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1.
Artigo em Inglês | MEDLINE | ID: mdl-33822898

RESUMO

OBJECTIVE: To further characterize the effect of guselkumab, a selective interleukin-23p19-subunit inhibitor approved for psoriatic arthritis (PsA), on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. METHODS: Adults with active PsA despite standard therapies in the Phase-3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every-4-weeks (Q4W); guselkumab 100 mg at Week0, Week4, Q8W; or placebo through Week20 followed by guselkumab 100 mg Q4W (Placebo→Q4W). Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0-6). Enthesitis findings through Week24 were prespecified to be pooled across studies; post hoc and Week52 analyses also employed pooled data. RESULTS: Among 1,118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation, and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at Week24 (45% and 50% vs 29%; both adjusted p= 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at Week52, including patients with mild (LEI = 1; 70-75%), moderate (LEI = 2; 69-73%), or severe (LEI = 3-6; 42-44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at Week24, 42% achieved minimal disease activity at Week52, vs 17% of patients with unresolved enthesitis. CONCLUSION: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by Week24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. CLINICAL TRIAL REGISTRATION: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285).

2.
Artigo em Inglês | MEDLINE | ID: mdl-33844022

RESUMO

OBJECTIVE: The efficacy of the novel interleukin (IL)-23p19 inhibitor guselkumab for psoriatic arthritis (PsA) has recently been demonstrated in two phase 3 trials (DISCOVER-1 & -2) but has not been evaluated vs other targeted therapies for PsA. The objective was to compare guselkumab to targeted therapies for PsA for safety and joint and skin efficacy through network meta-analysis (NMA). METHODS: A systematic literature review was conducted in January 2020 to identify randomized controlled trials. Bayesian NMAs were performed to compare treatments on American College of Rheumatology (ACR) 20/50/70 response, mean change from baseline in van der Heijde-Sharp (vdH-S) score, Psoriasis Area Severity Index (PASI) 75/90/100 response, adverse events (AEs) and serious adverse events (SAEs). RESULTS: Twenty-six phase 3 studies evaluating 13 targeted therapies for PsA were included. For ACR 20 response, guselkumab 100 mg every 8 weeks (Q8W) was comparable to IL-17A inhibitors and subcutaneous tumor necrosis factor (TNF) inhibitors. Similar findings were observed for ACR 50 and 70. For vdH-S score, guselkumab Q8W was comparable to other agents except intravenous TNF therapies. Results for PASI 75 and PASI 90 response suggested guselkumab Q8W was better than most other agents. For PASI 100, guselkumab Q8W was comparable to other active agents. For AEs and SAEs, guselkumab Q8W ranked highly but comparative conclusions were uncertain. Similar results were observed for all outcomes for guselkumab 100 mg every four weeks. CONCLUSIONS: In this NMA, guselkumab demonstrated favorable arthritis efficacy comparable to IL-17A and subcutaneous TNF inhibitors while offering better PASI response relative to many other treatments.

3.
RMD Open ; 7(1)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568556

RESUMO

OBJECTIVE: Evaluation of the efficacy and safety of guselkumab, a human monoclonal antibody targeting the interleukin-23p19 subunit, in patients with psoriatic arthritis (PsA) through 1 year. METHODS: Adults who met ClASsification criteria for Psoriatic ARthritis, with active disease (≥3 swollen and ≥3 tender joints; C reactive protein ≥0.3 mg/dL) despite standard treatment (31% previously received ≤2 tumour necrosis factor inhibitors (TNFi)), were randomised (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week0, Week4, then Q8W; or placebo with cross-over to guselkumab 100 mg Q4W at Week24 (PBO→Q4W) through Week48. Clinical efficacy through Week52 (employing non-responder imputation) and adverse events (AEs) through Week60 were evaluated. RESULTS: Of 381 treated patients, 90% completed the study. Numerical increases in the proportions of patients achieving ≥20% improvement in ACR criteria (ACR20) were observed post-Week24, reaching 73% (94/128) and 60% (76/127) for Q4W-randomised and Q8W-randomised patients, respectively, by Week52. Proportions of patients achieving ACR50/ACR70/skin responses and minimal/very low disease activity were maintained, as were improvements in physical function and health-related quality of life, through Week52 in guselkumab-randomised patients. Response to guselkumab was maintained in both TNFi-naïve and TNFi-experienced patients. Serious AEs and serious infections occurred in similar proportions of guselkumab Q4W-randomised (3% and 0%) and Q8W-randomised (6% and 2%) patients through Week60, with no new safety concerns versus observations through Week24. No guselkumab-treated patient and two patients receiving placebo died; no study participant developed opportunistic infection or inflammatory bowel disease. CONCLUSION: Guselkumab provided sustained improvement across multiple clinical manifestations of PsA, maintaining a favourable benefit-risk profile, through 1 year regardless of prior TNFi exposure.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33345456

