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BACKGROUND: Limited data exist comparing inhaled corticosteroid (ICS) plus adjunctive therapy vs ICS alone in pediatric asthma patients. OBJECTIVE: To evaluate the efficacy and safety of fluticasone furoate/vilanterol (FF/VI) vs FF in children and adolescents with asthma. METHODS: This phase 3, randomized, double-blind, multicenter study (NCT03248128) included participants aged 5 to 17 years with six months or more asthma history uncontrolled on ICS monotherapy. Participants received 4-week open-label fluticasone propionate (100 µg) twice daily before 1:1 randomization to 24-week double-blind FF (50 µg:100 µg) or FF/VI (50/25 µg:100/25 µg) once daily. Two populations with different primary endpoints were analyzed to meet United States (week 12 weighted mean forced expiratory volume in 1 second [FEV1; 0-4 hours]; participants aged 5-17 years) and European (change from baseline predose morning peak expiratory flow [ΔAM PEF] averaged over weeks 1-12; participants aged 5-11 years) regulatory requirements. RESULTS: Overall, 902 participants, including 673 children aged 5 to 11 years, were randomized and treated. In participants aged 5 to 17, week 12 weighted mean FEV1 (0-4 hours) was greater with FF/VI vs FF (difference: 0.083 L; P < .001). In participants aged 5 to 11, ΔAM PEF over weeks 1 to 12 showed numerical improvement with FF/VI vs FF but was not statistically significant (difference: 3.2 L/min; P = .228). No drug-related serious adverse events or deaths were reported. CONCLUSION: FF/VI significantly improved weighted mean FEV1 (0-4 hours; participants aged 5-17 years), but not ΔAM PEF (participants aged 5-11 years) vs FF. No new safety concerns were apparent. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03248128.
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INTRODUCTION: Growth impairment is a known adverse event (AE) of corticosteroids in children. This study aimed to assess the effect of once-daily (QD) inhaled fluticasone furoate (FF) versus placebo on growth velocity over 1 year in prepubertal children with well-controlled asthma. MATERIALS AND METHODS: This randomized, double-blind, parallel-group, placebo-controlled, multicenter study (NCT02889809) included prepubertal children, aged 5 to <9 years (boys), and 5 to <8 years (girls), with ≥6 months' asthma history. Children received inhaled placebo QD plus background open-label montelukast QD for a 16-week run-in period and were then randomized 1:1 to receive inhaled FF 50 µg QD or placebo QD (whilst continuing background open-label montelukast) for a 52-week treatment period. The primary endpoint was the difference in growth velocity (cm/year) over the treatment period. Other growth endpoints were measured, as were incidence of AEs and asthma exacerbation. Growth analyses included all intent-to-treat (ITT) participants with ≥3 post-randomization, on-treatment clinic visit height assessments (GROWTH population). RESULTS: Of 644 children in the run-in period, 477 (mean age 6.2 years, 63% male) entered the 52-week treatment period (ITT population: FF N = 238, placebo N = 239; GROWTH population: N = 457 [FF N = 231; placebo N = 226]). The least-squares mean difference in growth velocity for FF versus placebo was -0.160 cm/year (95% confidence interval: -0.462, 0.142). There were no new safety signals. CONCLUSIONS: Over 1 year, FF 50 µg QD had a minimal effect on growth velocity versus placebo, with no new safety signals.
