Terfenadina/administração & dosagem , Terfenadina/análogos & derivadosRESUMO
OBJECTIVE: Bilastine is a novel second-generation antihistamine. This open-label, single-arm, phase III study evaluated the safety and efficacy of long-term treatment with bilastine in Japanese patients with seasonal (SAR) or perennial allergic rhinitis (PAR). METHODS: Patients with SAR or PAR who met the registration criteria and did not violate the exclusion criteria received bilastine (20mg, once daily) for 12 weeks (treatment period). Patients with PAR who met the transition criteria could elect to continue the bilastine treatment for an additional 40 weeks (continuous treatment period: a total of 52 weeks). Safety and tolerability were the primary outcomes, and the main secondary endpoint was to evaluate changes in efficacy variables from baseline measurements. RESULTS: Fifty-eight patients with SAR and 64 patients with PAR received bilastine (20mg/day) for 12 weeks. Fifty-five patients with PAR transitioned to the continuous treatment period. Adverse events (AEs) were reported by 17.2% of patients with SAR and by 31.3% of patients with PAR, and adverse drug reactions (ADRs) were reported by 6.3% of patients with PAR but by no patients with SAR during the 12-week treatment period. All of the ADRs were mild in severity. During the 52-week treatment period, AEs and ADRs were reported by 73.4% and 6.3% of patients with PAR, respectively. All of the ADRs occurred during the 12-week treatment period, and none during the continuous treatment period. The AEs were categorized using the System Organ Class of nervous system disorders; 4.7% of patients reported headache, but none reported somnolence. One serious AE was reported, but it was considered to be unrelated to the bilastine treatment. There were no deaths, and no patients withdrew from the study because of AEs. In patients with SAR, bilastine significantly decreased the total nasal symptom score (TNSS), total ocular symptom score (TOSS), and total symptom score (TSS) relative to baseline. Prolonged treatment with bilastine resulted in the maintenance of a significant reduction in TNSS, TOSS, and TSS from the baseline in patients with PAR. Improvement of quality of life was also observed in patients with SAR and PAR. CONCLUSION: Bilastine was safe, well tolerated, and effective for patients with SAR and PAR. The observed improvement was maintained for the duration of the study, with no loss of drug efficacy (registration number JapicCTI-142622).
Assuntos
Benzimidazóis/uso terapêutico , Antagonistas não Sedativos dos Receptores H1 da Histamina/uso terapêutico , Piperidinas/uso terapêutico , Rinite Alérgica Perene/tratamento farmacológico , Rinite Alérgica Sazonal/tratamento farmacológico , Adulto , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
A number of second-generation non-sedating antihistamines are used in clinical practices over the world. However, long-term safety and efficacy have not been proved high level evidence based medicine. We have performed an open-label, multicenter, phase III study to evaluate the long-term safety and efficacy of bilastine, a novel non-sedating H1 -antihistamine for patients with chronic spontaneous urticaria (CSU) or pruritus associated with skin diseases (trial registration no. JapicCTI-142528). Patients aged 18-74 years were treated with bilastine 20 mg once daily for up to 52 weeks. Safety and tolerability were assessed on the basis of adverse events (AE), bilastine-related AE, laboratory tests and vital signs. Efficacy was assessed based on rash score, itch score, overall improvement and quality of life. One hundred and ninety-eight patients enrolled, 122 of whom (61.6%) completed the 52-week treatment period. AE were reported in 64.5% and bilastine-related AE in 2.5% of patients throughout the 52-week treatment period. All AE were mild to moderate in severity. AE associated with the nervous system occurred in 10 patients (5.1%) including seven patients (3.6%) with headache. Somnolence reported in two of these patients (1.0%) was related to bilastine. All efficacy variables improved during treatment with bilastine. In conclusion, long-term treatment with bilastine 20 mg once daily for 52 weeks is safe and well tolerated in Japanese patients with CSU or pruritus associated with skin diseases. Bilastine improved disease symptoms of both conditions early in treatment, and the efficacy was maintained throughout the treatment.
Assuntos
Benzimidazóis/uso terapêutico , Antagonistas não Sedativos dos Receptores H1 da Histamina/uso terapêutico , Piperidinas/uso terapêutico , Prurido/tratamento farmacológico , Urticária/tratamento farmacológico , Adulto , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Doença Crônica , Eczema/complicações , Feminino , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Humanos , Japão , Efeitos Adversos de Longa Duração/induzido quimicamente , Efeitos Adversos de Longa Duração/epidemiologia , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Prurigo/complicações , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. METHODS: In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). RESULTS: After single oral doses, maximum plasma concentrations (C max) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. CONCLUSION: Bilastine exhibits similar single- and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies.