RESUMO

OBJECTIVE: To identify discrete clusters of systemic lupus erythematosus (SLE) patients based on symptoms and investigate differences across clusters. METHODS: Data were collected in the United States of America and five European countries via the Adelphi Real World Lupus Disease Specific Programme™, a cross-sectional survey. Rheumatologists provided data for five consecutively consulting adult patients with SLE, who were invited to participate. Identified SLE symptoms were reduced to factors based on commonly concurrent symptoms, using principal-component factor analysis. Factors were used as covariates in a latent class cluster analysis to identify discrete patient clusters. Patient-reported outcomes and physician-reported data were compared across clusters. RESULTS: Among 1,376 patients, 87% of patients were female and 74% of patients were white. We identified four patient clusters ("very mild", "mild", "moderate", "severe") based on 39 signs/symptoms. Physician-reported symptom burden, organ involvement, disease activity and number of flares increased with increasing cluster severity (p<0.0001). Patient-reported impact (health status, fatigue, work productivity impairment, anxiety/depression, emotional impact) increased with increasing cluster severity (p<0.0001). Glucocorticoid and immunosuppressant use increased, and anti-malarial use decreased, with increasing cluster severity. In all clusters, <20% of patients received biologics; >15% of patients not receiving biologics were considered eligible for treatment by their physician. The proportion of physicians and patients satisfied with treatment decreased with increasing cluster severity (p<0.0001). CONCLUSION: Our large, international real-world survey of SLE patients and physicians demonstrated strong associations between increased impairment, organ involvement and humanistic burden in SLE, highlighting unmet need for effective treatment options in high disease activity patients.

5.
RMD Open ; 6(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32665433

RESUMO

OBJECTIVE: To evaluate the effect of guselkumab on enthesitis and dactylitis in a phase II trial of patients with active psoriatic arthritis (PsA). METHODS: This was a phase II, randomised, placebo-controlled, double-blind trial of adults with active PsA (≥3 swollen and ≥3 tender joints and C reactive protein ≥0.3 mg/dL) despite conventional synthetic disease-modifying anti-rheumatic drug, non-steroidal anti-inflammatory drug, and/or oral corticosteroid therapy. Patients were randomised to subcutaneous injections of guselkumab 100 mg or placebo at weeks 0, 4 and every 8 weeks, with placebo crossover to guselkumab at week 24. Dactylitis was scored on a scale of 0-3 on each digit; enthesitis was assessed using the Leeds Enthesitis Index (0-6). Other assessments included American College of Rheumatology (ACR) and Psoriasis Area and Severity Index responses. RESULTS: Of 149 randomised patients, 107 patients had enthesitis (mean score=2.7) and 81 patients had dactylitis (mean dactylitis score=5.7) at baseline. Mean improvements in enthesitis and dactylitis at week 24 were greater in the guselkumab group versus placebo and sustained through week 56. Similar results were observed for the proportions of patients with resolution of enthesitis and dactylitis. At week 56, mean improvements in enthesitis and dactylitis among patients who switched from placebo to guselkumab treatment were similar to those in the guselkumab group. In the guselkumab group, ACR20 responders had greater improvements in enthesitis and dactylitis versus non-responders (week 24). CONCLUSIONS: At week 24, the guselkumab group had greater mean improvements in enthesitis and dactylitis and greater proportions of patients with resolution of enthesitis and dactylitis versus placebo. ACR20 response was associated with improvements in enthesitis and dactylitis. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02319759.URL: https://clinicaltrials.gov/ct2/show/NCT02319759; Registered 18 December 2014.