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Asma , Broncodilatadores , Feminino , Humanos , Criança , Masculino , Broncodilatadores/uso terapêutico , Administração por Inalação , Asma/tratamento farmacológico , Método Duplo-Cego , Resultado do Tratamento , Fluticasona/uso terapêuticoRESUMO
RATIONALE: Asthma studies show many children use inhalers incorrectly even after instruction. For two age groups of children with asthma, we determined the proportions who used the once-daily ELLIPTA dry-powder inhaler (DPI) correctly, and who found it easy to use. METHODS: This was a multicenter, single-arm, stratified, open-label, placebo study (NCT03478657). Children aged 5-7 and 8-11 years were trained in, and required to demonstrate, correct placebo ELLIPTA DPI use at their first clinic visit. The inhaler was used at home once daily for 28 ± 2 days. On returning to the clinic, children were randomized to an age-appropriate, ease-of-use questionnaire that had been developed and validated previously, and which rated the inhaler as "easy" or "hard" to use. Following questionnaire completion, children were then asked to demonstrate correct inhaler use. Correct use and ease-of use were assessed in each age group (co-primary endpoints) and overall (secondary endpoints). RESULTS: Of 222 enrolled children, 221 completed the study. Among children aged 5-7 years, 92% (n = 81/88) demonstrated correct ELLIPTA use on their first attempt, compared with 93% (n = 124/133) aged 8-11 years. Of these children, 98% (5-7 years: n = 79/81; 8-11 years: n = 121/124) rated the inhaler easy to use. Overall, 93% (n = 205/221) demonstrated correct inhaler use on their first attempt, and 98% (n = 200/205) rated it easy to use. CONCLUSION: ELLIPTA DPI was used correctly and easily by most children on their first attempt without additional training.
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Asma/tratamento farmacológico , Inaladores de Pó Seco/métodos , Administração por Inalação , Adulto , Idoso , Assistência Ambulatorial , Instituições de Assistência Ambulatorial , Criança , Pré-Escolar , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pós/uso terapêutico , Inquéritos e QuestionáriosRESUMO
BACKGROUND: To evaluate the effects of fluticasone furoate on the hypothalamic-pituitary-adrenocortical axis, and the safety and tolerability of fluticasone furoate treatment in children with asthma. METHODS: This was a randomized, double-blind, placebo-controlled, multicenter, stratified, parallel-group, non-inferiority study of fluticasone furoate 50 µg inhalation powder administered once daily. The study enrolled children (aged 5-11 years inclusive) with a documented diagnosis of asthma for ≥ 6 months and a Childhood Asthma Control Test score of > 19. After a 7-14-day run-in period, eligible subjects were stratified by age and randomized to fluticasone furoate 50 µg once daily or placebo once daily via ELLIPTA for 6 weeks. The primary endpoint was the change from baseline (expressed as a ratio) in 0-24-h weighted mean serum cortisol at the end of the treatment period. RESULTS: Fifty-six randomized subjects received fluticasone furoate 50 µg once daily and 55 received placebo. The primary analysis was performed in the serum cortisol population (n = 104) and demonstrated that fluticasone furoate 50 µg once daily was non-inferior to placebo (ratio = 0.93; 95% confidence interval 0.8096, 1.0620), as the lower limit of the 95% confidence interval for the geometric mean treatment ratio of fluticasone furoate 50 µg once daily versus placebo was greater than 0.80. Findings from the intent-to-treat population (n = 111) were similar. CONCLUSIONS: Six weeks of treatment with inhaled fluticasone furoate 50 µg once daily had no clinically relevant effect on the hypothalamic-pituitary-adrenocortical axis function of children, as measured by 24-h serum cortisol profiles. The primary analysis showed that fluticasone furoate 50 µg once daily was non-inferior to placebo. Fluticasone furoate 50 µg once daily was well tolerated and no new safety concerns emerged during the study. TRIAL REGISTRATION: This study is registered in ClinicalTrials.gov (NCT02483975). Date of submission: 25 June 2015.
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Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25â mg, 1â mg and 2â mg twice daily for 8â days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2â mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.