Assuntos
Benzimidazóis/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Piperidinas/administração & dosagem , Adolescente , Adulto , Área Sob a Curva , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Relação Dose-Resposta a Droga , Feminino , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/farmacocinética , Piperidinas/farmacologia , Método Simples-Cego , Adulto JovemRESUMO
We investigated the role of hematopoietic prostaglandin D synthase (H-PGDS) in biphasic nasal obstruction in allergic rhinitis using a new specific inhibitor, (N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride (TAS-204). First, we developed a novel guinea pig model of allergic rhinitis. Guinea pigs sensitized to ovalbumin without adjuvant were challenged with intranasal exposure to ovalbumin once a week. After the 3rd antigen challenge, they exhibited biphasic nasal obstruction. Additionally, analysis of nasal lavage fluid revealed an increase in the level of prostaglandin D(2) in both early and late phases. Treatment with oral TAS-204 for 15 days during the period of antigen challenges suppressed increases in nasal airway resistance in both phases. It is noteworthy that the late phase nasal obstruction was almost completely abrogated by inhibiting H-PGDS alone. Eosinophil infiltration in nasal lavage fluid and nasal hyperresponsiveness to histamine was also reduced by TAS-204 administration. These findings suggest that H-PGDS plays a critical role in the development of allergic rhinitis, especially in the induction of late phase nasal obstruction.
Assuntos
Benzimidazóis/farmacologia , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Obstrução Nasal/enzimologia , Pirróis/farmacologia , Rinite/enzimologia , Animais , Benzimidazóis/uso terapêutico , Dinoprostona/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Cobaias , Histamina/imunologia , Histamina/metabolismo , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Leucotrienos/metabolismo , Lipocalinas/antagonistas & inibidores , Masculino , Líquido da Lavagem Nasal/imunologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Obstrução Nasal/tratamento farmacológico , Obstrução Nasal/imunologia , Obstrução Nasal/metabolismo , Ovalbumina/imunologia , Prostaglandina D2/biossíntese , Prostaglandina D2/metabolismo , Pirróis/uso terapêutico , Rinite/tratamento farmacológico , Rinite/imunologia , Rinite/metabolismo , Fatores de TempoRESUMO
TAS-203 (2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-5-(1H-1,2,4-triazol-1-yl)-1H-benzimidazole, CAS 223909-92-0) is a novel phosphodiesterase 4 (PDE4) inhibitor that has been found to have good anti-inflammatory effects and low emetogenic activity in vivo. In the present studies, the anti-inflammatory profile of TAS-203 was examined and compared with that of cilomilast (CAS 153259-65-5), the most advanced PDE4 inhibitor. TAS-203 inhibited the activity of purified human PDE4 with an IC50 value of 88 nM and also the recombinant PDE4 subtypes (4A, 4B, 4C and 4D) with respective IC50 values of 47, 35, 227 and 43 nM. In the experiments using inflammatory cells, TAS-203 concentration-dependently inhibited platelet-activating factor-induced eosinophil chemotaxis and lipopolysaccharide (LPS)-stimulated tumor necrosis factor-a release from human monocytes with respective IC50 values of 250 and 38.5 nM. For airway inflammation, TAS-203 at 10 mg/kg and cilomilast at 30 mg/kg significantly inhibited antigen-induced airway eosinophilia and LPS-induced airway neutrophilia in rats. The emetogenicity of TAS-203 and cilomilast was evaluated in a ferret model of emesis. The maximum dose of TAS-203 not carrying emesis was 100 mg/kg, while that of cilomilast was less than 10 mg/kg. Finally, TAS-203 was found to be poorly distributed to the brain after oral administration of 10 mg/kg TAS-203 in rats. These results indicate that TAS-203 is an orally active PDE4 inhibitor with potent anti-inflammatory activities and low emetogenicity that may be useful in the treatment of airway inflammatory conditions such as asthma and chronic obstructive pulmonary disease.
Assuntos
Anti-Inflamatórios , Benzimidazóis/farmacologia , Furões , Inflamação/tratamento farmacológico , Inibidores da Fosfodiesterase 4/farmacologia , Doenças Respiratórias/tratamento farmacológico , Triazóis/farmacologia , Vômito/prevenção & controle , Animais , Benzimidazóis/farmacocinética , Quimiotaxia de Leucócito/efeitos dos fármacos , Clonagem Molecular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/biossíntese , Ácidos Cicloexanocarboxílicos/farmacologia , Cobaias , Humanos , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Nitrilas/farmacologia , Inibidores da Fosfodiesterase 4/farmacocinética , Fator de Ativação de Plaquetas/farmacologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Doenças Respiratórias/patologia , Distribuição Tecidual , Triazóis/farmacocinética , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The effects of a newly synthesized compound, 6-acetoamido-1-acetyl-1-indazole (TAS-3-124), on autoimmune diseases were studied. We used animal models of collagen-induced arthritis (CIA) in mice and experimental autoimmune encephalomyelitis (EAE) in rats to evaluate the efficacy of TAS-3-124. TAS-3-124 at doses of 100 and 300 mg/kg p.o. inhibited the development of CIA, decreasing the swelling of fore- and hind-limbs and bone destruction in knee joints. This agent also suppressed the delayed type hypersensitivity reaction (DTH) against type II collagen. These effects were confirmed by histopathological examination and measurement of the expression of mRNA of proinflammatory cytokines in the knee joint. In addition, TAS-3-124 at a dose of 300 mg/kg inhibited the development of EAE and the DTH to myelin basic protein (MBP) in rats. Moreover, TAS-3-124 inhibited the production of proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 but not T cell derived cytokines in mice. These demonstrate the efficacy of TAS-3-124 against experimental autoimmune disease, probably due to the suppression of the production of proinflammatory cytokines in the pathological lesion.