6.
RMD Open ; 6(1)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32209721

RESUMO

BACKGROUND: The interleukin-12/23p40-subunit-inhibitor ustekinumab significantly improved spondylitis-related symptoms through Week 24 in psoriatic arthritis (PsA) patients with peripheral arthritis and physician-reported spondylitis (PA-PRS) in PSUMMIT-1&2. We further evaluated ustekinumab's effect on spondylitis-related endpoints in PSUMMIT-1&2 tumour necrosis factor-inhibitor (TNFi)-naïve patients with PA-PRS. METHODS: Patients with active PsA (≥5 swollen and ≥5 tender joints, C-reactive-protein ≥ 3.0 mg/L) despite conventional (PSUMMIT-1&2) and/or prior TNFi (PSUMMIT-2) therapy received subcutaneous ustekinumab 45 mg, 90 mg or placebo (Week 0, Week 4, Week 16). Changes in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) neck/back/hip pain question (#2) and modified BASDAI (mBASDAI, excluding PA) scores and Ankylosing Spondylitis Disease Activity Score (ASDAS) responses were assessed at Weeks 12 and 24. RESULTS: The pooled PSUMMIT-1&2, TNFi-naïve (n=747), PA-PRS (n=223) subset (158 with human-leucocyte-antigen (HLA)-B27 results) presented with moderate-to-severe spondylitis-related symptoms (mean BASDAI-neck/back/hip pain-6.51, mBASDAI-6.54, BASDAI-6.51, ASDAS-3.81). Mean Week 24 changes were larger among ustekinumab than placebo-treated patients for both neck/back/hip pain (-1.99 vs -0.18) and mBASDAI (-2.09 vs -0.59). Improvements in neck/back/hip pain and fatigue appeared numerically greater in HLA-B27+ than HLA-B27 - patients; those for other domains were generally consistent. Greater proportions of ustekinumab versus placebo-treated patients achieved ASDAS clinically important improvement at Week 24 (decrease ≥ 1.1; 49.6% vs 12.7%; nominal p<0.05). CONCLUSIONS: Improvements in BASDAI neck/back/hip pain and mBASDAI among ustekinumab-treated, TNFi-naïve, PsA patients with PA-PRS were clinically meaningful and consistent across assessment tools. Numerically greater improvements in neck/back/hip pain in HLA-B27+ than HLA-B27 - patients, noted in the context of similar overall mBASDAI improvements between the subgroups, suggest ustekinumab may improve disease activity in TNFi-naïve PsA patients likely to exhibit axial disease. CLINICAL TRIAL REGISTRATION NUMBERS: PSUMMIT 1, NCT01009086; PSUMMIT 2, NCT01077362.

7.
BMC Rheumatol ; 3: 43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673680

RESUMO

Background: The prevalence of mood disturbances such as anxiety and depression is greater in rheumatoid arthritis (RA) patients than in the general population. Given this association, the primary aim of this study was to assess the incremental impact of anxiety or depression on patients with RA from the United States of America (USA) and Europe, independent of the impact of the underlying RA disease. Methods: Rheumatologists (n = 408) from the USA and 5 European countries completed patient record forms for a predetermined number of RA patients who consulted consecutively during the study period; these patients completed patient-reported questionnaires. Descriptive statistics and multivariate regression were used to investigate the relationship between anxiety and depression with treatment and economic outcomes in RA patients. Results: Of 1015 physician and patient pairs who completed all relevant questionnaire sections, 390 (38.4%) patients self-reported anxiety or depression, while 180 (17.7%) patients were reported to have anxiety or depression by their physicians. Controlling for age, gender, body mass index and clinical factors (flaring and severity), multiple regression analyses suggested that patients with anxiety or depression more often experienced treatment dissatisfaction (odds ratio [OR] 2.28; P < .001), had greater impairment in work (coefficient [ß] = 11.82; P = .001) and usual activity (ß = 14.73; P < .001), greater disability (ß = .35; P < .001), and more often reported unemployment (OR 1.74; P = .001). Multinomial logistic regression revealed discordance between physician and patient satisfaction with treatment. For patients reporting anxiety or depression, physicians were more often satisfied with achievement of current disease control than patients (relative risk ratio 2.19; P = .002). Conclusion: Concomitant anxiety or depression was associated with a significant incremental impact on the health-related quality of life and economic aspects of life of patients with RA. In light of observed differences between physician recognition of patient anxiety and/or depression versus patient reporting of anxiety and/or depression symptoms, further research is warranted to develop optimal screening and management of depression and anxiety in patients with RA.