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Fibrose Pulmonar Idiopática/tratamento farmacológico , Quinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fluordesoxiglucose F18 , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Piridazinas , Serina-Treonina Quinases TOR/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Fluticasone furoate/Vilanterol trifenatate (FF/VI) is an inhaled corticosteroid/long-acting beta-agonist combination with a prolonged bronchodilator duration of action. We characterised the time-course of onset and offset of airway anti-inflammatory action of FF/VI, as assessed by fraction of exhaled nitric oxide (FeNO), and compared this to the bronchodilator duration of action. METHODS: A single-centre, randomised, double-blind, placebo-controlled, two-period, crossover study was undertaken in 28 steroid-naïve adults with asthma. Participants with an FEV1 ≥ 60% predicted, reversible airway disease, and FeNO > 40 ppb received FF/VI 100/25 mcg or placebo once daily for 14 days. FeNO and peak expiratory flow were measured twice-daily during treatment and during a 21-day washout period. FEV1 was measured for five days from treatment cessation. The primary outcome measure was FeNO change from baseline ratio for 21 days following treatment cessation. RESULTS: In the 27 subjects who completed the study, median (range) baseline FeNO was 87 ppb (42-212). FF/VI 100/25 mcg reduced FeNO by day 3, ratio FF/VI versus placebo 0.72 (95% confidence interval 0.61-0.86) with the maximum reduction occurring at day 14, 0.32 (0.27-0.37). Following cessation of treatment FeNO remained suppressed for 18 days, ratio on day 18 0.77 (0.59-1.00), whereas improvements in FEV1 and peak flow were maintained for 3 to 4 days post-treatment. CONCLUSIONS: The anti-inflammatory duration of action of FF/VI is consistent with the high glucocorticoid receptor affinity and long lung retention of fluticasone furoate. The anti-inflammatory effect of FF/VI was of greater duration than its bronchodilator effect in adults with mild asthma. Funding GlaxoSmithKline (201499). TRIAL REGISTRATION: Prospectively registered on ClinicalTrials.gov registry number NCT02712047 .
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Androstadienos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/diagnóstico , Asma/tratamento farmacológico , Álcoois Benzílicos/administração & dosagem , Clorobenzenos/administração & dosagem , Adolescente , Adulto , Asma/epidemiologia , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807.
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Lesão Pulmonar Aguda/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais/farmacologia , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Lesão Pulmonar Aguda/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Biomarcadores Farmacológicos , Líquido da Lavagem Broncoalveolar/citologia , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Citometria de Fluxo , Humanos , Inflamação/tratamento farmacológico , Macaca fascicularis , Terapia de Alvo Molecular , Nebulizadores e Vaporizadores , Farmacologia Clínica , Transdução de Sinais , Pesquisa Translacional BiomédicaRESUMO
PURPOSE: A dry powder inhaler formulation of the inhaled corticosteroid fluticasone furoate (FF) is being evaluated for use in children. An important potential risk associated with the use of inhaled corticosteroids in children is growth suppression. Therefore, the aim of this study was to assess the short-term lower leg growth in children with asthma treated for 2 weeks with inhaled FF versus placebo from the ELLIPTA inhaler. METHODS: Prepubertal children with persistent asthma (n = 60; aged 5 to <12 years) were recruited into a randomized, double-blind, placebo-controlled, 2-way crossover, noninferiority study. The study consisted of four 2-week periods: run-in, 2 treatment periods, 1 washout period, and a 1-week follow-up period. Interventions were FF 50 µg and placebo once daily in the evening. Lower leg length was measured by using knemometry. FINDINGS: The randomized ITT population comprised 36 boys and 24 girls with a mean age of 8.7 (standard deviation, 1.5; range, 5-11) years; 58% had a duration of asthma ≥5 years. Fifty-eight subjects completed both treatment periods. The least squares mean growth rate was 0.31 mm/week during treatment with FF and 0.36 mm/week during the placebo period. The difference in adjusted least squares mean growth rates between FF and placebo was -0.052 mm/week with a 95% CI of -0.122 to 0.018. This finding was greater than the prespecified noninferiority margin of -0.20 mm/week. The overall incidence of adverse events was 35% with placebo and 22% with FF. IMPLICATIONS: Inhaled FF 50 µg provided once daily for 2 weeks was noninferior to placebo in terms of effects on short-term lower leg growth in children with asthma. To further quantify the risk of growth suppression in children, intermediate-term growth studies should be conducted. Inhaled FF 50 µg was well tolerated in this study population. ClinicalTrials.gov identifier: NCT02502734.