8.
Clin Exp Rheumatol ; 36(4): 668-675, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29533755

RESUMO

OBJECTIVES: To describe the efficacy, safety, and exposure-response relationship of canakinumab in a subgroup of patients with systemic juvenile idiopathic arthritis (SJIA) aged ≥16 years, representative of adult-onset Still's disease (AOSD) patients, and to compare this subgroup with those of children and young adolescents with SJIA by pooling clinical data collected during the development programme of canakinumab. METHODS: Safety and efficacy data on canakinumab-treated patients were pooled from 4 SJIA studies (NCT00426218, NCT00886769, NCT00889863, and NCT00891046). In the majority of patients, canakinumab was administered at 4 mg/kg every 4 weeks. Efficacy parameters (adapted American College of Rheumatology [aACR] paediatric and juvenile idiopathic arthritis [JIA] ACR responses), quality of life, C-reactive protein levels, safety, and exposure-response relationship were assessed over 12 weeks in 3 age groups (children 2-<12, young adolescents 12-<16 and older adolescents and young adults ≥16 years). RESULTS: Efficacy outcomes were analysed in 216 children, 56 young adolescents and 29 older adolescents and young adults. Efficacy parameters across 3 age groups were largely comparable. At Day 15, at least 50% of patients from each age group exhibited aACR ≥70 and ACR responses. The safety profile of canakinumab was similar across age groups. One death was reported. CONCLUSIONS: Pooled analyses from SJIA studies indicate that older adolescents and young adults SJIA patients show similar efficacy, safety, and exposure-response relationship on a weight-based dosing regimen as observed in children and adolescent SJIA patients. These analyses suggest that canakinumab may be an effective therapy in young adults with Still's disease.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Doença de Still de Início Tardio/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Feminino , Humanos , Masculino
9.
Mod Rheumatol ; 25(5): 665-71, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25698370

RESUMO

OBJECTIVE: To assess the long-term safety, immunogenicity, and efficacy of subcutaneous (SC) abatacept in combination with methotrexate (MTX) in Japanese patients with rheumatoid arthritis who were MTX inadequate responders, in a long-term extension (LTE) to a double-dummy, double-blind study (NCT01001832). METHODS: Patients, who had previously received SC or intravenous (IV) abatacept with MTX (6-8 mg/week) for 24 weeks, received SC abatacept (125 mg/week) with MTX for an additional 52 weeks. Safety, immunogenicity, and efficacy were assessed. RESULTS: The LTE included 112 patients. SC abatacept was generally well tolerated in the LTE, with no new safety signals. American College of Rheumatology 20, 50, and 70 response rates, disease activity score 28 (C-reactive protein) remission rates (< 2.6), and Health Assessment Questionnaire-Disability Index response rates (≥ 0.3 improvement from baseline) achieved at the end of the double-blind period were maintained over the LTE and were comparable in patients who received SC or IV abatacept in the double-blind period. Seropositivity for immunogenicity occurred in 4 (3.6%) patients. Self-injection of SC abatacept was well controlled and not associated with additional safety events. CONCLUSIONS: SC abatacept had acceptable safety and was well tolerated and effective over the LTE (76 weeks in total), with low rates of immunogenicity in Japanese patients.


Assuntos
Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Abatacepte/administração & dosagem , Abatacepte/efeitos adversos , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Imunoconjugados/uso terapêutico , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Retratamento , Resultado do Tratamento
10.
Ann Rheum Dis ; 74(1): 19-26, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25367713

RESUMO

OBJECTIVES: To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12 months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment. METHODS: In the Assessing Very Early Rheumatoid arthritis Treatment phase 3b trial, patients with early active RA were randomised to double-blind, weekly, subcutaneous abatacept 125 mg plus MTX, abatacept 125 mg monotherapy, or MTX for 12 months. Patients with low disease activity (Disease Activity Score (DAS)28 (C reactive protein (CRP)) <3.2) at month 12 entered a 12-month period of withdrawal of all RA therapy. The coprimary endpoints were the proportion of patients with DAS28 (CRP) <2.6 at month 12 and both months 12 and 18, for abatacept plus MTX versus MTX. RESULTS: Patients had <2 years of RA symptoms, DAS28 (CRP) ≥3.2, anticitrullinated peptide-2 antibody positivity and 95.2% were rheumatoid factor positive. For abatacept plus MTX versus MTX, DAS28 (CRP) <2.6 was achieved in 60.9% versus 45.2% (p=0.010) at 12 months, and following treatment withdrawal, in 14.8% versus 7.8% (p=0.045) at both 12 and 18 months. DAS28 (CRP) <2.6 was achieved for abatacept monotherapy in 42.5% (month 12) and 12.4% (both months 12 and 18). Both abatacept arms had a safety profile comparable with MTX alone. CONCLUSIONS: Abatacept plus MTX demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile. The achievement of sustained remission following withdrawal of all RA therapy suggests an effect of abatacept's mechanism on autoimmune processes. TRIAL REGISTRATION NUMBER: NCT01142726.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/uso terapêutico , Metotrexato/uso terapêutico , Abatacepte , Adulto , Artrite Reumatoide/imunologia , Proteína C-Reativa/imunologia , Método Duplo-Cego , Quimioterapia Combinada , Intervenção Médica Precoce/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Resultado do Tratamento
11.
Mod Rheumatol ; 24(6): 885-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24708204

RESUMO

OBJECTIVE: To evaluate efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept and background methotrexate (MTX) in Japanese patients with rheumatoid arthritis (RA) and inadequate response to MTX (MTX-IR). METHODS: Double-dummy, double-blind study (NCT01001832); 118 adults with ≥ 10 swollen joints, ≥ 12 tender joints and C-reactive protein (CRP) ≥ 0.8 mg/dL randomized 1:1 to SC abatacept (125 mg weekly) with IV loading (∼10 mg/kg on Day 1), or IV abatacept (∼10 mg/kg monthly) for 169 days, both also receiving MTX (6-8 mg/week). Primary endpoint was Day 169 American College of Rheumatology (ACR)20 response; other efficacy endpoints, safety and immunogenicity were assessed. RESULTS: Similar proportions of patients achieved ACR20 responses at Day 169 with SC (91.5% [95% CI 81.3, 97.2]) and IV abatacept (83.1% [71.0, 91.6]). ACR50/70 responses, adjusted mean changes from baseline in Health Assessment Questionnaire-Disability Index scores and remission rates (28-joint Disease Activity Score [CRP] < 2.6) were also comparable between groups. Serious adverse event frequencies (5.1% vs. 3.4%) were similar with both formulations. One patient per group tested seropositive for immunogenicity. Weekly SC abatacept dosing achieved mean serum concentrations > 10 µg/mL (minimum therapeutic target). CONCLUSIONS: SC abatacept demonstrated comparable efficacy and safety to IV abatacept, with low immunogenicity rates, in MTX-IR Japanese patients with RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/uso terapêutico , Metotrexato/uso terapêutico , Abatacepte , Adulto , Idoso , Anticorpos/sangue , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Artrite Reumatoide/imunologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/imunologia , Imunoconjugados/farmacocinética , Injeções Intravenosas , Injeções Subcutâneas , Japão , Masculino , Pessoa de Meia-Idade , Retratamento , Resultado do Tratamento
12.
Diabetes Ther ; 4(2): 269-83, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23881432

RESUMO

INTRODUCTION: Saxagliptin added to metformin extended release (XR) and uptitrated metformin XR were evaluated for their impact on daily glucose measurements and their tolerability in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy. METHODS: Patients aged 18-78 years on metformin 850-1,500 mg with glycated hemoglobin (HbA1c) 7.5-11.5% at screening were eligible for this double-blind, active-controlled study. Patients were stabilized on metformin XR 1,500 mg before randomization. Patients with HbA1c 7-11% and fasting plasma glucose (FPG) ≥126 mg/dL after a 4- 8-week lead-in period were randomly assigned to saxagliptin 5 mg + metformin XR 1,500 mg or metformin XR 500 mg + metformin XR 1,500 mg (uptitrated metformin XR). The primary end point was change from baseline to week 4 in 24-h mean weighted glucose (MWG). Secondary end points were changes from baseline to week 4 in 2-h postprandial glucose (PPG) and FPG. RESULTS: At week 4, the adjusted mean ± SE change from baseline in 24-h MWG was -19.0 ± 5.7 mg/dL (95% CI -30.3 to -7.6) for saxagliptin + metformin XR and -8.2 ± 6.0 mg/dL (95% CI -20.0 to 3.7) for uptitrated metformin XR. Mean changes from baseline in 2-h PPG and FPG were numerically greater with saxagliptin + metformin XR versus uptitrated metformin XR. The incidence of adverse events was lower with saxagliptin + metformin XR (17.4%) versus uptitrated metformin XR (31.9%) mainly due to differences in gastrointestinal adverse event incidence (2.2% vs 10.6%, respectively). There were no reports of confirmed hypoglycemia in either group. CONCLUSION: In this 4-week study in patients with T2DM inadequately controlled with metformin monotherapy, saxagliptin added to metformin XR demonstrated a trend for improvement in measures of daily glycemic control, with fewer gastrointestinal adverse events, compared with uptitrated metformin.