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Androstadienos/uso terapêutico , Asma/tratamento farmacológico , Desenvolvimento Infantil/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Perna (Membro)/crescimento & desenvolvimento , Administração por Inalação , Criança , Pré-Escolar , Estudos Cross-Over , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
PURPOSE: The purpose of this study was to investigate potential systemic pharmacokinetic interactions between intranasal fluticasone furoate (FF) and levocabastine (LEVO) when delivered simultaneously via a metered atomizing spray pump. METHODS: This was a randomized, open-label, crossover study. Healthy male and female subjects (n = 30) received once-daily repeat doses of FF/LEVO (100/200 µg) as a fixed-dose combination (FDC), FF (110 µg), or LEVO (200 µg) for 7 days. FF and LEVO plasma pharmacokinetics (0-24 hours) were measured on day 7, with safety assessments over the study duration. RESULTS: Systemic exposure to LEVO was similar when administered as FF/LEVO FDC or LEVO alone. Following FF/LEVO FDC or FF alone, the majority (>99%) of FF concentrations were nonquantifiable, that is, below the lower limit of quantification of 10 pg/mL. All treatments were well tolerated, and adverse event incidence was similar across the treatment groups. CONCLUSIONS: These results suggest that in healthy subjects, for LEVO, there is no pharmacokinetic interaction with FF when delivered as FF/LEVO FDC. As the majority of data were below the assay sensitivity for FF, any potential differences in the bioavailability of FF when delivered alone or as FF/LEVO FDC could not be established. There was no clinically relevant impact on safety/tolerability when FF/LEVO was coadministered.
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Androstadienos/administração & dosagem , Glucocorticoides/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Piperidinas/administração & dosagem , Administração Intranasal , Adulto , Androstadienos/efeitos adversos , Androstadienos/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Combinação de Medicamentos , Feminino , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacocinética , Antagonistas não Sedativos dos Receptores H1 da Histamina/efeitos adversos , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Adulto JovemRESUMO
OBJECTIVES: To test the hypothesis that intranasal levocabastine (LEVO) may provide benefits as a oncedaily treatment in allergic rhinitis (AR), this non-inferiority study compared the effect at steady state of once- and twice-daily dosing with LEVO on allergen-induced nasal symptoms in AR patients. METHODS: This was a randomized, double-blind, three-way cross over study evaluating the effects of repeat doses of LEVO 200 µg once-daily, LEVO 200 µg twice-daily (total dose 400 µg) and placebo, all via intranasal spray, in 78 AR patients. The primary endpoint was weighted mean total nasal symptom score (TNSS) during a 4-hour allergen exposure in the Environmental Exposure Chamber measured at trough pharmacokinetic levels either 12 (LEVO twice-daily) or 24 (LEVO once-daily) hours post-dose. RESULTS: After 7 days dosing, the difference in weighted mean TNSS (0-4 hours) following LEVO once-daily versus twice-daily was 0.23 units (95% CI -0.36, 0.82), demonstrating noninferiority between the two LEVO dosing regimens by meeting the pre-specified criterion of an upper limit of 95% CI<1.0. Both dosing regimens of LEVO resulted in a statistically significant reduction in mean TNSS compared with placebo (adjusted mean difference from placebo: LEVO once-daily: -1.12 (95% CI -1.71, -0.53); LEVO twice-daily: -1.35 (-1.94, -0.76)), meeting the pre-specified criterion for superiority (upper limit of 95% CI<0). All treatments were well-tolerated. CONCLUSIONS: The results of this study support the hypothesis that at steady state LEVO 200 µg taken once-daily provides similar benefit to LEVO 200 µg dosed twice-daily.
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Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Piperidinas/administração & dosagem , Rinite Alérgica/tratamento farmacológico , Adulto , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Rinite Alérgica/fisiopatologia , Adulto JovemRESUMO
Topical corticosteroids remain the first-line therapy for atopic dermatitis (AD). Hence, we investigated the efficacy and safety profile of a novel selective corticosteroid, GW870086. We performed 2 randomised, double-blind, controlled studies with 25 AD patients and 20 healthy subjects. The changes in the Three-Item Severity (TIS) score and the skin thickness were the primary end points, respectively. The adjusted TIS score (day 22) shows that the novel corticosteroid resulted in a non-significant, but dose-dependent reduction compared to placebo (GW870086 0.2% vs. placebo = -0.38, GW870086 2% vs. placebo = -0.89). Significant skin thinning was observed in the second study on days 14 and 21 when patients were treated with the comparator but not with the novel corticosteroid compared to placebo. The clinical efficacy of the new selective corticosteroid was not superior to placebo, although a dose-dependent improvement upon treatment was noticed without the onset of skin thinning.
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Corticosteroides/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Esteroides/uso terapêutico , Adolescente , Corticosteroides/sangue , Corticosteroides/farmacocinética , Adulto , Idoso , Estudos Cross-Over , Dermatite Atópica/sangue , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Pele/diagnóstico por imagem , Pele/efeitos dos fármacos , Pele/patologia , Esteroides/sangue , Esteroides/farmacocinética , Resultado do Tratamento , Ultrassonografia , Adulto JovemRESUMO
PURPOSE: To investigate the potential for systemic pharmacokinetic (PK) and pharmacodynamic (PD) interactions between inhaled fluticasone furoate (FF) and vilanterol (VI) when delivered simultaneously via the ELLIPTA™ dry powder inhaler (DPI). METHODS: Randomized, double-blind, placebo-controlled, crossover study. Healthy subjects (n = 16) received single doses of FF (800 mcg), VI (100 mcg), FF/VI (800/100 mcg), and placebo. Endpoints measured were systemic PD (FF: serum cortisol; VI: heart rate), FF and VI plasma PK (0-48 hours), pharyngometry, inhalation and breath hold profiles and safety assessments. RESULTS: Treatment differences [90% confidence interval (CI)] in weighted mean serum cortisol (0-24 hours) were 12.3% [4.4, 20.9] (FF/VI vs. FF) and for maximum heart rate (0-4 hours) were -1.2 bpm [-4.6, 2.1] (FF/VI vs. VI). When delivered simultaneously, FF and VI systemic exposures were slightly lower (<20%) versus delivery of either agent alone (although this was not a formal bioequivalence study). In vitro simulation of selected inhalation profiles and modeling supported the PK and PD findings. FF/VI, FF and VI were well tolerated with an AE incidence comparable to placebo. CONCLUSIONS: These results suggest there was a slight PK interaction and no PD interactions of concern between inhaled FF and VI when delivered simultaneously via the ELLIPTA DPI in healthy subjects.