13.
Clin Interv Aging ; 8: 419-30, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23626461

RESUMO

PURPOSE: To assess safety and efficacy of saxagliptin in older patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: This was a post hoc analysis of pooled data from older patients (≥65 years of age) from five 24-week phase III trials: three studies of saxagliptin versus placebo as an add-on therapy to metformin, glyburide, or a thiazolidinedione; and two studies of saxagliptin versus placebo as monotherapy in drug-naïve patients. Separate analyses were conducted on one study of initial combination therapy with saxagliptin plus metformin versus metformin monotherapy in drug-naïve patients. The safety analysis population for the five-study pool included 428 patients ≥ 65 years of age with baseline glycated hemoglobin (HbA(1c)) 7.0% to 10.5% who received saxagliptin 2.5 or 5 mg or placebo, and for the study of initial combination therapy included 69 patients ≥ 65 years of age with baseline HbA(1c) 8.0% to 12.0% who received saxagliptin 5 mg in combination with metformin or metformin monotherapy. The primary efficacy endpoint was change from baseline HbA(1c). RESULTS: In the five-study pool, the differences in the adjusted mean change from baseline HbA(1c) among older patients receiving saxagliptin versus placebo were -0.60% (95% confidence interval [CI], -0.99% to -0.21%) for saxagliptin 2.5 mg and -0.55% (-0.97% to -0.14%) for saxagliptin 5 mg; in the initial combination study, the difference was -1.22% (-2.27% to -0.17%) among older patients receiving saxagliptin 5 mg plus metformin versus metformin monotherapy. The results were generally similar in older and younger patients. Saxagliptin was well tolerated; the incidence and types of adverse events were similar for saxagliptin and comparators. Hypoglycemia was reported in 3.0% to 9.4% of patients receiving saxagliptin (0%-8.0% for comparators) and was confirmed (finger stick glucose ≤ 50 mg/dL, with associated symptoms) in 0% to 0.7% (0%-0.7% for comparators); hypoglycemic episodes did not vary by age category and did not require medical intervention. CONCLUSION: Saxagliptin was effective and well tolerated, with a low risk of hypoglycemia, when used as monotherapy, add-on therapy, or initial combination therapy with metformin in older patients with T2DM.


Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/uso terapêutico , Incretinas/uso terapêutico , Adamantano/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Área Sob a Curva , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glibureto/uso terapêutico , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Tiazolidinedionas/uso terapêutico , Resultado do Tratamento
14.
Int J Pharm ; 306(1-2): 122-31, 2005 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-16274945

RESUMO

OBJECTIVE: The objective of this study was to evaluate the ability of DeltaG, the 12 kDa active fragment of ZOT, to increase the brain distribution of MTX and paclitaxel, two commonly used anticancer agents with poor distribution into the brain. METHODS: As part of dose estimation of DeltaG, [14C]-sucrose (40 microCi/kg), a hydrophilic paracellular marker, was co-administered with DeltaG (0, 400 and 800 microg/kg) with and without protease inhibitors to male Sprague-Dawley rats (n=3 per group) via an intracarotid cannula. MTX (50 mg/kg) and [3H]-paclitaxel (120 microCi/kg) were co-administered with the effective doses of DeltaG determined from the above study via the intracarotid cannula. Animals were euthanized by carbon dioxide asphyxiation at the specified time periods and brain and plasma samples were analyzed for the respective drug. RESULTS: The brain distribution of [14C]-sucrose was significantly enhanced at both doses of DeltaG. A fold enhancement in the B/P ratios of 1.88 and 2.68 was observed at the 400 and 800 microg/kg doses respectively, when the protein was protected from metabolic degradation with PIs. DeltaG significantly increased the brain distribution of MTX at each of the doses administered, with over a seven-fold increase at the 600 microg/kg dose. [3H]-paclitaxel brain AUC(0-60 min) was significantly higher in the presence of DeltaG (800 microg/kg with PIs) with a 2.5-fold enhancement in brain exposure. CONCLUSIONS: DeltaG significantly enhances the brain distribution of MTX (hydrophilic) and paclitaxel (lipophilic) and has the potential to be further developed as adjunct therapy to increase delivery of poorly permeable chemotherapeutic and other CNS targeted compounds.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Encéfalo/metabolismo , Toxina da Cólera/química , Portadores de Fármacos/química , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Área Sob a Curva , Composição de Medicamentos , Endotoxinas , Masculino , Metotrexato/administração & dosagem , Metotrexato/química , Metotrexato/farmacocinética , Paclitaxel/administração & dosagem , Paclitaxel/química , Paclitaxel/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
15.
J Clin Pharmacol ; 45(8): 910-8, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16027401

RESUMO

ABT-578, a sirolimus analog, is being developed for administration from drug-eluting stents to prevent postimplantation neointimal hyperplasia. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of multiple doses of ABT-578. Healthy subjects randomly received placebo or ABT-578 (200, 400, or 800 microg) as daily intravenous infusions for 14 days. ABT-578 blood pharmacokinetics and urine excretion on days 1 and 14 were determined. The effect of ABT-578 on mitogen-stimulated lymphocyte proliferation was assessed. ABT-578 pharmacokinetics was described by a 3-compartment open model. The mean CL, V(ss), and t(1/2) ranges were 4.0 to 4.6 L/h, 92.5 to 118.0 L, and 24.7 to 31.0 hours, respectively. ABT-578 pharmacokinetics was dose and time invariant. Approximately 0.1% of ABT-578 was excreted in the urine. ABT-578 was well tolerated, and no systemic changes were observed in the mitogen-stimulated lymphocyte proliferation. ABT-578 was shown to be safe over a wide range of systemic exposures.


Assuntos
Imunossupressores/farmacocinética , Sirolimo/análogos & derivados , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Sirolimo/administração & dosagem , Sirolimo/sangue , Sirolimo/farmacocinética
16.
J Clin Pharmacol ; 44(8): 919-27, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15286096

RESUMO

Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antiulcerosos/farmacocinética , Antifúngicos/farmacologia , Cimetidina/farmacocinética , Antagonistas dos Receptores Histamínicos H2/farmacocinética , Itraconazol/farmacologia , Túbulos Renais/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Adulto , Área Sob a Curva , Cimetidina/sangue , Cimetidina/urina , Interações Medicamentosas , Feminino , Taxa de Filtração Glomerular , Meia-Vida , Humanos , Ácido Iotalâmico , Túbulos Renais/metabolismo , Masculino
17.
Artigo em Inglês | MEDLINE | ID: mdl-14670753

RESUMO

A HPLC method was developed for determination of cimetidine in human plasma and urine. Plasma samples were alkalinized followed by liquid extraction with water-saturated ethyl acetate then evaporated under nitrogen. The extracts were reconstituted in mobile phase and injected onto a C(18) reversed-phase column; UV detection was set at 228 nm. Urine samples were diluted with an internal standard/mobile phase mixture (1:9) prior to injection. The lower limit of quantification in plasma and urine were 100 ng/ml and 10 microg/ml, respectively; intra- and inter-day coefficients of variation were

Assuntos
Antiulcerosos/sangue , Antiulcerosos/urina , Cromatografia Líquida/métodos , Cimetidina/sangue , Cimetidina/urina , Espectrofotometria Ultravioleta/métodos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
18.
Clin Pharmacol Ther ; 73(5): 427-34, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12732843

RESUMO

BACKGROUND: The cytochrome p450 (CYP) oxidative enzyme system, located primarily in the liver and small intestine, is responsible for metabolism and detoxification of numerous endogenous and exogenous substances. The most abundant CYP enzyme, CYP3A, is known to be involved in the metabolism of more than 200 commonly used medications. In experimental models of renal failure, both hepatic function and CYP enzyme content are reduced; however, direct evidence in humans is lacking. Evaluation of drug metabolism in patients with end-stage renal disease is important because these patients use a large number of medications and are at risk of adverse reactions and drug-drug interactions. METHODS: We measured hepatic CYP3A activity at baseline and after rifampin (INN, rifampicin) enzyme induction in 12 patients with end-stage renal disease and 12 healthy, age-matched controls. Hepatic CYP3A phenotype was characterized with the erythromycin breath test, and enzyme induction capacity was evaluated with a short course of rifampin (600 mg/d for 6 days). RESULTS: The end-stage renal disease group had 28% lower baseline erythromycin breath test values than controls (P <.05); however, enzyme induction capacity after rifampin administration was similar between groups (P =.70). CONCLUSION: The findings suggested that one mechanism by which patients with end-stage renal disease are at increased risk of drug toxicity is reduced activity of the CYP3A enzyme pathway.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Falência Renal Crônica/enzimologia , Fígado/enzimologia , Oxirredutases N-Desmetilantes/metabolismo , Adulto , Idoso , Antibióticos Antituberculose/farmacologia , Hidrocarboneto de Aril Hidroxilases/biossíntese , Testes Respiratórios , Citocromo P-450 CYP3A , Indução Enzimática/efeitos dos fármacos , Eritromicina , Feminino , Humanos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Oxirredutases N-Desmetilantes/biossíntese , Fenótipo , Estudos Prospectivos , Inibidores da Síntese de Proteínas , Rifampina/farmacologia
19.
Pharmacotherapy ; 23(4): 436-42, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12680473