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Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Androstadienos/administração & dosagem , Androstadienos/farmacocinética , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/farmacocinética , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Clorobenzenos/administração & dosagem , Clorobenzenos/farmacocinética , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacocinética , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/sangue , Adulto , Androstadienos/efeitos adversos , Androstadienos/sangue , Álcoois Benzílicos/efeitos adversos , Álcoois Benzílicos/sangue , Biomarcadores/sangue , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Clorobenzenos/efeitos adversos , Clorobenzenos/sangue , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Inaladores de Pó Seco , Feminino , Glucocorticoides/efeitos adversos , Glucocorticoides/sangue , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , New South Wales , Adulto JovemRESUMO
BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1)-expressing sensory C-fibers may play a role in the development of nasal hyper-responsiveness and symptoms of non-allergic rhinitis (NAR). OBJECTIVE: To evaluate the effects of a TRPV1-antagonist, SB-705498, on cold dry air (CDA)-induced symptoms in patients with NAR. METHODS: This randomized, double-blind, placebo-controlled, crossover study evaluated 14 days of once daily, topical intranasal SB-705498 12 mg in 40 patients with NAR using a CDA challenge experimental model in an environmental exposure chamber (EEC, Cetero Research, Mississauga, Ontario). The primary endpoint was total symptom score (TSS), expressed as weighted mean over 60 minutes (WM0-60) or maximum TSS at 1 hour and 24 hours postdosing. RESULTS: Treatment with SB-705498, relative to placebo, did not improve WM0-60 or maximum TSS at 1 hour and 24 hours post-dosing on days 1 or 14. Mean (95% CI) treatment differences (SB-705498 - placebo) on day 14 were, for WM0-60 at 1 hour: -0.12 (-0.60, 0.36); for maximum TSS at 1 hour: -0.03 (-0.58, 0.51). SB-705498 had no impact on any other efficacy parameters. SB-705498 was well tolerated and pharmacokinetics analysis supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 14 days did not alleviate the CDA-induced symptoms of NAR. Despite engagement of the TRPV1 receptor, there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.
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Pirrolidinas/uso terapêutico , Rinite/prevenção & controle , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Adulto , Temperatura Baixa , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Ureia/efeitos adversos , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
OBJECTIVE: To assess the efficacy of inhaled, repeat doses (28 days) of the glucocorticoid agonist GW870086, which has been designed to inhibit gene transrepression of the glucocorticoid receptor while preserving its transactivation. METHODS: This was a randomised, placebo-controlled, two-way crossover study, approved by the independent ethics committees of the study centres. Subjects with FEV(1) 40-85% of the predicted normal value (n = 36) received GW870086 (1 mg, once-daily) and placebo. RESULTS: No significant change from baseline in forced expiratory volume in one second (FEV(1)) was seen following administration of GW8780086 1 mg relative to placebo; mean FEV(1) (day 28), relative to placebo, was (95% confidence intervals [CI]) -0.077 L (-0.192, 0.038). A moderate positive placebo response was observed on Days 14 and 28: Mean FEV(1) (95% CI) was 0.115 L (0.040, 0.189) and 0.115 L (0.019, 0.212), respectively. The placebo response was more notable in treatment period 1 and was larger than the response to GW870086 1 mg on day 28, irrespective of period. Peak expiratory flow rate results were consistent with FEV(1) and no difference was seen between the GW870086 and placebo for rescue medication usage. CONCLUSION: This total lack of effect suggests that repeat-dose GW8700861 mg has suboptimal efficacy in mild to moderate asthma.
Assuntos
Asma/tratamento farmacológico , Esteroides/administração & dosagem , Adulto , Idoso , Asma/fisiopatologia , Estudos Cross-Over , Esquema de Medicação , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Esteroides/efeitos adversos , Falha de Tratamento , Adulto JovemRESUMO
BACKGROUND: Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS: This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 µg (FP), FP 200 µg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS: At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.