RESUMO

STUDY OBJECTIVE: To evaluate P-glycoprotein (P-gp)-mediated renal drug interactions in an in vitro model of tubular secretion. DESIGN: In vitro experiment. SETTING: University-affiliated pharmacokinetics laboratory. CELL LINES: Madin-Darby canine kidney (MDCK), multidrug-resistant-1 (MDR1)-MDCK, and human colon carcinoma (Caco-2) cells. INTERVENTION: Transepithelial transport (basolateral-to-apical and apical-to-basolateral) of cimetidine was assessed in the absence and presence of various concentrations of the P-gp inhibitors itraconazole and PSC-833 in a renal P-gp cell culture model (MDR1-MDCK). MEASUREMENTS AND MAIN RESULTS: Apparent permeability of cimetidine was characterized, and level of P-gp expression was determined by Western blot analysis, in MDCK (wild type), MDR1-MDCK, and Caco-2 cells (for relative comparison). In the presence of PSC-833, cimetidine's apparent permeability value for basolateral-to-apical transport decreased from 2.96 to 1.15 x 10(-6) cm/second, coupled with a decrease in efflux ratio from 2.36 to 1.80. The effect of itraconazole was concentration dependent, with cimetidine's apparent permeability value for basolateral-to-apical transport decreasing from 3.96 to 1.92 x 10(-6) cm/second (p < 0.05), resulting in a 50% decrease in efflux ratio. Expression of P-gp was negligible in MDCK (wild-type) cells, but high-level expression was confirmed in both MDR1-MDCK and Caco-2 cells. CONCLUSION: P-glycoprotein plays a significant role in the renal tubular secretion of organic cations such as cimetidine, and the high level of P-gp expression in MDR1-MDCK cells makes this a well-suited model for evaluating mechanisms of renal drug interactions.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Rim/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Células CACO-2 , Linhagem Celular , Cimetidina/farmacocinética , Ciclosporinas/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Itraconazol/farmacocinética , Rim/citologia , Rim/efeitos dos fármacos
20.
J Pharm Sci ; 92(2): 414-23, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12532391

RESUMO

The purpose of this study was to examine the ability of Zonula occludens toxin (Zot) to reversibly open tight junctions in bovine brain microvessel endothelial cells (BBMECs) to enhance drug delivery via the paracellular pathway. Transport across BBMEC monolayers was examined for molecular weight markers and chemotherapeutic agents ([(14)C]sucrose, [(14)C]inulin, [(3)H]propranolol, [(3)H]doxorubicin, and [(14)C]paclitaxel) with Zot (0.0-4.0 microg/mL). TEER of monolayers was measured to assess effect and reversibility of Zot. Cell viability of BBMEC in the presence of Zot was assessed by trypan blue exclusion staining. Apparent permeability (P(app)), enhancement ratio (R), and percent increase in transport determined were statistically compared by ANOVA. A significant increase (p < 0.05) in P(app) was observed for the transport of [(14)C]sucrose, [(14)C]inulin, [(3)H]doxorubicin, and [(14)C]paclitaxel at a 4.0 microg/mL concentration of Zot. A significant concentration-dependent decrease in TEER was observed on treatment with Zot with rapid reversal to baseline after removal. Zot (4 micro/ml) was found to be nontoxic to the BBMECs after 2 hours incubation. In conclusion, Zot increased paracellular transport across the BBMEC in a reversible, concentration-dependent manner. Modulation of paracellular transport with Zot may be used to increase the brain permeability of potent central nervous system-active drugs, including anticancer agents.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Toxina da Cólera/farmacologia , Endotélio Vascular/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Animais , Transporte Biológico Ativo , Capilares/efeitos dos fármacos , Capilares/metabolismo , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotoxinas , Corantes Fluorescentes , Técnicas In Vitro , Peso Molecular , Permeabilidade , Rodamina 123/metabolismo , Junções Íntimas/metabolismo
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