Assuntos
Antialérgicos/uso terapêutico , Pirrolidinas/uso terapêutico , Rinite Alérgica Sazonal/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/análogos & derivados , Administração Intranasal , Adulto , Androstadienos/uso terapêutico , Antialérgicos/administração & dosagem , Antialérgicos/efeitos adversos , Antialérgicos/sangue , Antialérgicos/farmacocinética , Áustria , Estudos Cross-Over , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fluticasona , Humanos , Masculino , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/sangue , Pirrolidinas/farmacocinética , Rinite Alérgica Sazonal/diagnóstico , Rinite Alérgica Sazonal/metabolismo , Canais de Cátion TRPV/metabolismo , Resultado do Tratamento , Ureia/administração & dosagem , Ureia/efeitos adversos , Ureia/sangue , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
BACKGROUND: Fluticasone furoate (FF; GW685698) is a novel inhaled corticosteroid that is active at 24 h and under development for once-daily administration in combination with the long-acting ß(2)-adrenoceptor agonist vilanterol (GW642444) for chronic obstructive pulmonary disease and asthma. In vitro studies examining the respiratory tissue-binding properties of corticosteroids showed FF to have the largest cellular accumulation and slowest rate of efflux compared with other clinically used inhaled corticosteroids, consistent with greater tissue retention. The enhanced affinity of the glucocorticoid receptor binding of FF, coupled with its extended tissue association, may be expected to lead to greater and more prolonged anti-inflammatory effects and should provide relevant once-daily efficacy. OBJECTIVE: The aim of this study was to assess the rate and extent of systemic absorption of FF from the lung following inhaled administration of FF from three exploratory dry powder formulations (via DISKHALER(®)) compared with inhaled fluticasone propionate (FP) [via DISKHALER(®)] using deconvolution analysis. METHODS: This open-label, part-randomized, six-way crossover study evaluated three early development dry powder inhaled formulations of FF administered as single doses via DISKHALER(®). Healthy male subjects (n = 24) each received FF (2,000 µg; three formulations), inhaled FP (1,000 µg; via DISKHALER(®)) and 250 µg of each molecule by intravenous infusion. The bioavailability of both inhaled FF and FP represents absorption from the lung as the oral bioavailability from the swallowed portion of the inhaled dose is negligible (<1.5 %). To investigate the absorption kinetics from the lung, the inhaled concentration-time data were subjected to deconvolution analysis using derived pharmacokinetic parameters from fitting of the intravenous concentration-time data. RESULTS: The terminal elimination half-life (t(½ß)) for inhaled FF was considerably longer (range 17-24 h) than the t(½ß) estimated for intravenous FF (14 h), whereas t(½ß) for FP was similar whether inhaled or given intravenously (11 and 14 h, respectively). This would suggest that FF is exhibiting absorption rate-limited pharmacokinetics following inhaled FF dosing and that the apparent t(½ß) is an estimate of absorption rate. The lung mean absorption time for FF was approximately 7 h irrespective of formulation, which was considerably longer than FP (2.1 h). The time for 90 % absorption from the lung was significantly longer for FF (20-30 h) than for FP (8 h), indicating a significantly longer lung retention time for FF. CONCLUSION: In comparison with inhaled FP, inhaled FF (independent of formulation) demonstrated prolonged absorption from the lung into the systemic circulation, indicating a longer lung retention time and suggesting the potential for maintained efficacy with once-daily administration.
Assuntos
Androstadienos/farmacocinética , Broncodilatadores/farmacocinética , Absorção , Administração por Inalação , Adulto , Androstadienos/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Broncodilatadores/administração & dosagem , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada , Fluticasona , Meia-Vida , Humanos , Pulmão/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nebulizadores e VaporizadoresRESUMO
Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) and liquid extraction surface analysis (LESA) with nanoelectrospray ionization mass spectrometry (nESI-MS) have both been successfully employed to determine the degree of percutaneous absorption of three novel nonsteroid glucocorticoid receptor (GR) agonists in porcine ear sections. Historically, the ability of a glucocorticoid to elicit a skin blanching response when applied at low dose in ethanol solution to the forearms of healthy human volunteers has been a reliable predictor of their topical anti-inflammatory activity. While all three nonsteroidal GR agonists under investigation caused a skin blanching effect, the responses did not correlate with in vitro GR agonist potencies and different time courses were also observed for the skin blanching responses. MALDI MSI and LESA with nESI-MS were used to investigate and understand these different responses. The findings of the investigation was that the depth of porcine skin penetration correlates to the degree of skin blanching obtained for the same three compounds in human volunteers.
Assuntos
Fracionamento Químico , Nanotecnologia , Receptores de Glucocorticoides/agonistas , Absorção Cutânea , Pele/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adolescente , Adulto , Animais , Pressão Atmosférica , Orelha , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Propriedades de Superfície , Adulto JovemRESUMO
PURPOSE: A considerable body of non clinical evidence has accumulated to support peroxisomal proliferator-activated receptor gamma agonists as candidate anti-inflammatory drugs in asthma. We utilized rosiglitazone as a tool compound in the inhaled allergen challenge model of asthma. METHODS: A single centre, double-blind, randomised, placebo controlled, two period cross-over study. Subjects received rosiglitazone 4mg and placebo twice daily for 28 days in random order. On day 28, inhaled allergen challenge was performed 1 hour post-dose. A methacholine challenge was performed on day 29 and an adenosine monophosphate challenge on day 14. Exhaled nitric oxide was measured on days 1, 14, 28, 29. Blood was collected pre dose on days 1, 14 and 28 and analysed for markers associated with PPAR activity and systemic markers of inflammation. RESULTS: The late asthmatic reaction (LAR) change from post saline FEV(1) from 4-10 hrs post allergen on day 28 was statistically significant for the weighted mean LAR. The difference in weighted mean was 0.06 L (95% CI 0.01 to 0.11) which equates to a 15% attenuation of the response during placebo treatment. This was accompanied by trends in other markers of efficacy and anti-inflammatory activity but none were considered major effects. DISCUSSION: Treatment with a PPARgamma agonist (rosiglitazone) was associated with a modest (15%) reduction in the late asthmatic reaction in the allergen challenge model of asthma. Based on the results of this study, PPARgamma agonist monotherapy is unlikely to represent a clinically useful intervention in human asthma. Registered with www.clinicaltrials.gov (NCT00318630).
Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , PPAR gama/agonistas , Tiazolidinedionas/uso terapêutico , Adiponectina/sangue , Adolescente , Adulto , Alérgenos , Anti-Inflamatórios/efeitos adversos , Asma/imunologia , Asma/fisiopatologia , Biomarcadores/sangue , Testes Respiratórios , Testes de Provocação Brônquica , Broncoconstritores , Estudos Cross-Over , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Cloreto de Metacolina , Pessoa de Meia-Idade , Óxido Nítrico/análise , Rosiglitazona , Tiazolidinedionas/efeitos adversos , Adulto JovemRESUMO
OBJECTIVE: The Vienna Challenge Chamber (VCC) offers a controlled and controllable paradigm in which to reproducibly evaluate the efficacy of anti-allergic treatment. The aim of this study was to assess the efficacy of the novel intranasal corticosteroid fluticasone furoate (FF) in the VCC. METHODS: The single-centre, randomised, double-blind, placebo-controlled, two-period crossover study was conducted in 59 adult males with grass pollen allergic rhinitis (AR). Patients received either Fluticasone furoate 200 mcg once-daily, or placebo intranasally for 8 days. AR symptoms were induced during 4-hour allergen challenges with grass pollen in the VCC at the end of each 8-day treatment period. A first challenge was conducted at 1-5 hours post-dose, followed by a second challenge at 22-26 hours post-dose. The primary endpoint was total nasal symptom score (TNSS; sum of itch, sneeze, rhinorrhoea, obstruction symptoms assessed on a categorical scale of 0-3) weighted mean over 2-5 hours post-dose. Secondary endpoints included: TNSS weighted mean over 23-26 hours post-dose and global symptom score, eye symptom score, nasal secretions and nasal airflow weighted means over 2-5 and 23-26 hours post-dose. RESULTS: Fluticasone furoate showed consistent attenuation of AR symptoms in both the early and late challenges. Compared with placebo, weighted mean of TNSS was reduced on average by 4.14 point-scores at 2-5 hours post-dose and 3.63 point scores at 23-26 hours post-dose. These positive effects were also seen across all secondary endpoints. CONCLUSION: An 8-day treatment course of intranasal FF 200 mcg given once-daily statistically significantly reduced symptoms of AR including associated eye symptoms. Statistical significance was declared where the relevant two-sided 95% confidence interval did not contain zero. This positive effect was sustained over 24 hours suggesting that fluticasone furoate could be efficacious as a once daily steroid.